High-Risk TYR Albinism Haplotypes are Common, Rarely Penetrant, and of European Origin in Latin Americans

Common variants in the tyrosinase gene (TYR) shape albinism risk when combined on one haplotype. Homozygosity for the haplotype formed by c.−301C, c.575A (p.Ser192Tyr) and c.1205A (p.Arg402Gln) carries an odds ratio above 82 for albinism, yet these estimates come from European cohorts and say nothing about penetrance or about other ancestries. Using public data, I reconstructed TYR haplotypes in 2,504 unrelated phased genomes from the 1000 Genomes Project, combined them with quality-filtered rare pathogenic variants in 18 albinism genes from gnomAD v4.1, estimated penetrance with Bayes’ rule from published genotype shares among patients, and traced the ancestral origin of each risk allele with gnomAD local-ancestry frequencies in admixed Americans. Homozygosity for a high-risk haplotype ([C;A;A] or [C;C;A]) occurred in about 1 in 4,700 Europeans, four times more often than albinism of any cause, implying a penetrance of 0.77% (95% CI 0.28–2.4%), whereas a high-risk haplotype in trans with a rare pathogenic TYR variant implied a penetrance of 6.4% (3.9–11.4%). The [C;A;A] haplotype was rare (0.8% of European chromosomes) because c.575A and c.1205A lie mainly on different haplotypes, the latter with the protective c.−301T allele. The high-risk haplotypes were absent from African and East Asian samples and, among Latin Americans, were found only in the most European-admixed populations. In admixed Americans, 98–99% of c.575A and c.1205A copies lay on European ancestry tracts, whereas the promoter risk allele c.−301C was more common on Indigenous American tracts. I also show that the rsID reported by Green et al. (2024) for the OCA2 partner variant, rs74653330, corresponds to a different variant (p.Ala481Thr), and identify the correct one as rs121918166. High-risk TYR albinism haplotypes are therefore common but rarely penetrant, and in Latin Americans their risk scales with European ancestry, so ancestry-aware interpretation is needed when these genotypes are reported in diagnostic testing.