MC2R

Chr 18

melanocortin 2 receptor

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.

ResearchSummary from RefSeq, OMIM, UniProt

G protein-coupled receptor for corticotropin/ACTH, primarily expressed in adrenal cortex where it plays a key role in the regulation of adrenocortical function (PubMed:1325670, PubMed:17596328, PubMed:36588120). Upon activation, couples to G(s) protein, stimulating adenylate cyclase and activating the cAMP-dependent signaling pathway, the MAPK cascade as well as the PKA pathway, leading to steroidogenic factor 1/NR5A1-mediated transcriptional activation (PubMed:1325670). Activation by ACTH facilitates the release of adrenal glucocorticoids, including cortisol and corticosterone (PubMed:12213892, PubMed:8636348). In addition, MC2R is required for fetal and neonatal adrenal gland development (By similarity)

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtGlucocorticoid deficiency 1

Clinical highlights

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.85

LOEUF

LOF

Mechanism· G2P

Some data sources returned errors (2)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

omim: Error: OMIM fetch failed: 429

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

Background carrier burden — how many people carry a rare variant somewhere in MC2R?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

400 rare PASS variants

Rare truncating (LoF)

1 in 4,700

48 rare PASS variants

Rare synonymous (reference)

1 in 170

201 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MC2R. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 190	1 in 4,500
South Asian	~43k	1 in 100	1 in 3,600
Remaining (unassigned)	~30k	1 in 88	1 in 5,000
European (Finnish)	~27k	1 in 140	none seen
Admixed American	~22k	1 in 110	1 in 3,800
African / African American	~21k	1 in 100	1 in 3,300
East Asian	~20k	1 in 140	≈ 1 in 9,900
Ashkenazi Jewish	~13k	1 in 570	none seen
Middle Eastern	~2,884	1 in 130	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 1 coding exons well covered in gnomAD exomes and genomes.? see exons ↓