MC2R

Chr 18AR

melanocortin 2 receptor

Also known as: ACTHR

NCBI Gene: 4158ENSG00000185231UniProt: Q01718

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]

Primary Disease Associations & Inheritance

Glucocorticoid deficiency, due to ACTH unresponsivenessMIM #202200
AR
280
ClinVar variants
114
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— MC2R
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
114 Pathogenic / Likely Pathogenic· 114 VUS of 280 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.01Z-score
OE missense 1.00 (0.88–1.13)
174 obs / 174.2 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.1.08 (0.55–1.85)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.00 (0.88–1.13)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.15
0≤1.21.6
LoF obs/exp: 5 / 4.6Missense obs/exp: 174 / 174.2Syn Z: -1.04

ClinVar Variant Classifications

280 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic97
Likely Pathogenic17
VUS114
Likely Benign19
Benign25
Conflicting5
97
Pathogenic
17
Likely Pathogenic
114
VUS
19
Likely Benign
25
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
4
11
82
0
97
Likely Pathogenic
5
9
3
0
17
VUS
0
42
69
3
114
Likely Benign
0
5
9
5
19
Benign
0
1
24
0
25
Conflicting
—5
Total9681878277

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

View in ClinVar →

Protein Context — Lollipop Plot

MC2R · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

MC2R-related glucocorticoid deficiency

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersSkin
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Glucocorticoid deficiency, due to ACTH unresponsiveness

MIM #202200

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The multifunctional human ocular melanocortin system.
Wu CS et al.·Prog Retin Eye Res
2023Review
Adrenocorticotropin resistance syndromes.
Cooray SN et al.·Endocr Dev
2008Review
Isolated glucocorticoid deficiency: Genetic causes and animal models.
Maharaj A et al.·J Steroid Biochem Mol Biol
2019Review
Severe adrenal insufficiency in six neonates with normal newborn screening for CAH.
Kurt I et al.·Clin Endocrinol (Oxf)
2024
Adrenal gland development and defects.
Kempná P et al.·Best Pract Res Clin Endocrinol Metab
2008Review
The genetics of ACTH resistance syndromes.
Metherell LA et al.·Best Pract Res Clin Endocrinol Metab
2006Review
Clinical and Genetic Mechanisms in Patients with MC2R Deficiency Presenting with Early Puberty.
Karakilic Ozturan E et al.·Horm Res Paediatr
2025Cohort
[Clinical characteristics and genetic analysis of two children with Familial glucocorticoid deficiency type 1 due to variants of MC2R gene].
Gao J et al.·Zhonghua Yi Xue Yi Chuan Xue Za Zhi
2023
Rare causes of pediatric primary adrenal insufficiency: Data from a large nationwide Tunisian cohort.
Khalfallah R et al.·Ann Endocrinol (Paris)
2025Cohort
A variant in the 3'-untranslated region of the MC2R gene decreases the risk of schizophrenia in a female Han Chinese population.
Tang L et al.·J Int Med Res
2021
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools