Federal Grant Award Summary

The Pennsylvania State University received a $806,828 Project Grant award from the National Human Genome Research Institute (NHGRI) under the Human Genome Research program (CFDA 93.172), effective February 16, 2026, with completion targeted for January 31, 2030. This award supports comprehensive research to predict and experimentally validate the functional effects of point mutations across all human tyrosine kinases, a critical protein family implicated in Mendelian disorders, cancer, and common diseases for which 62 approved therapeutic drugs currently exist. The project employs a hybrid experimental and computational approach to address the significant gap in functional understanding of the thousands of germ-line and somatic variants present across the kinome.

The research deliverables include: (1) mutational scanning data generated across at least 15 diverse tyrosine kinases with ancestral reconstructions and family-wide computational models using Gaussian process regression and transformer-based protein language models; (2) benchmarking and validation of CRISPR Cas9 base editors as tools for variant annotation, with functional characterization of segregating variants and their interactions with xenobiotics; and (3) investigation of higher-order epistatic interactions inferred from kinase superfamily multiple sequence alignments. These outputs will substantially advance the capacity to predict mutation effects across gene families, reducing experimental burden and improving the identification of functionally significant variants relevant to disease and drug resistance.