rs1805009
badMag 5.5This is a variant in the MC1R gene that changes a aspartate to an histidine.
Key Literature Trait Associations
Cutaneous melanoma
The D294H variant is classified as a high-risk 'red hair color' (RHC) MC1R allele that confers significantly elevated cutaneous melanoma risk. A 2008 meta-analysis (11 studies) found RHC variants including D294H associated with melanoma (OR up to 2.45), while a 2011 meta-analysis of 20 studies across 25 populations confirmed RHC variants show a summary OR of 2.44 (95% CI 1.72–3.45) for melanoma. The risk likely reflects both reduced photoprotection from eumelanin and UV-independent mechanisms. D294H is also listed as a 'risk factor' for cutaneous melanoma in ClinVar, and carriers show compounded risk when CDKN2A mutations are present.
Red Hair Color
The C allele of rs1805009 encodes the Asp294His (D294H) substitution in the MC1R protein, one of three canonical high-penetrance 'R' alleles strongly associated with red hair. D294H disrupts normal receptor signalling, markedly reducing cAMP-mediated eumelanin induction in melanocytes. Individuals homozygous or compound-heterozygous for D294H and other MC1R R alleles almost invariably present with red hair and fair skin. The variant has its highest prevalence in the British Isles.
Non-melanoma skin cancer
D294H is among the MC1R variants demonstrating consistent significant association with non-melanoma skin cancers (NMSC), including basal cell carcinoma and squamous cell carcinoma. A 2015 pooled analysis from the M-SKIP project (3,527 NMSC cases, 9,391 controls across multiple countries) found D294H among the variants with significant summary ORs ranging from 1.42 to 2.66 across all investigated MC1R alleles, with D294H showing consistent significant results. The mechanism parallels melanoma susceptibility: reduced eumelanin synthesis leads to impaired UV-induced DNA damage repair.
Skin pigmentation
The D294H variant is associated with lighter, less UV-tanning-capable skin via reduced MC1R-mediated eumelanin production. GWAS data from the GWAS Catalog shows rs1805009-C associated with decreased skin pigmentation at p=6×10⁻¹² (beta=6.52, SE=0.94) and reduced skin sensitivity to sun (tanning ability) at p=3×10⁻¹⁰ (beta=0.39). These effects reflect the functional consequence of D294H: impaired MC1R signaling leading to a phaeomelanin-dominant pigmentation phenotype with reduced photoprotection.
▶GWAS Catalog Trait Associations (6)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
GWAS Catalog Trait Associations (6)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
▶ClinVar annotation
Skin/hair/eye pigmentation 2, red hair/fair skin; not provided; Tyrosinase-positive oculocutaneous albinism; Skin and Hair Hypopigmentation; Melanoma, cutaneous malignant, susceptibility to, 5; Melanoma; MC1R-related disorder
View on ClinVar →▶Research that mentions this SNP (4)
▶Technical note: Quantitative measures of iris color using high resolution photographsAssociationN=402Melissa Edwards et al.(2012)· American Journal of Physical Anthropology
This genome-wide association study (GWAS) of pigmentary traits in East Asian populations (N=305 skin, N=342 iris) identifies a genome-wide significant signal for iris color in the OCA2 region, with rs1800414 (His615Arg) explaining 11.9%, 10.4%, and 6% of variation in b*, a*, and L* coordinates respectively. While no genome-wide significant signals were detected for skin pigmentation, rs2373391 in ZNF804B was replicated in independent Chinese samples (p=0.003).
▶Model-based prediction of human hair color using DNA variantsAssociationN=385Wojciech Branicki et al.(2011)· Human Genetics
This study demonstrates that human hair color can be predicted from DNA variants with high accuracy using a multinomial logistic regression model. A subset of 13 genetic markers from 11 genes (MC1R, HERC2, IRF4, TYR, EXOC2, SLC45A2, TYRP1, OCA2, SLC24A4, KITLG, ASIP) predicted hair color categories in Polish Europeans with AUC values of 0.93 for red hair, 0.87 for black hair, 0.82 for brown hair, and 0.81 for blond hair. MC1R variants showed the strongest association with red hair (OR=12.64 for R variants, P=2.5×10⁻¹⁷), while rs12913832 in HERC2 was significantly associated with darker hair colors (OR=3.33 for black, P=4.3×10⁻⁶).
▶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.
▶Identification of novel functional variants of the melanocortin 1 receptor gene originated from AsiansFunctionalN=995Kazuhiro Nakayama et al.(2006)· Human Genetics
This functional genetics study identified three novel MC1R gene variants with Asian origins: Phe147Δ, Thr157Ile, and Pro159Thr. In vitro cAMP assays demonstrated that these variants showed impaired signaling similar to or more severe than the European red-hair variant Arg151Cys, suggesting functional constraint on MC1R varies geographically, possibly due to UV light adaptation in Eurasian populations.
Gene information from NCBI Gene. Variant classifications from ClinVar.
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