Previous large-scale sequencing studies have repeatedly shown that some purported Mendelian disease-causing genetic variants are implausibly common in the population21–23 (Figure 4c). The average ExAC participant harbors ~54 variants reported as disease-causing in two widely-used databases of disease-causing variants (Supplementary Information Section 5.2). Most (~41) of these are high-quality genotypes but with implausibly high (>1%) popmax AF. We therefore hypothesized that most of the supposed burden of Mendelian disease alleles per person is due not to genotyping error, but rather to misclassification in the literature and/or in databases.
