MC2R

Chr 18AR

melanocortin 2 receptor

Also known as: ACTHR

NCBI Gene: 4158 ENSG00000185231 UniProt: Q01718 OMIM: 607397

The melanocortin 2 receptor (MC2R) is a G protein-coupled receptor that responds specifically to adrenocorticotropic hormone (ACTH) and regulates adrenocortical function by stimulating cortisol and corticosterone release from the adrenal cortex. Mutations cause familial glucocorticoid deficiency due to ACTH unresponsiveness, presenting with adrenal insufficiency that can manifest in the neonatal period since MC2R is required for normal fetal and neonatal adrenal gland development. This condition follows autosomal recessive inheritance.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

MC2R encodes one member of the five-member G-protein associated melanocortin receptor family. Melanocortins (melanocyte-stimulating hormones and adrenocorticotropic hormone) are peptides derived from pro-opiomelanocortin (POMC). MC2R is selectively activated by adrenocorticotropic hormone, whereas the other four melanocortin receptors recognize a variety of melanocortin ligands. Mutations in MC2R can result in familial glucocorticoid deficiency. Alternate transcript variants have been found for this gene. [provided by RefSeq, May 2014]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.851 OMIM phenotype

Clinical Summary— MC2R

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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

33 unique Pathogenic / Likely Pathogenic· 105 VUS of 189 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — MC2R

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.85LOEUF

pLI 0.000

Z-score -0.16

OE 1.08 (0.55–1.85)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.01Z-score

OE missense 1.00 (0.88–1.13)

174 obs / 174.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.08 (0.55–1.85)

0≤0.351.4

Missense OE?1.00 (0.88–1.13)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 5 / 4.6Missense obs/exp: 174 / 174.2Syn Z: -1.04

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveMC2R-related glucocorticoid deficiencyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7325th %ile

GOF

0.77top 25%

LOF

0.2678th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

189 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17

Likely Pathogenic16

VUS105

Likely Benign19

Benign25

Conflicting5

Pathogenic

Likely Pathogenic

105

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	6	11	0	0	17
Likely Pathogenic	7	9	0	0	16
VUS	0	43	59	3	105
Likely Benign	0	5	9	5	19
Benign	0	1	24	0	25
Conflicting	—				5
Total	13	69	92	8	187

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

View in ClinVar →

81 pathogenic / likely-pathogenic (of 92) ClinVar copy-number / structural variants overlap MC2R — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →