Human Proteome-wide Mechanistic Interpretation of Missense Variants through Protein Feature Enrichment Score (opens in new tab)

Missense variant interpretation remains a central challenge in clinical and medical genetics, with most observed variants being variants of uncertain significance (VUS). Computational variant effect predictors can achieve high pathogenicity classification performance, but without revealing the underlying mechanism and a translatable interpretation. Here we present the Protein Feature Enrichment Score (PFES), which quantifies the molecular context of missense variants through statistical enric...