Stratifying variant deleteriousness and trait-modulating effect under human recent adaptation using the FIND model

Existing methods to distinguish deleterious/pathogenic from neutral variants still inadequately capture the full spectrum of genetic variant impact on fitness and disease susceptibility. We introduce the FIND model, which stratifies genetic variants into refined categories based on fitness spectrum and derived allele frequency. FIND demonstrates enhanced resolution in differentiating trait-modulating alleles from those that are deleterious or neutral, delivering higher performance over existing genome-wide methods. Applying FIND to the interpretation of clinical variants demonstrates its substantial potential in reclassifying variants of unknown significance, providing a new tool to explore the complexities of genetic contributions to health.