SPRI: Structure-Based Pathogenicity Relationship Identifier for Predicting Effects of Single Missense Variants and Discovery of Higher-Order Cancer Susceptibility Clusters of Mutations

Abstract

AbstractWe report the Structure-based Pathogenicity Relationship Identifier (SPRI), a novel computational tool for accurate evaluation of pathological effects of missense single mutations and prediction of higher-order spatially organized units of mutation clusters. SPRI can effectively extract properties determining pathogenicity encoded in protein structures, and can identify deleterious missense mutations of germ line origin associated with Mendelian diseases, as well as mutations of somatic origin associated with cancer drivers. It compares favorably to other methods in predicting deleterious mutations. Furthermore, SPRI can discover spatially organized pathogenic higher-order spatial (patHOS) units of dele-terious mutations, including those of low recurrence, and can be used for discovery of candidate cancer driver genes and cancer driving mutations. We further demonstrate that SPRI can take advantage of AlphaFold2 predicted structures and can be deployed for saturation mutation analysis of the whole protein universe.