The article introduces a scoring system, the Residual Variation Intolerance Score (RVIS), to assess the intolerance of genes to functional genetic variation. This system ranks genes based on the strength and consistency of purifying selection acting against functional variation. The RVIS is derived using sequence data from the NHLBI Exome Sequencing Project (ESP) and is evaluated by its correlation with known Mendelian disease genes. The study finds that genes responsible for Mendelian diseases are significantly more intolerant to functional genetic variation than genes without known disease associations, with notable differences among different disease types. The RVIS is also shown to be useful in prioritizing candidate de novo mutations identified in patient genomes and integrating gene- and variant-level information to improve the interpretation of personal genomes. The authors conclude that the RVIS can aid in identifying pathogenic mutations and facilitating the interpretation of personal genomes.The article introduces a scoring system, the Residual Variation Intolerance Score (RVIS), to assess the intolerance of genes to functional genetic variation. This system ranks genes based on the strength and consistency of purifying selection acting against functional variation. The RVIS is derived using sequence data from the NHLBI Exome Sequencing Project (ESP) and is evaluated by its correlation with known Mendelian disease genes. The study finds that genes responsible for Mendelian diseases are significantly more intolerant to functional genetic variation than genes without known disease associations, with notable differences among different disease types. The RVIS is also shown to be useful in prioritizing candidate de novo mutations identified in patient genomes and integrating gene- and variant-level information to improve the interpretation of personal genomes. The authors conclude that the RVIS can aid in identifying pathogenic mutations and facilitating the interpretation of personal genomes.