The above curation efforts confirm the importance of AF filtering in analysis of candidate disease variants6,26,27. However, literature and database errors are prevalent even at lower AFs: the average ExAC individual contains 0.89 (<1% popmax AF) reportedly Mendelian variants in well-characterized dominant disease genes28 and 0.21 at <0.1% popmax AF. This inflation likely results from a combination of false reports of pathogenicity and incomplete penetrance, as we have recently shown for PRNP29. The abundance of rare functional variation in many disease genes in ExAC is a reminder that such variants should not be assumed to be causal or highly penetrant without careful segregation or case-control analysis7,24.
