Significance The protein-coding exome of a patient with a monogenic disease contains about 20,000 variations, of which only one or two are disease causing. When attempting to select disease-causing candidate mutation(s), a challenge is to filter out as many false-positive (FP) variants as possible. In this study, we describe the gene damage index (GDI), a metric for the nonsynonymous mutational load in each protein-coding gene in the general population. We show that the GDI is an efficient gene-level method for filtering out FP variants in genes that are highly damaged in the general population.