Glucocorticoid deficiency 1

Summary

Glucocorticoid deficiency 1 (MONDO:0024536) is a disease caused by MC2R (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: MC2R (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 131

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	glucocorticoid deficiency 1
Mondo ID	MONDO:0024536
OMIM	202200
DOID	DOID:0080621
UMLS	C4049650
MedGen	885551
GARD	0025418
Is cancer (heuristic)	no

Also known as: familial glucocorticoid deficiency caused by mutation in MC2R · GCCD1 · glucocorticoid deficiency 1 · glucocorticoid deficiency, due to ACTH unresponsiveness · MC2R familial glucocorticoid deficiency

Data availability: 131 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › familial glucocorticoid deficiency › glucocorticoid deficiency 1

Related subtypes (5): adrenocortical unresponsiveness to ACTH with postreceptor defect, glucocorticoid deficiency 2, glucocorticoid deficiency 3, glucocorticoid deficiency 4, glucocorticoid deficiency 5

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

131 retrieved; paginated sample, class counts are floors:

66 uncertain significance, 25 benign, 17 pathogenic, 9 likely benign, 6 likely pathogenic, 5 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1691320	NM_000529.2(MC2R):c.681_688dup (p.Phe230fs)	MC2R	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18425	NM_000529.2(MC2R):c.376G>T (p.Ala126Ser)	MC2R	Pathogenic	no assertion criteria provided
3258	NM_000529.2(MC2R):c.221G>T (p.Ser74Ile)	MC2R	Pathogenic	criteria provided, multiple submitters, no conflicts
3260	NM_000529.2(MC2R):c.360C>G (p.Ser120Arg)	MC2R	Pathogenic	no assertion criteria provided
3261	NM_000529.2(MC2R):c.382C>T (p.Arg128Cys)	MC2R	Pathogenic	no assertion criteria provided
3262	NM_000529.2(MC2R):c.319G>A (p.Asp107Asn)	MC2R	Pathogenic	no assertion criteria provided
3263	NM_000529.2(MC2R):c.652_653insA (p.Ala218fs)	MC2R	Pathogenic	no assertion criteria provided
3264	NM_000529.2(MC2R):c.752G>T (p.Cys251Phe)	MC2R	Pathogenic	no assertion criteria provided
3265	NM_000529.2(MC2R):c.409C>T (p.Arg137Trp)	MC2R	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3266	NM_000529.2(MC2R):c.761A>G (p.Tyr254Cys)	MC2R	Pathogenic	no assertion criteria provided
3602724	NM_000529.2(MC2R):c.676G>A (p.Gly226Arg)	MC2R	Pathogenic	criteria provided, single submitter
444063	NM_000529.2(MC2R):c.702del (p.Phe235fs)	MC2R	Pathogenic	criteria provided, single submitter
444064	NM_000529.2(MC2R):c.674T>G (p.Leu225Arg)	MC2R	Pathogenic	criteria provided, single submitter
444065	NM_000529.2(MC2R):c.459dup (p.Ile154fs)	MC2R	Pathogenic	criteria provided, multiple submitters, no conflicts
444066	NM_000529.2(MC2R):c.424G>T (p.Val142Leu)	MC2R	Pathogenic	criteria provided, single submitter
492868	NM_000529.2(MC2R):c.560del (p.Val187fs)	MC2R	Pathogenic	criteria provided, single submitter
631794	NM_000529.2(MC2R):c.437G>A (p.Arg146His)	MC2R	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1841	NM_001379228.1(MRAP):c.3G>A (p.Met1Ile)	MRAP	Pathogenic	criteria provided, multiple submitters, no conflicts
444067	NM_001379228.1(MRAP):c.1A>G (p.Met1Val)	MRAP	Pathogenic	criteria provided, single submitter
444068	NM_001379228.1(MRAP):c.106+1del	MRAP	Pathogenic	criteria provided, multiple submitters, no conflicts
1285296	NM_000529.2(MC2R):c.676G>C (p.Gly226Arg)	MC2R	Likely pathogenic	criteria provided, single submitter
3259	NM_000529.2(MC2R):c.601C>T (p.Arg201Ter)	MC2R	Likely pathogenic	criteria provided, single submitter
3377610	NM_000529.2(MC2R):c.548dup (p.Leu184fs)	MC2R	Likely pathogenic	criteria provided, single submitter
3775355	NM_000529.2(MC2R):c.434_440del (p.Arg145fs)	MC2R	Likely pathogenic	criteria provided, single submitter
3776246	NM_000529.2(MC2R):c.696G>A (p.Trp232Ter)	MC2R	Likely pathogenic	criteria provided, single submitter
492866	NM_000529.2(MC2R):c.433C>T (p.Arg145Cys)	MC2R	Likely pathogenic	criteria provided, single submitter
326192	NM_000529.2(MC2R):c.795C>T (p.Ile265=)	MC2R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
326194	NM_000529.2(MC2R):c.537G>A (p.Thr179=)	MC2R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
326196	NM_000529.2(MC2R):c.435C>T (p.Arg145=)	MC2R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
492864	NM_000529.2(MC2R):c.80C>G (p.Pro27Arg)	MC2R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
MC2R	Definitive	Autosomal recessive	glucocorticoid deficiency 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MC2R	Orphanet:361	Familial glucocorticoid deficiency
MRAP	Orphanet:361	Familial glucocorticoid deficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MC2R	HGNC:6930	ENSG00000185231	Q01718	Adrenocorticotropic hormone receptor	gencc,clinvar
MRAP	HGNC:1304	ENSG00000170262	Q8TCY5	Melanocortin-2 receptor accessory protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MC2R	Adrenocorticotropic hormone receptor	G protein-coupled receptor for corticotropin/ACTH, primarily expressed in adrenal cortex where it plays a key role in the regulation of adrenocortical function.
MRAP	Melanocortin-2 receptor accessory protein	Modulator of melanocortin receptors (MC1R, MC2R, MC3R, MC4R and MC5R).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
GPCR	1	12.0×	0.164
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MC2R	GPCR	yes		GPCR_Rhodpsn, ACTH_rcpt, Melcrt_ACTH_rcpt
MRAP	Other/Unknown	no		MRAP

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	2
right adrenal gland	2
left adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MC2R	38	tissue_specific	marker	adrenal tissue, right adrenal gland, left adrenal gland
MRAP	154	tissue_specific	yes	right adrenal gland, adrenal tissue, right adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MC2R	972
MRAP	357

Intra-cohort edges

A	B	Sources
MC2R	MRAP	biogrid_interaction, intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MC2R	Q01718	2
MRAP	Q8TCY5	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective ACTH causes obesity and POMCD	1	5710.0×	0.002	MC2R
Diseases of metabolism	1	80.4×	0.026	MC2R
Class A/1 (Rhodopsin-like receptors)	1	74.2×	0.026	MC2R
Peptide ligand-binding receptors	1	74.2×	0.026	MC2R
G alpha (s) signalling events	1	73.2×	0.026	MC2R
GPCR ligand binding	1	64.2×	0.026	MC2R
GPCR downstream signalling	1	43.4×	0.031	MC2R
Signaling by GPCR	1	40.1×	0.031	MC2R
Disease	1	13.1×	0.085	MC2R
Signal Transduction	1	10.2×	0.098	MC2R

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	1685.2×	0.003	MRAP
positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	1404.3×	0.003	MRAP
negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	842.6×	0.003	MRAP
negative regulation of protein localization to plasma membrane	1	312.1×	0.006	MRAP
G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger	1	156.0×	0.010	MC2R
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	56.5×	0.021	MC2R
protein localization to plasma membrane	1	54.4×	0.021	MRAP
G protein-coupled receptor signaling pathway	1	18.1×	0.054	MC2R

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MC2R	1	2
MRAP	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ATUMELNANT	2	MC2R

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MC2R	12	Functional:7, Binding:5

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
ATUMELNANT	2	MC2R

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	MC2R
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MRAP

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MRAP	0	MC2R

Clinical trials & evidence

Clinical trials

Clinical trials: 0.