rs1126809
badMag 5.0This is a variant in the TYR gene that changes a arginine to an glutamine.
Key Literature Trait Associations
Oculocutaneous albinism type 1
rs1126809 (p.Arg402Gln) is a hypomorphic TYR allele that, when inherited in trans with a second loss-of-function TYR mutation, causes oculocutaneous albinism type 1B (OCA1B) — a milder form of albinism with residual pigmentation. Compound heterozygous OCA1B patients (R402Q + severe allele) show lighter hair and skin at birth, blue eyes, and visual acuity measurably better than classical OCA1 (mean logMAR 0.38 vs. 0.76). ClinVar records conflicting pathogenicity classifications for this variant, reflecting its context-dependent role: benign as a heterozygous carrier, clinically relevant only when paired with a second TYR null allele.
Melanoma
The TYR R402Q A allele is associated with increased risk of cutaneous melanoma. The Gudbjartsson et al. 2008 study (2,121 melanoma cases, 40,000+ controls) found OR=1.21 (p=2.8×10⁻⁷), with TYR representing one of the most consistently replicated pigmentation loci in melanoma GWAS. The A/A homozygous genotype is enriched in amelanotic and hypomelanotic melanoma subtypes (OR=2.7 vs. pigmented melanoma controls). The risk is mediated through reduced photoprotective melanin production rather than direct DNA repair pathways.
Skin Sun Sensitivity
rs1126809 encodes the Arg402Gln (R402Q) substitution in tyrosinase. The glutamine-402 enzyme is thermolabile and subject to endoplasmic reticulum retention at 37C, retaining only ~25% of wild-type catalytic activity. This partial loss-of-function reduces constitutive skin pigmentation and impairs the tanning response to UV exposure. The A allele is common in Europeans (~28%) but rare in Africans (~5%) and absent in East Asians.
Squamous cell carcinoma
rs1126809-A is associated with increased risk of cutaneous squamous cell carcinoma (cSCC) at genome-wide significance. A large two-stage GWAS (Chahal et al. 2016; 7,404 cases, 292,076 controls) confirmed TYR as one of seven replicated pigmentation loci for cSCC. GWAS Catalog data show OR=1.19 (p=2×10⁻²⁰) and a beta of 0.15 (p=2×10⁻³⁸) in the largest skin neoplasm analyses. The haplotype carrying the Arg402Gln allele was associated with cSCC risk (OR=1.35) in an earlier candidate-gene study of European Americans.
Basal cell carcinoma
The TYR R402Q A allele is associated with increased risk of basal cell carcinoma (BCC) at genome-wide significance. The landmark Gudbjartsson et al. 2008 study (n>44,000) demonstrated OR=1.14 (p=6.1×10⁻⁴) in an Icelandic discovery cohort, and GWAS Catalog data confirm a replicated association at OR=1.12 (p=3×10⁻¹⁹) in larger combined analyses. TYR is one of six pigmentation loci consistently replicated across BCC, melanoma, and cSCC GWAS, with the risk attributable to reduced melanin photoprotection in carriers of the Gln402 allele.
Actinic keratosis
The TYR A allele (R402Q) is associated with increased risk of actinic keratosis (AK), a UV-induced pre-malignant skin lesion, at genome-wide significance (OR=1.14, p=9×10⁻²⁵ in GWAS Catalog data). A large meta-analysis of 92,240 participants (Kim et al. 2022) confirmed TYR as part of a pigmentation pathway cluster for AK susceptibility, alongside SLC45A2, IRF4, BNC2, and other melanin-pathway genes. The biological basis is impaired UV-protective melanin synthesis in A allele carriers, increasing cumulative photodamage to keratinocytes.
▶GWAS Catalog Trait Associations (33)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
GWAS Catalog Trait Associations (33)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
▶ClinVar annotation
Oculocutaneous albinism type 1B; Temperature-sensitive oculocutaneous albinism type 1; Melanoma, cutaneous malignant, susceptibility to, 8; SKIN/HAIR/EYE PIGMENTATION 3, LIGHT/DARK SKIN; Skin/hair/eye pigmentation 3, blue/green eyes; not provided; not specified; Oculocutaneous albinism type 1A; 6 conditions; Autosomal recessive ocular albinism; Malignant tumor of breast; Oculocutaneous albinism type 1; Albinism or congenital nystagmus; Pigmentary skin disorders
View on ClinVar →▶Research that mentions this SNP (4)
▶Variants at chromosome 20 (ASIP locus) and melanoma riskAssociationN=1,033Maccioni L. et al.(2013)· International Journal of Cancer
This study examined associations between sun-sensitive pigmentary gene variants and serum PSA levels in 1033 older Australian men. Variants in SLC45A2 (rs28777: -19.6%, rs16891982: -17.3%) were associated with lower PSA levels in all men. Variants in MC1R (rs1805007) and ASIP (rs4911414) showed significant interactions with birth region, with higher PSA levels in ANZ-born men carrying the variants. Post-hoc analysis found increased testosterone in MC1R rs1805007 carriers and elevated dihydrotestosterone in ASIP rs1015362 carriers.
▶The R402Q tyrosinase variant does not cause autosomal recessive ocular albinismReviewOetting WS et al.(2009)· American Journal of Medical Genetics Part A
Genome-wide association studies and comparative genomics have identified major pigmentation loci (SLC24A5, SLC45A2, TYR, OCA2, MC1R, IRF4, TPCN2) showing evidence of strong natural selection in human populations. Light skin variants in Europeans and Asians underwent complete or near-complete selective sweeps, with SLC24A5 rs1426654 and SLC45A2 variants representing independent evolutionary mechanisms. Critical skin-lightening variants arose 11,000-30,000 years ago during human demographic expansion, driven by UV radiation exposure, vitamin D synthesis requirements, and possibly sexual selection.
▶Genetic variants in pigmentation genes, pigmentary phenotypes, and risk of skin cancer in CaucasiansAssociationN=1,673Hongmei Nan et al.(2009)· International Journal of Cancer
Nested case-control study of 1,673 Caucasian women examining 15 SNPs in pigmentation genes. TYR Arg402Gln (rs1126809) and SLC45A2 Phe374Leu (rs16891982) were significantly associated with skin color and tanning ability. ASIP haplotype (rs4911414[T], rs1015362[G]) increased melanoma risk (OR 1.68) and SCC risk (OR 1.54), while TYRP1 rs1408799 and SLC45A2 -1721 C>G (rs13289) showed protective effects against melanoma (OR 0.77, 0.75 respectively). No associations remained significant after Bonferroni correction.
▶SLC45A2: a novel malignant melanoma-associated geneAssociationN=376Fernandez LP et al.(2008)· Human Mutation
A Spanish case-control study (131 melanoma patients, 245 controls) investigated 23 SNPs in six pigmentation genes (ASP, OCA2, TYR, TYRP1, SILV, SLC45A2) for melanoma susceptibility. The variant allele of SLC45A2 c.1122C>G (p.Phe374Leu, rs16891982) was associated with protection from melanoma (OR 0.41, 95% CI 0.24-0.70, adjusted P=0.008), validated by associations with dark hair, skin, and eye color.
Gene information from NCBI Gene. Variant classifications from ClinVar.
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