GeVIR is a continuous gene-level metric that uses variant distribution patterns to prioritize disease candidate genes

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 sequences², 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 genes⁵, that outperforms missense constraint metrics³ and that is comparable-but complementary-to loss-of-function (LOF) constraint metrics². GeVIR is also able to prioritize short genes, for which LOF constraint cannot be estimated with confidence². The majority of the most intolerant genes identified here have no defined phenotype and are candidates for severe dominant disorders.