Obesity due to pro-opiomelanocortin deficiency

Summary

Obesity due to pro-opiomelanocortin deficiency (MONDO:0012335) is a disease caused by POMC (GenCC Strong), with 1 cohort gene and 2 clinical trials. Top therapeutic interventions include setmelanotide.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: POMC (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 44
• Phenotypes (HPO): 18
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 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:0001010	Hypopigmentation of the skin	Frequent (30-79%)
HP:0001396	Cholestasis	Frequent (30-79%)
HP:0002297	Red hair	Frequent (30-79%)
HP:0008915	Childhood-onset truncal obesity	Frequent (30-79%)
HP:0011734	Central adrenal insufficiency	Frequent (30-79%)
HP:0000823	Delayed puberty	Occasional (5-29%)
HP:0000824	Decreased response to growth hormone stimulation test	Occasional (5-29%)
HP:0000842	Hyperinsulinemia	Occasional (5-29%)
HP:0000956	Acanthosis nigricans	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0002173	Hypoglycemic seizures	Occasional (5-29%)
HP:0002750	Delayed skeletal maturation	Occasional (5-29%)
HP:0008213	Gonadotropin deficiency	Occasional (5-29%)
HP:0008245	Pituitary hypothyroidism	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	obesity due to pro-opiomelanocortin deficiency
Mondo ID	MONDO:0012335
MeSH	C565726
OMIM	609734
Orphanet	71526
DOID	DOID:0051068
ICD-11	530374033
SNOMED CT	702949005
UMLS	C1857854
MedGen	341863
GARD	0010823
NORD	110450
Is cancer (heuristic)	no

Also known as: OBAIRH · obesity, adrenal insufficiency, and red hair due to POMC deficiency · POMC Deficiency · POMC deficiency

Data availability: 44 ClinVar variants · 5 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 pro-opiomelanocortin deficiency

Related subtypes (6): obesity due to prohormone convertase I deficiency, obesity due to congenital leptin deficiency, obesity due to leptin receptor gene deficiency, obesity due to CEP19 deficiency, obesity due to SIM1 deficiency, obesity due to melanocortin 4 receptor 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

44 retrieved; paginated sample, class counts are floors:

20 uncertain significance, 12 pathogenic, 9 conflicting classifications of pathogenicity, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1706561	NM_000939.4(POMC):c.-21+1G>A	LOC108167315	Pathogenic	no assertion criteria provided
13358	NM_000939.4(POMC):c.151A>T (p.Lys51Ter)	LOC129933280	Pathogenic	no assertion criteria provided
13353	NM_000939.4(POMC):c.313G>T (p.Glu105Ter)	POMC	Pathogenic	no assertion criteria provided
13354	NM_000939.4(POMC):c.433del (p.Arg145fs)	POMC	Pathogenic	no assertion criteria provided
13355	NM_000939.4(POMC):c.-11C>A	POMC	Pathogenic	criteria provided, multiple submitters, no conflicts
13357	NM_000939.4(POMC):c.403_404dup (p.Lys136fs)	POMC	Pathogenic	no assertion criteria provided
13359	POMC, 1-BP DEL, NT6996	POMC	Pathogenic	no assertion criteria provided
3767318	NM_000939.4(POMC):c.132+1G>A	POMC	Pathogenic	criteria provided, single submitter
436364	NM_000939.4(POMC):c.133-2A>C	POMC	Pathogenic	criteria provided, single submitter
492966	POMC, 1-BP INS, 6922C	POMC	Pathogenic	no assertion criteria provided
666581	NM_000939.4(POMC):c.416dup (p.Tyr139Ter)	POMC	Pathogenic	criteria provided, single submitter
666582	NM_000939.4(POMC):c.84C>A (p.Cys28Ter)	POMC	Pathogenic	criteria provided, single submitter
335362	NM_001035256.1(POMC):c.-203A>G	LOC108167315	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
335357	NM_000939.4(POMC):c.158A>G (p.Asp53Gly)	LOC129933280	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
13356	NM_000939.4(POMC):c.706C>G (p.Arg236Gly)	POMC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
335358	NM_000939.4(POMC):c.18C>T (p.Cys6=)	POMC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
710881	NM_000939.4(POMC):c.261C>A (p.Phe87Leu)	POMC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
716681	NM_000939.4(POMC):c.583G>A (p.Ala195Thr)	POMC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895580	NM_000939.4(POMC):c.498C>T (p.Asp166=)	POMC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
896986	NM_000939.4(POMC):c.394C>G (p.Pro132Ala)	POMC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
898576	NM_000939.4(POMC):c.662A>G (p.Tyr221Cys)	POMC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895643	NM_001035256.1(POMC):c.-263C>A	LOC108167315	Uncertain significance	criteria provided, single submitter
1368345	NM_000939.4(POMC):c.434G>A (p.Arg145His)	POMC	Uncertain significance	criteria provided, multiple submitters, no conflicts
1396815	NM_000939.4(POMC):c.285_286insAGCAGCAGCGGCAGCAGC (p.94_95S[5]GSS[1])	POMC	Uncertain significance	criteria provided, single submitter
2584571	NM_000939.4(POMC):c.-20-675A>G	POMC	Uncertain significance	criteria provided, single submitter
335351	NM_000939.4(POMC):c.*120A>G	POMC	Uncertain significance	criteria provided, single submitter
335355	NM_000939.4(POMC):c.474G>T (p.Lys158Asn)	POMC	Uncertain significance	criteria provided, single submitter
335359	NM_000939.4(POMC):c.4C>T (p.Pro2Ser)	POMC	Uncertain significance	criteria provided, single submitter
335360	NM_000939.4(POMC):c.-20-904T>C	POMC	Uncertain significance	criteria provided, single submitter
335361	NM_000939.4(POMC):c.-20-906C>T	POMC	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
POMC	Strong	Semidominant	inherited obesity	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POMC	Orphanet:71526	Obesity due to pro-opiomelanocortin 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
POMC	HGNC:9201	ENSG00000115138	P01189	Pro-opiomelanocortin	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POMC	Pro-opiomelanocortin	Precursor protein of pituitary hormones that are involved in diverse physiological processes, including the regulation of energy balance, stress response, immune function and skin pigmentation.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
POMC	Other/Unknown	no		PMOC, Mcrtin_ACTH_cent, Opioid_neuropept

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adenohypophysis	1
pituitary gland	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POMC	161	broad	marker	adenohypophysis, pituitary gland, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POMC	3,655

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POMC	P01189	13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
Defective ACTH causes obesity and POMCD	1	5710.0×	0.002	POMC
Peptide hormone biosynthesis	1	1427.5×	0.004	POMC
Androgen biosynthesis	1	1038.2×	0.004	POMC
Glucocorticoid biosynthesis	1	878.5×	0.004	POMC
G-protein activation	1	475.8×	0.005	POMC
Endogenous sterols	1	393.8×	0.005	POMC
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	380.7×	0.005	POMC
Opioid Signalling	1	265.6×	0.006	POMC
Transcriptional and post-translational regulation of MITF-M expression and activity	1	178.4×	0.008	POMC
Interleukin-4 and Interleukin-13 signaling	1	102.9×	0.013	POMC
Peptide ligand-binding receptors	1	74.2×	0.015	POMC
G alpha (s) signalling events	1	73.2×	0.015	POMC
G alpha (i) signalling events	1	39.0×	0.026	POMC

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
cellular pigmentation	1	16852.0×	5e-04	POMC
positive regulation of oxytocin production	1	16852.0×	5e-04	POMC
regulation of corticosterone secretion	1	8426.0×	6e-04	POMC
response to melanocyte-stimulating hormone	1	5617.3×	7e-04	POMC
regulation of glycogen metabolic process	1	3370.4×	9e-04	POMC
positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	2808.7×	9e-04	POMC
regulation of appetite	1	1685.2×	0.001	POMC
generation of precursor metabolites and energy	1	343.9×	0.006	POMC
negative regulation of tumor necrosis factor production	1	251.5×	0.007	POMC
regulation of blood pressure	1	221.7×	0.007	POMC
calcium-mediated signaling	1	183.2×	0.008	POMC
neuropeptide signaling pathway	1	172.0×	0.008	POMC
glucose homeostasis	1	130.6×	0.009	POMC
cell-cell signaling	1	69.6×	0.016	POMC
signal transduction	1	16.1×	0.066	POMC
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	POMC

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
POMC	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

0 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.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	POMC

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)
POMC	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05194124	PHASE3	COMPLETED	Phase 3 Crossover Trial of Two Formulations of Setmelanotide in Participants With Specific Gene Defects in the MC4R Pathway
NCT06239064	Not specified	ACTIVE_NOT_RECRUITING	Early Genetic Identification of Obesity

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SETMELANOTIDE	4	1
CHEMBL4067491	0	1