PT - JOURNAL ARTICLE AU - Vikas Pejaver AU - Jorge Urresti AU - Jose Lugo-Martinez AU - Kymberleigh A. Pagel AU - Guan Ning Lin AU - Hyun-Jun Nam AU - Matthew Mort AU - David N. Cooper AU - Jonathan Sebat AU - Lilia M. Iakoucheva AU - Sean D. Mooney AU - Predrag Radivojac TI - MutPred2: inferring the molecular and phenotypic impact of amino acid variants AID - 10.1101/134981 DP - 2017 Jan 01 TA - bioRxiv PG - 134981 4099 - http://biorxiv.org/content/early/2017/05/09/134981.short 4100 - http://biorxiv.org/content/early/2017/05/09/134981.full AB - We introduce MutPred2, a tool that improves the prioritization of pathogenic amino acid substitutions, generates molecular mechanisms potentially causative of disease, and returns interpretable pathogenicity score distributions on individual genomes. While its prioritization performance is state-of-the-art, a novel and 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 diseases have the potential to significantly accelerate the discovery of clinically actionable variants.Availability: http://mutpred.mutdb.org/