rs1042602 — TYR S192Y

Tyrosinase S192Y — Your Melanin Production Blueprint

Tyrosinase is the rate-limiting enzyme in melanin biosynthesis¹¹ melanin biosynthesis
the production of melanin, the pigment that gives skin, hair, and eyes their color, functioning as a copper-containing oxidase that converts the amino acid tyrosine into dopaquinone²² dopaquinone
the first intermediate in melanin production, which then undergoes a series of reactions to form melanin. The S192Y variant (serine to tyrosine at position 192) is one of the most common polymorphisms in the TYR gene, particularly prevalent in European populations where approximately 35% carry at least one copy, while the variant is virtually absent in East Asian and African populations³³ virtually absent in East Asian and African populations
fixed at the ancestral C allele in Asian and Nigerian Yoruba populations.

The Mechanism

The S192Y substitution occurs at a critical position in the tyrosinase enzyme. While the variant enzyme retains catalytic activity, biochemical studies in primary melanocytes⁴⁴ biochemical studies in primary melanocytes
functional analysis comparing melanocytes with different TYR genotypes demonstrate that the 192Y form exhibits reduced tyrosine hydroxylase and DOPA oxidase activities compared to the ancestral 192S form. This missense change affects post-translational regulation of the enzyme rather than transcription levels, meaning cells produce similar amounts of tyrosinase protein, but the Y192 variant functions less efficiently at converting tyrosine to dopaquinone, the committed step in melanin synthesis.

The variant appears to have undergone positive natural selection in European populations⁵⁵ positive natural selection in European populations
evidence of recent positive selection with the derived A allele, possibly as populations migrated to higher latitudes with lower UV exposure, where lighter pigmentation reduced vitamin D deficiency risk while maintaining adequate photoprotection.

The Evidence

Large-scale population studies⁶⁶ Large-scale population studies
GWAS in 2,986 Icelanders with replication in 2,718 Icelanders and 1,214 Dutch individuals established that rs1042602 is strongly associated with freckling (OR=1.32, p=1.5×10⁻¹¹), with the A allele (192Y) associated with absence of freckles. Interestingly, no association was found with overall skin or eye color, suggesting this variant specifically affects the melanocytic response to UV exposure rather than constitutive pigmentation. In South Asian populations⁷⁷ South Asian populations
GWAS of 737 South Asian individuals in the UK, the same variant showed strong association with darker skin pigmentation (OR=4.36 for the C allele, p=4.48×10⁻¹⁰).

The most clinically significant finding emerged from melanoma risk studies⁸⁸ melanoma risk studies
analysis of 1,025 melanoma patients and 773 healthy controls in Spain: the A allele (192Y) was significantly associated with increased melanoma susceptibility (p=0.0035) and, strikingly, with poorer disease-free survival, particularly in men. Carriers of the A allele⁹⁹ Carriers of the A allele
patients with at least one A allele showed shorter disease-free survival periods, and in multivariate analysis adjusted for age, Breslow thickness, ulceration, and melanoma subtype, the association remained significant (HR=0.4, 95% CI 0.20-0.83, p=0.0139 for men).

Practical Implications

If you carry one or two copies of the A allele (192Y variant), your melanocytes produce less melanin in response to UV exposure, which translates to reduced tanning ability and altered freckling patterns. More importantly, this variant appears to increase melanoma risk beyond its effect on pigmentation alone—suggesting the variant may influence melanocyte biology in ways that affect both UV response and malignant transformation potential.

Functional studies¹⁰¹⁰ Functional studies
compound heterozygosity analysis in OCA1B patients have shown that when S192Y occurs in cis (on the same chromosome) with another TYR variant (R402Q), the compound haplotype can cause a mild but penetrant form of oculocutaneous albinism in homozygotes. However, the S192Y variant alone, even in homozygous form, produces only subtle pigmentation differences rather than clinical albinism.

Interactions

TYR S192Y interacts significantly with rs1126809 (R402Q), another common TYR variant. The two SNPs show high linkage disequilibrium (r²=0.86), and when inherited together in cis as the S192Y/R402Q haplotype, they produce a temperature-sensitive reduction in tyrosinase activity that can lead to mild albinism phenotypes when homozygous or compound heterozygous with a pathogenic TYR variant. This highlights the importance of considering both variants together when assessing pigmentation-related phenotypes.

The variant also shows epistatic interactions with other pigmentation genes including SLC45A2 (rs16891982, L374F) and SLC24A5 (rs1426654, A111T), as these genes encode proteins involved in melanosome pH regulation and trafficking, which affect the cellular environment where tyrosinase functions. Geographic correlation studies¹¹¹¹ Geographic correlation studies
analysis across Chinese populations demonstrate that rs1042602 allele frequencies correlate with latitude, sunshine hours, and temperature, confirming environmental selective pressure on this locus.