variant interpretation

Proceedings of the National Academy of Sciences

Significance Recent large-scale sequencing efforts have enabled the detection of millions of missense variants. Elucidating their functional effect is of crucial importance but challenging. We approach this problem by performing a wide-scale characterization of missense variants from 1,330 disease-associated genes using &gt;14,000 protein structures. We identify 3D features associated with pathogenic and benign variants that unveiled the mutations’ effect at the molecular level. We further extend our analysis to account for the different essential structural regions in proteins performing different functions. By analyzing variants from 24 gene groups encoding for different protein functional families, we capture function-specific characteristics of missense variants, which match the experimental readouts. We show that our results derived using structural data will effectively inform variant interpretation.

Comprehensive characterization of amino acid positions in protein structures reveals molecular effect of missense variants