Inferring the molecular and phenotypic impact of amino acid variants with MutPred2

Vikas Pejaver, Jorge Urresti, Jose Lugo-Martinez, Kymberleigh A. Pagel, Guan Ning Lin, Hyun Jun Nam, Matthew Mort, David N. Cooper, Jonathan Sebat, Lilia M. Iakoucheva, Sean D. Mooney, Predrag Radivojac

Research output: Contribution to journalArticlepeer-review

121 Scopus citations


Identifying pathogenic variants and underlying functional alterations is challenging. To this end, we introduce MutPred2, a tool that improves the prioritization of pathogenic amino acid substitutions over existing methods, generates molecular mechanisms potentially causative of disease, and returns interpretable pathogenicity score distributions on individual genomes. Whilst its prioritization performance is state-of-the-art, a distinguishing feature of MutPred2 is the probabilistic modeling of variant impact on specific aspects of protein structure and function that can serve to guide experimental studies of phenotype-altering variants. We demonstrate the utility of MutPred2 in the identification of the structural and functional mutational signatures relevant to Mendelian disorders and the prioritization of de novo mutations associated with complex neurodevelopmental disorders. We then experimentally validate the functional impact of several variants identified in patients with such disorders. We argue that mechanism-driven studies of human inherited disease have the potential to significantly accelerate the discovery of clinically actionable variants.

Original languageEnglish
Article number5918
JournalNature Communications
Issue number1
StatePublished - Dec 2020
Externally publishedYes


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