Prior evidence of pathogenicity is extremely strong for four missense variants - P102L, A117V, D178N and E200K - each of which has been observed to segregate with disease in multiple multigenerational families (–, –) and to cause spontaneous disease in mouse models (–). These account for >50% of genetic prion disease cases (), yet are absent from ExAC (), and collectively appear on ≤5 alleles in 23andMe’s cohort (), indicating allele frequencies sufficiently low to be consistent with the prevalence of genetic prion disease (). Conversely, the variants most common in controls and rare in cases had categorically weak prior evidence for pathogenicity. R208C (8 alleles in 23andMe) and P39L were observed in patients presenting clinically with other dementias, with prion disease suggested as an alternative diagnosis solely on the basis of finding a novel PRNP variant (, ). E196A was originally reported in a single patient, with a sporadic Creutzfeldt-Jakob disease phenotype and no family history (), and appeared in only 2 of 790 Chinese prion disease patients in a recent case series (), consistent with the ~0.1% allele frequency among Chinese individuals in ExAC (). At least three variants (M232R, V180I, and V210I) occupy a space inconsistent with either neutrality or with complete penetrance (see main text and ). R148H, T188R, V203I, R208H and additional variants are discussed in .