PolyPhen (37) was used to predict the effects of rare nonsynonymous variants on protein function. Among the 20 types of rare missense variants observed in the exon 5 cytoplasmic loop region, PolyPhen predicted 8 to be possibly or probably damaging (Table 3). Comparison subjects had a total of 19 alleles of these variants and cases had 6, a significant difference (FET p=0.005; association test p=0.008, OR=0.29, 95%CI=0.11-0.72; WSM p=0.005), suggesting that functional rare variants in this region had protective effects against ND.
