Obesity due to melanocortin 4 receptor deficiency

Summary

Obesity due to melanocortin 4 receptor deficiency (MONDO:0019115) is a disease caused by MC4R (GenCC Strong), with 1 cohort gene and 1 clinical trial. Top therapeutic interventions include setmelanotide.

At a glance

• Prevalence: 1-5 / 10 000 (France) [Orphanet-validated]
• Causal gene: MC4R (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 17
• Phenotypes (HPO): 10
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	50	France	Validated
Point prevalence	1-5 / 10 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0001513	Obesity	Obligate (100%)
HP:0009126	Increased adipose tissue	Obligate (100%)
HP:0002591	Polyphagia	Very frequent (80-99%)
HP:0005616	Accelerated skeletal maturation	Frequent (30-79%)
HP:0008915	Childhood-onset truncal obesity	Frequent (30-79%)
HP:0000822	Hypertension	Occasional (5-29%)
HP:0000842	Hyperinsulinemia	Occasional (5-29%)
HP:0000956	Acanthosis nigricans	Occasional (5-29%)
HP:0002155	Hypertriglyceridemia	Occasional (5-29%)
HP:0005978	Type II diabetes mellitus	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	obesity due to melanocortin 4 receptor deficiency
Mondo ID	MONDO:0019115
Orphanet	71529
NCIT	C120394
SNOMED CT	717269008
UMLS	C4273958
MedGen	903905
GARD	0016690
Is cancer (heuristic)	no

Also known as: MC4R deficiency

Data availability: 17 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inherited obesity › obesity due to melanocortin 4 receptor deficiency

Related subtypes (6): obesity due to prohormone convertase I deficiency, obesity due to pro-opiomelanocortin deficiency, obesity due to congenital leptin deficiency, obesity due to leptin receptor gene deficiency, obesity due to CEP19 deficiency, obesity due to SIM1 deficiency

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

17 retrieved; paginated sample, class counts are floors:

7 pathogenic/likely pathogenic, 4 conflicting classifications of pathogenicity, 3 pathogenic, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1060589	NM_005912.3(MC4R):c.418del (p.Leu140fs)	MC4R	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1284736	NM_005912.3(MC4R):c.493C>T (p.Arg165Trp)	MC4R	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14318	NM_005912.2(MC4R):c.105C>A (p.Tyr35Ter)	MC4R	Pathogenic	criteria provided, multiple submitters, no conflicts
14329	NM_005912.3(MC4R):c.812G>A (p.Cys271Tyr)	MC4R	Pathogenic	criteria provided, multiple submitters, no conflicts
14331	NM_005912.3(MC4R):c.947T>G (p.Ile316Ser)	MC4R	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14332	NM_005912.3(MC4R):c.861T>A (p.Tyr287Ter)	MC4R	Pathogenic	criteria provided, single submitter
3076075	NM_005912.3(MC4R):c.346_347del (p.Ser116fs)	MC4R	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
327713	NM_005912.3(MC4R):c.494G>A (p.Arg165Gln)	MC4R	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
36487	NM_005912.3(MC4R):c.835_836dup (p.Phe280fs)	MC4R	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
435831	NM_005912.3(MC4R):c.181G>A (p.Glu61Lys)	MC4R	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14334	NM_005912.3(MC4R):c.185A>G (p.Asn62Ser)	MC4R	Likely pathogenic	criteria provided, single submitter
3076076	NM_005912.3(MC4R):c.906T>G (p.Tyr302Ter)	MC4R	Likely pathogenic	criteria provided, single submitter
3076077	NM_005912.3(MC4R):c.706del (p.Arg236fs)	MC4R	Likely pathogenic	criteria provided, single submitter
14336	NM_005912.3(MC4R):c.380C>T (p.Ser127Leu)	MC4R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
36488	NM_005912.3(MC4R):c.896C>A (p.Pro299His)	MC4R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
492860	NM_005912.3(MC4R):c.63_64del (p.Tyr21_Arg22delinsTer)	MC4R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
586138	NM_005912.3(MC4R):c.913C>T (p.Arg305Trp)	MC4R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · 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
MC4R	Strong	Autosomal dominant	inherited obesity	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MC4R	Orphanet:71529	Obesity due to melanocortin 4 receptor deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MC4R	HGNC:6932	ENSG00000166603	P32245	Melanocortin receptor 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MC4R	Melanocortin receptor 4	G protein-coupled receptor that binds melanocyte-stimulating hormones (alpha- and beta-MSH) and corticotropin/ACTH, which are peptide products of the POMC precursor.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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	23.9×	0.042

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MC4R	GPCR	yes		Mcort_rcpt_4, GPCR_Rhodpsn, Melcrt_ACTH_rcpt

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

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

Top tissues across cohort

Tissue	Cohort genes
pancreatic ductal cell	1
prefrontal cortex	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MC4R	69	broad	yes	pancreatic ductal cell, right uterine tube, prefrontal cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MC4R	1,892

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MC4R	P32245	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 1 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
Transcriptional and post-translational regulation of MITF-M expression and activity	1	178.4×	0.026	MC4R
MITF-M-regulated melanocyte development	1	114.2×	0.026	MC4R
Class A/1 (Rhodopsin-like receptors)	1	74.2×	0.026	MC4R
Peptide ligand-binding receptors	1	74.2×	0.026	MC4R
G alpha (s) signalling events	1	73.2×	0.026	MC4R
GPCR ligand binding	1	64.2×	0.026	MC4R
GPCR downstream signalling	1	43.4×	0.031	MC4R
Signaling by GPCR	1	40.1×	0.031	MC4R
Developmental Biology	1	14.5×	0.077	MC4R
Signal Transduction	1	10.2×	0.098	MC4R

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of eating behavior	1	8426.0×	1e-03	MC4R
response to melanocyte-stimulating hormone	1	5617.3×	1e-03	MC4R
negative regulation of eating behavior	1	2808.7×	0.001	MC4R
regulation of feeding behavior	1	1872.4×	0.001	MC4R
positive regulation of bone resorption	1	991.3×	0.002	MC4R
feeding behavior	1	543.6×	0.003	MC4R
response to food	1	495.6×	0.003	MC4R
insulin secretion	1	432.1×	0.003	MC4R
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1	337.0×	0.004	MC4R
response to insulin	1	230.8×	0.005	MC4R
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	113.1×	0.009	MC4R

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
MC4R	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MC4R	57	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	MC4R
CLOTRIMAZOLE	4	MC4R
IMIPRAMINE	4	MC4R
RIMONABANT	4	MC4R
DESLORATADINE	4	MC4R
DULOXETINE	4	MC4R
SORAFENIB TOSYLATE	4	MC4R
DESERPIDINE	4	MC4R
NAFARELIN	4	MC4R
GRAMICIDIN	4	MC4R
ROSIGLITAZONE	4	MC4R
ROFECOXIB	4	MC4R
ANTAZOLINE	4	MC4R
MODAFINIL	4	MC4R
PIMOZIDE	4	MC4R
AMLODIPINE	4	MC4R
RIFAXIMIN	4	MC4R
CLEMASTINE	4	MC4R
TERFENADINE	4	MC4R
IVACAFTOR	4	MC4R
BREMELANOTIDE	4	MC4R
COSYNTROPIN	4	MC4R
LINAGLIPTIN	4	MC4R
PRENYLAMINE	4	MC4R
METHACYCLINE	4	MC4R
BOSUTINIB	4	MC4R
ASTEMIZOLE	4	MC4R
FENOTEROL	4	MC4R
SETMELANOTIDE	4	MC4R
CLOMIPRAMINE	4	MC4R

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MC4R	663	Binding:364, Functional:293, ADMET:6

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
MC4R	663

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

29 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)
BEPRIDIL	4	MC4R
CLOTRIMAZOLE	4	MC4R
IMIPRAMINE	4	MC4R
RIMONABANT	4	MC4R
DESLORATADINE	4	MC4R
DULOXETINE	4	MC4R
SORAFENIB TOSYLATE	4	MC4R
DESERPIDINE	4	MC4R
NAFARELIN	4	MC4R
GRAMICIDIN	4	MC4R
ROSIGLITAZONE	4	MC4R
ROFECOXIB	4	MC4R
ANTAZOLINE	4	MC4R
MODAFINIL	4	MC4R
PIMOZIDE	4	MC4R
AMLODIPINE	4	MC4R
RIFAXIMIN	4	MC4R
CLEMASTINE	4	MC4R
TERFENADINE	4	MC4R
IVACAFTOR	4	MC4R
BREMELANOTIDE	4	MC4R
COSYNTROPIN	4	MC4R
LINAGLIPTIN	4	MC4R
PRENYLAMINE	4	MC4R
METHACYCLINE	4	MC4R
BOSUTINIB	4	MC4R
ASTEMIZOLE	4	MC4R
FENOTEROL	4	MC4R
CLOMIPRAMINE	4	MC4R

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MC4R
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03013543	PHASE2	COMPLETED	Setmelanotide Phase 2 Treatment Trial in Participants With Rare Genetic Disorders of Obesity

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SETMELANOTIDE	4	1
CHEMBL4067491	0	1