We previously introduced the Residual Variation Intolerance Score (RVIS), a framework to rank protein-coding genes based on their intolerance to functional variation. The basic idea is similar to measures of phylogenetic conservation that rank genes by the degree to which they are conserved across species, except using standing human genetic variation to identify genes in which genetic variation is strongly selected against in humans. This approach proved successful in prioritizing genes most likely to result in Mendelian disease. More recently, we have expanded the intolerance framework to both sub-region (within gene) and noncoding intolerance applications. These novel approaches and their applications to patient populations will be presented.