We manually curated the evidence of pathogenicity for 192 previously reported pathogenic variants with AF >1% either globally or in South Asian or Latino individuals, populations that are underrepresented in previous reference databases. Nine variants had sufficient data to support disease association, typically with either mild or incompletely penetrant disease effects; the remainder either had insufficient evidence for pathogenicity, no claim of pathogenicity, or were benign traits (Supplementary Information Section 5.3). It is difficult to prove the absence of any disease association, and incomplete penetrance or genetic modifiers may contribute in some cases. Nonetheless, the high cumulative AF of these variants combined with their limited original evidence for pathogenicity suggest little contribution to disease, and 163 variants met American College of Medical Genetics criteria24 for reclassification as benign or likely benign (Figure 4d). 126 of these 163 have been reclassified in source databases as of December 2015 (Supplementary Information Table 20). Supporting functional data were reported for 18 of these variants, highlighting the need to review cautiously even variants with experimental support.
