UCLA

Deciphering the functional and therapeutic relevance of missense variants—mutations that change a single amino acid to an alternative residue—is a central challenge in modern genetics. In this work, we address this gap using an innovative approach that integrates genetic variants, in silico predictions of pathogenicity, and proteomic measures of amino acid functionality. First, we found that chemoproteomic methods that use a mass spectrometry-based approach to quantify amino acid sidechain reactivity proteome-wide can identify amino acid positions enriched for disease-associated missense variants. Second, by globally characterizing the positional and contextual relationships between reactive residues and genetic variation, we prioritized several likely functional amino acids proximal to rare variants of uncertain significance in monogenic disorder genes. While many advanced methods exist to discern the pathogenicity of genetic variants, this work uniquely focuses on both the pathogenicity and reactivity of variants in human proteins, given the druggable nature of nucleophilic (or reactive) amino acids. In summary, this work has important implications in variant prioritization and in therapeutics development, where it can support drug discovery efforts through prioritization of attractive residues for small molecule drug targeting.