RFA-HG-27-007-Full-Announcement.html

Department of Health and Human Services

Part 1. Overview Information

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Human Genome Research Institute (NHGRI)

Note: Not all NIH Institutes, Centers, and Offices (ICOs) participate in Announcements. Applicants should carefully note which ICOs participate in this announcement and view their respective areas of research interest at the ICO-Specific Scientific Interests website. ICOs that do not participate in this announcement will not consider applications for funding.

Funding Opportunity Title

Systematic Characterization of Genomic Variation to Assess Effects of Individual Variants on Genome Function and Phenotype (UM1 Clinical Trials Not Allowed)

Activity Code

UM1 Research Project with Complex Structure Cooperative Agreement

Announcement Type

New

Related Notices

Check for any recent Notices of NIH Policy Changes that may impact application requirements.

Funding Opportunity Number (FON)

RFA-HG-27-007

Companion Funding Opportunity

RFA-HG-27-008

, U24 Resource-Related Research Project (Cooperative Agreements)

RFA-HG-27-009

, UM1

Research Project with Complex Structure Cooperative Agreement

RFA-HG-27-010

, UM1

Research Project with Complex Structure Cooperative Agreement

Number of Applications

See Part 2, Section III. 3. Additional Information on Eligibility.

Assistance Listing Number(s)

93.172

Funding Opportunity Purpose

The purpose of this Notice of Funding Opportunity (NOFO) is to solicit applications to characterize genomic variation to assess the impact of individual variants on genome function. This will be accomplished by systematically perturbing variants or elements using one or more high-throughput methods; collecting data on the effects of variants in DNA, RNA, or protein-coding elements on molecular, cellular, or organismal phenotypes; and developing robust, reproducible, and portable data processing pipelines. Centers funded through this initiative will become a part of the Impact of Genomic Variation on Function (IGVF) Consortium. As consortium members, centers will work together to ensure all consortium resources are accessible to a wide variety of potential users. Centers are also expected to collaborate with other consortium components to coordinate assays, variants, and cell types, and to develop shared analysis strategies to meet consortium goals.

Funding Opportunity Goal(s)

As a leading authority in the field of genomics, the mission of the National Human Genome Research Institute (NHGRI) is to accelerate scientific and medical breakthroughs that improve human health by driving cutting-edge research, developing new technologies, and studying the impact of genomics on society. Congress initially established NHGRI to characterize the structure and function of the human genome, including the mapping and sequencing of individual genes. This also includes reviewing and funding research proposals, developing training programs, coordinating international genome research, communicating advances in genome science to the public, and reviewing and funding proposals to address the ethical and legal issues associated with this research. NHGRI supports the development of methods, resources and technologies to improve the health of all humans through advances in genomics research. NHGRI supports research that accelerates foundational resources, technology development, and experimental and computational approaches for basic genomics and functional genomics research; for the application of genomics to medical science and clinical care; and to support ethical, legal and social implications (ELSI) research concerning societal issues that need to be addressed, especially as genomic science advances. For years, NHGRI has participated in the NIH effort to turn discovery into health by helping small businesses develop innovative genomics technologies that improve health and save lives. NHGRI also develops and supports initiatives that expand opportunities for genomics education and careers, cultivating genomics training programs and workforce development initiatives.

Key Dates

Posted Date

October 09, 2026

Open Date (Earliest Submission Date)

November 14, 2026

December 14, 2026

Not Applicable

Not Applicable

September 2027

All applications are due by 5:00 PM local time of applicant organization.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

No late applications will be accepted for this Notice of Funding Opportunity (NOFO).

Expiration Date

December 15, 2026

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the How to Apply - Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the How to Apply - Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the How to Apply - Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

Table of Contents

Part 1. Overview Information Key Dates Part 2. Full Text of Announcement Section I. Notice of Funding Opportunity Description Section II. Award Information Section III. Eligibility Information Section IV. Application and Submission Information Section V. Application Review Information Section VI. Award Administration Information Section VII. Agency Contacts Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Background A major challenge in genomics is defining the role of genomic variation in influencing phenotypes in human biology and diseases. As outlined in NHGRI's 2020 Strategic Vision, studies characterizing the functional consequences of variants have not kept pace with studies of variant discovery or association, and this lack of functional genomic information remains a barrier that impedes progress in genomics.

The Impact of Genomic Variation on Function Consortium (IGVF) was established in 2021 to address the challenge of understanding how genomic variation affects genome function to influence phenotypes using a coordinated team-science approach. The program utilizes emerging experimental and computational genomic approaches to build a catalog of the impact of genomic variants on genome function and phenotypes and to share data and other resources with the scientific community.

Program Goals and Notices of Funding Opportunity (NOFOs) NHGRI is issuing an open call for applications to participate in a second phase of IGVF, based on recent community recommendations on functional variant interpretation and input from the National Advisory Council for Human Genome Research. The goals of the second phase of IGVF are to:

To achieve these goals the following NOFOs are issued:

NHGRI encourages all investigators with ideas aligned with the goals of this NOFO to submit applications.

Research Scope and Objectives There is a continued need for systematic efforts to characterize the impact of individual variants on genome function and phenotype. In the first phase of IGVF, multidisciplinary teams worked together as functional characterization centers to start variant assessments across variant types, non-coding and protein-coding regions, cell types, tissues, and diseases. They planned to characterize more than two million genomic perturbations (i.e., variants, elements, and genes) across biological systems including hematopoietic and immune, cardiometabolic, and neuronal utilizing a variety of assays. Most importantly, they worked together to develop a collaborative framework for generating and analyzing data, and the building of a community resource.

It is currently not possible to experimentally test every variant. However, it is imperative to explore the extent to which we can effectively characterize variants and learn about their impact on function. In this second phase, NHGRI seeks to support centers to continue studies focused on perturbing variants and elements to test and characterize the roles of individual variants on genome function. In this phase, centers will work towards increasing testing throughput and will maximize the variant space covered to enable others to utilize these data and analyses.

The objectives of these centers are to:

The scope of this NOFO also includes the following:

Select genomic variants and/or elements for systematic testing in these studies. Characterization centers will testnon-coding (DNA, RNA) variants, protein-coding variants and/or elements, using individual and/or multiplexed assays, in one or more cell types and states that are of high value to the research community. These centers are encouraged to foucs on variants or elements associated with disease, or those likely to provide new insights into variat function. Examples of variants that could be tested include, but are not limited to, human variants associated with common disease (e.g., Genome-Wide Association Studies (GWAS)), rare disease (e.g., Mendelian), clinically annotated variants (e.g., Clinical Genome Resource (ClinGen)), uncharacterized variants (e.g., from resources such as the ClinVar database, and the Genome Aggregation Database (gnomAD)), or variants not yet observed in humans. Systematic focus on variants associated with disease areas are encouraged and the likelihood to provide new insights into variant function should be well justified. Examples of elements include those that harbor candidate disease association variants or candidate regulatory elements for disease-associated genes. Applicants should propose study of one or more cell types and states that are of high value to the research community.

Characterization centers must balance systematic sampling of variants and/or elements with the testing capacity of the proposed assays. A continued goal of IGVF is to maximize the utility of the generated data and analyses by balancing the breadth and depth of biology that are sampled by IGVF to cover as many areas as possible. To meet this goal, Characterization centers should be flexible enough to accommodate work on cell types and variants that may differ from what was specifically proposed in their application.

Apply genomic perturbation methods and assay the impact on biologically relevant phenotypes. Characterization centers must balance will apply up to three existing, state-of-the-art high-throughput genomic perturbation methods. Examples include, but are not limited to, massively parallel reporter assays, genome editing, epigenome editing and high-throughput protein mutagenesis. Characterization centers will use biological systems relevant to human health and disease that include, but are not limited to, primary cells, organoids, intact animals, cell lines, and cell-free assays. Applicants may propose to detect phenotypic changes at one or more scales, such as molecular (e.g., RNA abundance or kinase activity), cellular (e.g., morphology), multi-cellular (phenotypes that require interaction of more than one cell type, which need not be cell autonomous phenotypes), or organismal phenotypes (e.g., behavior or development).

Develop robust, reproducible, and portable data processing pipelines. Characterization centers will develop or adopt data processing pipelines consistent with their proposed assays. These may include standardized pipelines currently in use by IGVF. If pipeline development is proposed, the proposed pipeline should be at a state of development at the start of year 1 where the primary focus is to complete development and move towards production (hardening). Each center is expected to specify data processing pipelines appropriate for their assays that are containerized, robust, reproducible, and portable. The IGVF Data and Coordinating Center (DACC) will work with the consortium to harden pipelines. Pipeline development and hardening are expected to be completed by the end of year 1. In some cases, a center may be responsible for running these pipelines themselves, or they may work with the DACC on data processing. The consortium will make decisions about data processing pipelines and implementation responsibilities early during the first year of phase 2.

Contribute to expansion of the IGVF catalog for the community. A primary goal of the IGVF Consortium is to collaboratively produce a set of resources centered on a searchable catalog of measured and predicted variant impacts. For all variants and elements tested by the consortium, the catalog will enable the search for information about variants and elements such as perturbations, phenotypic assays, biological systems, assay results, interpretations, and predictions. The DACC will lead on the development of the catalog in collaboration with other IGVF components. Characterization centers will be expected to provide feedback to the DACC about representations of their data and analyses and specify use cases that should be supported by the catalog.

Generate multi-omic reference maps of gene and regulatory element activity at single-cell resolution (optional). In phase 1 of IGVF, shared reference maps of single cell and gene regulatory element activity were collected across all characterization samples to enable integrative analyses and further insight into measured and predicted variant and gene function. Characterization centers may use propose a portion of their resources for limited generation of multiome profiling data (not to exceed 10% of budget) for samples proposed for study in their centers that were not previously mapped in IGVF phase 1 or in other studies. Mapped assays should include collection of single cell transcription and chromatin accessibility data (single cell RNA sequencing (scRNA-seq) and single cell Assay for Transposase-Accessible Chromatin sequencing (scATAC-seq)). Paired multiome methods that enable assaying of transcription and accessibility in the same cell are highly encouraged. Data should be collected at high depth to be consistent with data collection in phase 1 (>5,000 cells per cell state, >5,000 ATAC unique molecular identifiers per cell).

Improve generalizable approaches for high-throughput functional characterization assays (optional). Characterization centers will collect data collection based on genomic methods that are robust and ready to be utilized at the time of funding. However, Characterization centers may propose to use a small portion of their resources (not to exceed 10% of budget) to develop or refine experimental and computational approaches for functional characterization. Such improvements should directly aid experimental data generation. Technology development under this NOFO is limited to approaches for functional characterization that are high-throughput, generalizable across experimental systems and diseases, with the potential to be implemented during the current project period.

Consortium Formation and Coordination This NOFO uses the cooperative agreement award instrument. Characterization centers will become members of the IGVF Consortium. Consortium members are expected to work collaboratively with NHGRI and the larger consortium towards meeting consortium goals, in addition to the specific research goals outlined in their individual applications.

Recipient responsibilities will include:

Consortium members are expected to coordinate assays, variants, and cell types and to develop shared analysis strategies and uniform computational workflows, when applicable, to meet consortium goals, rather than function as independent projects with independent goals. When appropriate, selection of variants and cell types in this second program phase should be done in consideration of variants and cell types characterized in the first phase of IGVF. IGVF research is limited to mammalian systems, with a preference for human studies including samples derived from individuals across a breadth of genetic ancestries and the consideration of sex as a biological variable. Variants selected for testing should account for allele frequencies and disease associations within and across human populations. Proposed cell types and states should be derived from tissues important in development, differentiation, or human diseases.

A central goal of IGVF is the development of data, tools, and other resources that can be used by researchers not funded by this program. Consortium members will be expected to generate pipelines, tools, and educational materials that facilitate community uptake of IGVF data and methods, and to work together to ensure all consortium resources are accessible to a wide variety of potential users. Data, predictions, and models should be shared early and organized in ways that enable a variety of uses by the broader scientific community, from searches of individual variant impacts to large scale integrative or machine learning approaches.

Consortium members will also be expected to continue to collaborate with other projects and consortia with interests in variant interpretation and coordination across resources, especially in efforts to develop shared data processing and analysis pipelines to enable data sharing and comparisons. This includes work with the Atlas of Variant Effects (AVE) Alliance, The Molecular Phenotypes of Null Alleles in Cells (MorPhiC), the Clinical Genome (ClinGen) Resource, the Genomics Research to Elucidate the Genetics of Rare Diseases: Innovation (GREGoRi), the Human Pangenome Reference Consortium (HPRC), and other NHGRI-led consortia, as relevant.

Consents and Data Sharing in IGVF A key deliverable of IGVF is the development of two public data resources, the IGVF Catalog and Data Portal. To facilitate user access to these resources, NHGRI expects that centers will prioritize the use of samples derived from research participants that have been consented for the broadest possible sharing of genomic data, such as consent for unrestricted access, or for general research use and broad sharing through controlled access. Consent language should also avoid restrictions on the types of users who may access these data for genomics research.

To Learn More An informational webinar will be held where NIH staff will present overviews of IGVF NOFOs and answer NOFO-related questions from prospective applicants. Time, date, and webinar links will made available through a Notice in the NIH Guide. The webinar is open to all prospective applicants, but participation is not required to apply.

Prospective applicants are strongly encouraged to contact the email address listed as the Scientific/Research Contact(s) below to discuss the responsiveness and alignment of their proposed work with program goals.

Applications Not Responsive to this NOFO The following types of applications are not responsive to this NOFO and will not be reviewed:

See Section VIII. Other Information for award authorities and regulations.

Section II. Award Information

Funding Instrument

Cooperative Agreement: A financial assistance mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this NOFO.

Application Types Allowed

New

The OER Glossary and the How to Apply - Application Guide provide details on these application types. Only those application types listed here are allowed for this NOFO.

Clinical Trial?

Not Allowed: Only accepting applications that do not propose clinical trials. Note: Applications may propose activities involving human subjects that are not deemed clinical trials.

Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards

NHGRI intends to commit $15M total costs per year in FY2027-FY2031 to fund up to 5 awards.

Award Budget

Application budgets must reflect the actual needs of the proposed project. Application budgets are limited to $2M direct costs per year.

Award Project Period

The maximum project period is 5 years.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO.

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Nonprofits Other Than Institutions of Higher Education

For-Profit Organizations

Local Governments

Federal Governments

Eligible Agencies of the Federal Government

U.S. Territory or Possession

Other

Independent School Districts

Public Housing Authorities/Indian Housing Authorities

Native American Tribal Organizations (other than Federally recognized tribal governments)

Faith-based or Community-based Organizations

Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Organizations)

Foreign Organizations/Foreign Collaborations

Non-domestic (non-U.S.) Entities (Foreign Organizations) are eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

NIH will no longer issue awards (i.e., new, renewal, or non-competing continuation) to domestic or foreign entities that involve foreign subawards/subcontracts. All NIH-funded research involving foreign subawards/subcontracts must be submitted in response to a NOFO that is specifically designated for funded international collaborations. See NIH Grants Policy Statement 16.8 Collaborative International Research Awards.

Applications involving foreign subawards/subcontracts submitted in response to this NOFO will be deemed noncompliant and will not be considered for funding. This policy applies to all monetary international collaborations resulting in foreign subawards/subcontracts, however, it does not preclude unfunded international collaborations or foreign components, funding for foreign consultants, or procurement of unique equipment or supplies from foreign vendors.

Required Registrations

Applicant Organizations Applicant organizations must complete and maintain the following registrations as described in the How to Apply - Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code. Foreign organizations must obtain a NATO Commercial and Government Entity (NCAGE) Code (in lieu of a CAGE code) in order to register in SAM. Unique Entity Identifier (UEI)- A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.

Program Directors/Principal Investigators (PD(s)/PI(s)) All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. Obtaining an eRA Commons account can take up to 2 weeks.

All PD(s)/PI(s) must be registered with ORCID. The personal profile associated with the PD(s)/PI(s) eRA Commons account must be linked to a valid ORCID ID. For more information on linking an ORCID ID to an eRA Commons personal profile see the ORCID topic in our eRA Commons online help.

Eligible Individuals (Program Director/Principal Investigator)

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the How to Apply - Application Guide.

2. Cost Sharing This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement NIH Grants Policy Statement Section 1.2 Definition of Terms.

3. Additional Information on Eligibility Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. This means that the NIH will not accept:

Section IV. Application and Submission Information

1. Requesting an Application Package The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise (in this NOFO, in a policy notice, or other notice from NIH Guide for Grants and Contracts). Conformance to the requirements in the How to Apply - Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Page Limitations All page limitations described in the How to Apply – Application Guide and the Table of Page Limits must be followed.

For this specific NOFO, the Research Strategy is limited to 30 pages (exclusive of the Specific Aims page).

Instructions for Application Submission

The following section supplements the instructions found in the How to Apply – Application Guide and should be used for preparing an application to this NOFO.

SF424(R&R) Cover All instructions in the How to Apply - Application Guide must be followed.

SF424(R&R) Project/Performance Site Locations

SF424(R&R) Other Project Information

SF424(R&R) Senior/Key Person Profile

The PD(s)/PI(s) must designate a dedicated Project Manager to direct the day-to-day operations of the Coordinating Center. A PD/PI may serve as the Project Manager.

R&R Budget

R&R Subaward Budget

PHS 398 Cover Page Supplement

PHS 398 Research Plan All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

Specific Aims: Describe the specific goals of the Individual Variant Characterization Center and its role in achieving the overall objectives of the IGVF Consortium.

Research Strategy: In the Research Strategy, applicants should propose plans, approaches, and potential alternative strategies for carrying out the goals of the Individual Variant Characterization Center. The Research Strategy should consist of the following sections uploaded as a single PDF attachment:

Details about what should be discussed in each section are described below.

Center Overview

Approach–Genomic Variant/Element Selection and Experimental Assays

Approach–Data Processing and Data Management

Approach–Reference Mapping and/or Assay Improvements (Optional)

Center Management

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply - Application Guide.

The following instructions also apply:

The Resource Sharing Plan should summarize whether and how resources (e.g., educational materials; methods; models; physical products, materials, and reagents; protocols; research findings and products; and software) will be made available. Applicants should include a description of the format, an indication of who will be responsible for implementation and plans for long-term maintenance, whether there will be opportunities for community input and feedback, platform(s) or mechanism(s) that will be used to make resources publicly accessible, and proposed timeline for implementing the Resource Sharing Plan. Resource Sharing Plans should not duplicate other sections of the main Research Plan but should refer to them when appropriate. After initial review, NHGRI program staff may negotiate revisions of this plan with the prospective awardee. The final negotiated version of this plan will become a term and condition of the award.

In addition to the above expectations, NHGRI expects that plans for sharing software generated under this funding opportunity will meet the following expectations:

For more guidance on writing a Resource Sharing Plan, see https://www.genome.gov/about-nhgri/Policies-Guidance/Writing-a-Resource-Sharing-Plan.

Other Plan(s):

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply - Application Guide.

No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply - Application Guide, with the following additional instructions:

If you answered "Yes" to the question "Are Human Subjects Involved?" on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).