LAUSR

With large-scale population sequencing projects gathering pace, there is a need for strategies that advance disease gene prioritization 1 , 2 . Metrics that provide information about a gene and its ability to tolerate protein-altering variation can aid in clinical interpretation of human genomes and can advance disease gene discovery 1 – 4 . Previous reported methods analyzed the total variant load in a gene 1 – 4 , but did not analyze the distribution pattern of variants within a gene. Using data from 138,632 exome and genome sequences 2 , we developed gene variation intolerance rank (GeVIR), a continuous gene-level metric for 19,361 genes that is able to prioritize both dominant and recessive Mendelian disease genes 5 , that outperforms missense constraint metrics 3 and that is comparable—but complementary—to loss-of-function (LOF) constraint metrics 2 . GeVIR is also able to prioritize short genes, for which LOF constraint cannot be estimated with confidence 2 . The majority of the most intolerant genes identified here have no defined phenotype and are candidates for severe dominant disorders. GeVIR is a continuous gene-level metric that uses variant distribution patterns to prioritize both dominant and recessive Mendelian disease genes. GeVIR outperforms missense constraint metrics and complements loss-of-function constraint metrics.