rs12821256

neutralMag 4.5

This is a regulatory region variant variant in the KITLG gene.

Key Literature Trait Associations

Blonde Hair Color

rs12821256 lies within a hair-follicle-specific enhancer approximately 355 kb upstream of the KITLG (KIT Ligand / SCF) transcription start site. The C allele alters a binding motif for the LEF1 transcription factor, reducing enhancer activity by ~20% in keratinocytes and lowering KITLG expression in hair follicle melanocytes, which decreases melanin production and produces lighter (blonde) hair. The C allele is almost exclusively present in northern European populations.

Hysi PG et al. “Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability.” Nature Genetics 50(5):652-656 (2018)
Allele C
OR 1.66
p 2.0e-308
N 318,756
Meta-analysisLarge GWAS
European
Guenther CA et al. “A molecular basis for classic blond hair color in Europeans.” Nature Genetics 46(7):748-752 (2014)
Allele C
OR 2.32
p 5.5e-14
Large GWAS
Morgan MD et al. “Genome-wide study of hair colour in UK Biobank explains most of the SNP heritability.” Nature Communications 9(1):5271 (2018)
Allele C
OR 1.45
p 1.0e-62
N 323,317
Major Consortium StudyLarge GWAS
European
Lona-Durazo F et al. “A large Canadian cohort provides insights into the genetic architecture of human hair colour.” Communications Biology 4(1):1253 (2021)
Allele C
OR 1.48
p 1.0e-10
N 12,398
Large GWAS
European
Lin BD et al. “Heritability and Genome-Wide Association Studies for Hair Color in a Dutch Twin Family Based Sample.” Genes (2015)
Allele C
OR 1.49
p 1.0e-10
N 7,091
Large GWAS
European
Sulem P et al. “Genetic determinants of hair, eye and skin pigmentation in Europeans.” Nature Genetics 39(12):1443-1452 (2007)
Allele C
OR —
β 0.180 ±0.020
p 7.0e-19
N 6,918
Large GWAS
European
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GWAS Catalog Trait Associations (2)

Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.

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ClinVar annotation

affects
1 submitter2 publications

SKIN/HAIR/EYE PIGMENTATION 7, DARK/LIGHT SKIN

View on ClinVar →
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Research that mentions this SNP (3)

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Association of TGFβ1 and clinical factors with scar outcome following melanoma excision
AssociationN=202Ward SV et al.(2012)· Archives of Dermatological Research

Genetic association study of 202 melanoma patients examining SNPs in 24 candidate genes related to pigmentation and wound healing in relation to scar outcome. SNP rs8110090 in TGFβ1 was significantly associated with poorer scar outcomes (p=0.0002). Clinical factors including younger age, shorter time since surgery, and presence of infection or eczema were also associated with worse scarring.

Traits studied:Scar heightScar outcome following melanoma excisionScar vascularityWound healing
PubMedDOIMetascience Observatory
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Model-based prediction of human hair color using DNA variants
AssociationN=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).

Traits studied:Auburn hairBlack hairBlond hairBlond-red hairBrown hairDark-blond hairHair colorRed hair
PubMedDOIMetascience Observatory
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The R402Q tyrosinase variant does not cause autosomal recessive ocular albinism
ReviewOetting 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.

Traits studied:Basal cell carcinomaCutaneous melanomaEye colorHair colorMelanin contentOculocutaneous albinismPigmentationRed hairSkin color
PubMedDOIMetascience Observatory

Gene information from NCBI Gene. Variant classifications from ClinVar.

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