MAVISp: A Modular Structure-Based Framework for Protein Variant Effects

Abstract

The role of genomic variants in disease has expanded significantly with the advent of advanced sequencing techniques. The rapid increase in identified genomic variants has led to many variants being classified as Variants of Uncertain Significance or as having conflicting evidence, posing challenges for their interpretation and characterization. Additionally, current methods for predicting pathogenic variants often lack insights into the underlying molecular mechanisms. Here, we introduce MAVISp (Multi-layered Assessment of VarIants by Structure for proteins), a modular structural framework for variant effects, accompanied by a web server (https://services.healthtech.dtu.dk/services/MAVISp-1.0/) to enhance data accessibility, consultation, and reusability. MAVISp currently provides data over 1000 proteins, encompassing more than eight million variants. A team of biocurators regularly analyzes and updates protein entries using standardized workflows, incorporating free energy calculations or biomolecular simulations. We illustrate the utility of MAVISp through selected case studies. The framework facilitates the analysis of variant effects at the protein level and has the potential to advance the understanding and application of mutational data in disease research.