Human genome sequencing efforts have greatly expanded, and a plethora of missense variants identified both in patients and in the general population is now publicly accessible. Interpretation of the molecular-level effect of missense variants, however, remains challenging and requires a particular investigation of amino acid substitutions in the context of protein structure and function. Answers to questions like 'Is a variant perturbing a site involved in key macromolecular interactions and/or cellular signaling?', or 'Is a variant changing an amino acid located at the protein core or part of a cluster of known pathogenic mutations in 3D?' are crucial. Motivated by these needs, we developed MISCAST (missense variant to protein structure analysis web suite; http://miscast.broadinstitute.org/). MISCAST is an interactive and user-friendly web server to visualize and analyze missense variants in protein sequence and structure space. Additionally, a comprehensive set of protein structural and functional features have been aggregated in MISCAST from multiple databases, and displayed on structures alongside the variants to provide users with the biological context of the variant location in an integrated platform. We further made the annotated data and protein structures readily downloadable from MISCAST to foster advanced offline analysis of missense variants by a wide biological community.

Center for Development of Therapeutics Broad Institute of MIT and Harvard Cambridge MA 02142 USA Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard Cambridge MA 02142 USA

Center for Development of Therapeutics Broad Institute of MIT and Harvard Cambridge MA 02142 USA Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard Cambridge MA 02142 USA Analytic and Translational Genetics Unit Massachusetts General Hospital Boston MA 02114 USA

Computer Science and Engineering Bangladesh University of Engineering and Technology ECE Building West Palashi Dhaka 1205 Bangladesh

Department of Bio and Health Informatics Technical University of Denmark Lyngby Denmark

Genomic Medicine Institute Lerner Research Institute Cleveland Clinic Cleveland OH 44195 USA

Luxembourg Centre for Systems Biomedicine University of Luxembourg Esch sur Alzette Luxembourg

Luxembourg Centre for Systems Biomedicine University of Luxembourg Esch sur Alzette Luxembourg Department of Software Engineering Faculty of Mathematics and Physics Charles University Prague Czech Republic

Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard Cambridge MA 02142 USA

Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard Cambridge MA 02142 USA Analytic and Translational Genetics Unit Massachusetts General Hospital Boston MA 02114 USA Institute for Molecular Medicine Finland University of Helsinki 00100 Helsinki Finland

Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard Cambridge MA 02142 USA Genomic Medicine Institute Lerner Research Institute Cleveland Clinic Cleveland OH 44195 USA Cologne Center for Genomics University of Cologne Cologne Germany Epilepsy Center Neurological Institute Cleveland Clinic Cleveland OH 44195 USA

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