NR2E3 and melanoma: Substantial evidence suggests that this amino acid change alters NR2E1 protein functioning: 1) the high conservation of Arg274 not only in NR2E1 but also in NR2E3 (Arg309) and the association of the NR2E3 variant, Arg309Gly, with eye disease [56]; 2) the low SIFT score indicating the substitution would not be tolerated; and 3) the possible clinical relevance of the Arg274Gln variant found in melanoma tissue [55], which, interestingly, has a SIFT score of only 0.04.