Ensemble and consensus approaches to prediction of recessive inheritance for missense variants in human disease.

Mode of inheritance (MOI) is necessary for clinical interpretation of pathogenic variants; however, the majority of variants lack this information. Furthermore, variant effect predictors are fundamentally insensitive to recessive-acting diseases. Here, we present MOI-Pred, a variant pathogenicity prediction tool that accounts for MOI, and ConMOI, a consensus method that integrates variant MOI predictions from three independent tools. MOI-Pred integrates evolutionary and functional annotations to produce variant-level predictions that are sensitive to both dominant-acting and recessive-acting pathogenic variants. Both MOI-Pred and ConMOI show state-of-the-art performance on standard benchmarks. Importantly, dominant and recessive predictions from both tools are enriched in individuals with pathogenic variants for dominant- and recessive-acting diseases, respectively, in a real-world electronic health record (EHR)-based validation approach of 29,981 individuals. ConMOI outperforms its component methods in benchmarking and validation, demonstrating the value of consensus among multiple prediction methods. Predictions for all possible missense variants are provided in the "Data and code availability" section.