MC1R

Chr 16AR

melanocortin 1 receptor

Also known as: CMM5, MSH-R, SHEP2

NCBI Gene: 4157 ENSG00000258839 UniProt: Q01726 OMIM: 155555

The MC1R protein is a G protein-coupled receptor that binds melanocyte-stimulating hormones and activates cAMP signaling to promote melanogenesis and eumelanin production in melanocytes. Mutations cause autosomal recessive skin and hair pigmentation disorders including red hair/fair skin and blond hair/fair skin phenotypes, and serve as modifier factors for oculocutaneous albinism type II. The gene has low constraint against loss-of-function variants (high LOEUF score) and mutations are also associated with increased susceptibility to UV-induced skin damage and melanoma risk.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This intronless gene encodes the receptor protein for melanocyte-stimulating hormone (MSH). The encoded protein, a seven pass transmembrane G protein coupled receptor, controls melanogenesis. Two types of melanin exist: red pheomelanin and black eumelanin. Gene mutations that lead to a loss in function are associated with increased pheomelanin production, which leads to lighter skin and hair color. Eumelanin is photoprotective but pheomelanin may contribute to UV-induced skin damage by generating free radicals upon UV radiation. Binding of MSH to its receptor activates the receptor and stimulates eumelanin synthesis. This receptor is a major determining factor in sun sensitivity and is a genetic risk factor for melanoma and non-melanoma skin cancer. Over 30 variant alleles have been identified which correlate with skin and hair color, providing evidence that this gene is an important component in determining normal human pigment variation. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 1.976 OMIM phenotypes

Clinical Summary— MC1R

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 496 VUS of 823 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.97LOEUF

pLI 0.000

Z-score -2.21

OE 1.97 (1.12–1.97)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-2.34Z-score

OE missense 1.46 (1.33–1.61)

299 obs / 204.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.97 (1.12–1.97)

0≤0.351.4

Missense OE?1.46 (1.33–1.61)

0≤0.61.4

Synonymous OE?1.39

0≤1.21.6

LoF obs/exp: 12 / 6.1Missense obs/exp: 299 / 204.9Syn Z: -3.14

This gene — mechanism propensity

0.7326th %ile

GOF

0.84top 5%

LOF

0.2776th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

823 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic2

VUS496

Likely Benign244

Benign34

Conflicting46

Likely Pathogenic

496

VUS

244

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	2	0	0	0	2
VUS	34	401	54	7	496
Likely Benign	0	17	4	223	244
Benign	0	1	30	3	34
Conflicting	—				46
Total	36	419	88	233	822

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

40 pathogenic / likely-pathogenic (of 64) ClinVar copy-number / structural variants overlap MC1R — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →