POMC

Summary

POMC (proopiomelanocortin, HGNC:9201) is a protein-coding gene on chromosome 2p23.3, encoding Pro-opiomelanocortin (P01189). 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.

This gene encodes a preproprotein that undergoes extensive, tissue-specific, post-translational processing via cleavage by subtilisin-like enzymes known as prohormone convertases. There are eight potential cleavage sites within the preproprotein and, depending on tissue type and the available convertases, processing may yield as many as ten biologically active peptides involved in diverse cellular functions. The encoded protein is synthesized mainly in corticotroph cells of the anterior pituitary where four cleavage sites are used; adrenocorticotrophin, essential for normal steroidogenesis and the maintenance of normal adrenal weight, and lipotropin beta are the major end products. In other tissues, including the hypothalamus, placenta, and epithelium, all cleavage sites may be used, giving rise to peptides with roles in pain and energy homeostasis, melanocyte stimulation, and immune modulation. These include several distinct melanotropins, lipotropins, and endorphins that are contained within the adrenocorticotrophin and beta-lipotropin peptides. The antimicrobial melanotropin alpha peptide exhibits antibacterial and antifungal activity. Mutations in this gene have been associated with early onset obesity, adrenal insufficiency, and red hair pigmentation. Alternatively spliced transcript variants encoding the same protein have been described.

Source: NCBI Gene 5443 — RefSeq curated summary.

At a glance

• Gene–disease (curated): inherited obesity (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 18
• Clinical variants (ClinVar): 188 total — 16 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 31
• MANE Select transcript: NM_000939

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9201
Approved symbol	POMC
Name	proopiomelanocortin
Location	2p23.3
Locus type	gene with protein product
Status	Approved
Aliases	MSH, POC, CLIP, ACTH, NPP, LPH
Ensembl gene	ENSG00000115138
Ensembl biotype	protein_coding
OMIM	176830
Entrez	5443

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000264708, ENST00000380794, ENST00000395826, ENST00000405623, ENST00000449220, ENST00000942339

RefSeq mRNA: 4 — MANE Select: NM_000939 NM_000939, NM_001035256, NM_001319204, NM_001319205

CCDS: CCDS1717

Canonical transcript exons

ENST00000395826 — 3 exons

Exon	Start	End
ENSE00000727086	25164641	25164792
ENSE00001834880	25160860	25161752
ENSE00001928690	25168498	25168580

Expression profiles

Bgee: expression breadth ubiquitous, 161 present calls, max score 99.96.

FANTOM5 (CAGE): breadth broad, TPM avg 7.7326 / max 5514.6012, expressed in 747 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
27353	4.9203	12
27350	2.1284	711
27347	0.1719	4
27349	0.1295	74
27354	0.0972	4
27351	0.0640	5
27355	0.0609	9
27352	0.0459	3
27357	0.0379	4
27356	0.0296	6

Top tissues by expression

283 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
adenohypophysis	UBERON:0002196	99.96	gold quality
pituitary gland	UBERON:0000007	99.87	gold quality
right testis	UBERON:0004534	85.50	gold quality
left testis	UBERON:0004533	84.92	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.66	gold quality
body of pancreas	UBERON:0001150	82.11	gold quality
right adrenal gland cortex	UBERON:0035827	81.25	gold quality
testis	UBERON:0000473	81.09	gold quality
left adrenal gland	UBERON:0001234	80.62	gold quality
right adrenal gland	UBERON:0001233	80.42	gold quality
apex of heart	UBERON:0002098	79.46	gold quality
left adrenal gland cortex	UBERON:0035825	79.37	gold quality
right atrium auricular region	UBERON:0006631	79.32	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.93	gold quality
adrenal cortex	UBERON:0001235	77.32	gold quality
cardiac atrium	UBERON:0002081	76.78	gold quality
lower esophagus mucosa	UBERON:0035834	76.54	gold quality
adrenal gland	UBERON:0002369	76.29	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	75.96	gold quality
lower esophagus	UBERON:0013473	75.37	gold quality
lower esophagus muscularis layer	UBERON:0035833	75.34	gold quality
hindlimb stylopod muscle	UBERON:0004252	75.29	gold quality
heart left ventricle	UBERON:0002084	74.87	gold quality
hypothalamus	UBERON:0001898	74.69	gold quality
omental fat pad	UBERON:0010414	74.62	gold quality
peritoneum	UBERON:0002358	74.53	gold quality
muscle layer of sigmoid colon	UBERON:0035805	74.30	gold quality
cardiac ventricle	UBERON:0002082	74.28	gold quality
adipose tissue of abdominal region	UBERON:0007808	73.86	gold quality
granulocyte	CL:0000094	73.80	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.96

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
CDKN2A	Activation

Upstream regulators (CollecTRI, top): AP1, AR, CEBPB, CREB1, CRHR1, CXXC1, ESR1, ETV1, FOS, FOXO1, GLI1, ID1, ID2, IRF6, JDP2, JUN, KLF10, NCOA2, NEUROD1, NFKB, NR1H2, NR1H3, NR3C1, NR4A1, NR4A2, NR4A3, PITX1, POU4F1, PTX3, SMAD1, SP1, SPI1, STAT1, STAT3, TBX19, TCF3, TFCP2, TP53, TTF1, USF1

miRNA regulators (miRDB)

19 targeting POMC, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-377-3P	99.37	70.18	1905
HSA-MIR-329-5P	99.27	68.11	1597
HSA-MIR-3973	99.20	69.19	1990
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-485-5P	99.10	64.78	1889
HSA-MIR-6884-5P	99.10	64.50	1987
HSA-MIR-520G-3P	98.91	67.38	1914
HSA-MIR-520H	98.91	67.38	1914
HSA-MIR-4764-5P	98.88	65.53	894
HSA-MIR-12114	98.70	63.45	730
HSA-MIR-6730-5P	98.03	68.12	1299
HSA-MIR-4257	97.86	68.05	1190

Literature-anchored findings (GeneRIF, showing 40)

• In CRH positive melanomas, seven out of nine cases (78%) of primary melanoma, and 7 out of 12 cases (58%) of MetM showed colocalization of CRH and POMC peptides. CRH induced POMC mRNA expression (PMID:11936276)
• microsatellite polymorphism in exon 3 of POMC is associated with elevated serum leptin (PMID:11979399)
• results suggest that mutations in the POMC gene are unlikely to be a major factor of obesity or diabetes in Japanese subjects (PMID:12032760)
• Data suggest that the loss of ACTH peptide expression in these late passage cells is in part due to the loss of the POMC signal sequence. (PMID:12039064)
• Mutations that disrupts a dibasic prohormone processing site in POMC confers an inherited susceptibility to obesity (PMID:12165561)
• Processing of this hormone is involved in contagious maladaptive behavior. (PMID:12220743)
• Prolactin and ACTH either increased or remained level during emotion induction, or decreased only after the induction. Degree of change in circulating hormones in response to emotions was very small and possibly not functionally significant. (PMID:12475731)
• MSH/ACTH peptides are immunomodulatory/anti-inflammatory regulators, and in keratinocytes there is a novel IkappaBalpha mechanism, identifying an abnormal IkappaBalpha mechanism in the immortal HaCaT versus normal keratinocyte. (PMID:12485424)
• ghrelin-induced growth hormone secretion was severely blunted in patients with active Cushing’s syndrome, in addition to a remarkable hyper-response in ACTH and cortisol secretion (PMID:12566947)
• expression reduced in the arcuate and paraventricular nucleus in schizophrenia and depression (PMID:12643442)
• Subpopulation of POMC neurons is leptin-responsive and suggest that stimulation of hypothalamic POMC gene expression in these cells requires STAT3 activation. (PMID:12697721)
• Human epidermal melanocytes express a fully functioning beta-endorphin/mu-opiate receptor system. Beta-endorphin/mu-opiate receptor system participates in the regulation of skin pigmentation. (PMID:12787137)
• POMC has become a paradigmatic polypeptide precursor model illustrating the variable roles of a single gene and its various products in different localities–review (PMID:12887283)
• NF-kappaB is the key molecule involved in alpha-MSH-mediated cell death and this may help to regulate mast cell-mediated inflammation (PMID:12914931)
• alpha-melanocyte-stimulating hormone-triggered expression of microphthalmia-associated transcription factor in melanocytes is modulated by SOX10 (PMID:12944398)
• Mesothelioma cells were found to express mRNA for POMC and its processing enzymes, release alpha-MSH peptide into supernatants, and express melanocortin 1 receptor; an autocrine-inhibitory circuit based on alpha-MSH and its receptor MC1R was observed. (PMID:14576363)
• alpha-melanocyte-stimulating hormone has a role in collagen metabolism (PMID:14645373)
• Nur77 activated by HIF under hypoxic conditions regulates production of the peptide hormone precursor POMC. (PMID:14729605)
• Chronic ACTH hypersecretion may lead to diffuse adrenal hyperplasia in patients with ACTH-dependent Cushing’s syndrome. (PMID:15004414)
• Proopiomelanocortin-derived neuropeptides, such as alpha-melanocyte-stimulating hormone may therefore play an important part in modulating ultraviolet-induced inflammation. (PMID:15009732)
• show that plasmin is involved in the processing of hormones derived from the pro-opiomelanocortin precursor in the intermediate pituitary (PMID:15099286)
• ACTH secretion was higher in PHA subjects during placebo experiments, but equal to controls after alcohol administration. The alcohol-induced attenuation of ACTH response was statistically significant in PHA, but not FHN, subjects. (PMID:15100697)
• Stable transfection of Chinese hamster ovary cells with the MC-1 receptor showed that alpha-MSH and the KPV peptides elevated intracellular calcium. (PMID:15102092)
• PT-141, an alpha-melanocyte stimulating hormone receptor agonist, encourages female rats to have sex. (PMID:15226502)
• melanocytes produce prostaglandins and alpha-MSH, by inhibiting this response, may play an important role in regulating inflammatory responses in the skin (PMID:15251468)
• UV-induced expression of POMC and MC1R is dependent on the p-38-activated upstream stimulating factor-1 (PMID:15358786)
• Data show that alpha-MSH and ACTH-like levels were not markedly different between groups with dark and light skin, and between seasons. (PMID:15464199)
• POMC variant may be involved in the natural history of polygenic obesity in late adolescence and adulthood, contributing to the link between type 2 diabetes and obesity. (PMID:15472174)
• functional recycling of retained hormones is not shared by all anterior pituitary cell types (PMID:15480745)
• role for POMC peptides in regulating human hair follicle melanocyte differentiation. (PMID:15498881)
• Serum alpha-MSH levels did not correlate with body composition parameters and were not associated with caloric or macronutrient intake. (PMID:15546902)
• alpha-MSH plays a protective role in the skin by reducing infection and the inflammatory process (PMID:15560758)
• Link between ACTH/cAMP-dependent steroidogenesis and sphingolipid metabolism in the human adrenal cortex. Sphingolipids may serve as signaling mediators in ACTH-stimulated cortisol biosynthesis. (PMID:15666826)
• We report largest series of congenital ACTH deficiency and demonstrate molecular mechanism involves Tpit in majority of cases. (PMID:15666849)
• Two phylogenetically conserved neuronal POMC enhancers designated nPE1 (600 bp) and nPE2 (150 bp) located approximately 10 to 12 kb upstream of POMC transcriptional units were identified. (PMID:15798195)
• Associations of BMI, weight and total fat with SNPs in regions flanking the POMC gene in this powerful study suggest that regulation of POMC expression may be influential in determining body weight. (PMID:15812563)
• Eexpression of alpha-MSH may markedly increase in the split-thickness grafted skin and correlate with its pigmentation after the skin graft. (PMID:15835810)
• single nucleotide polymorphisms in the promoter region of the pro-opiomelanocortin gene is associated with low bone mineral density leading to osteoporosis and dyslipidemia (PMID:15864412)
• alpha-MSH peptide in human dermal fibroblast cells plays a cytoprotective and anti-apoptotic role. (PMID:15949633)
• data show that genetic variants at the POMC locus influence body fat distribution within the normal range, suggesting a novel role for proopiomelanocortin (POMC) in metabolic regulation (PMID:16046320)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	pomca	ENSDARG00000043135
danio_rerio	pomcb	ENSDARG00000069307
mus_musculus	Pomc	ENSMUSG00000020660
rattus_norvegicus	Pomc	ENSRNOG00000012686

Protein

Protein identifiers

Pro-opiomelanocortin — P01189 (reviewed: P01189)

Alternative names: Corticotropin-lipotropin

All UniProt accessions (2): E9PHK5, P01189

UniProt curated annotations — full annotation on UniProt →

Function. 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. Functions as a ligand for the melanocortin receptors MC1R, MC2R, MC3R and MC5R. Activation of MC1R increases melanogenesis in melanocytes found in the skin and hair. Binding to MC2R stimulates the adrenal glands to secrete cortisol. Contributes to the regulation of energy homeostasis through activation of MC3R. Involved in the regulation exocrine gland function through MC5R activation. Serves as a ligand for the melanocortin receptors MC1R, MC3R, MC4R and MC5R. Activation of MC1R promotes melanogenesis in melanocytes of the skin and hair. Contributes to the regulation of energy homeostasis through activation of MC3R. Through MC4R activation, functions as an anorexigenic peptide. Promotes immunosuppression and involved in the regulation exocrine gland function through MC5R activation. Functions as a ligand for the melanocortin receptors MC1R, MC3R, MC4R and MC5R. Activation of MC1R increases melanogenesis in melanocytes found in the skin and hair. Contributes to the regulation of energy homeostasis through activation of MC3R. Through MC4R activation, functions as an anorexigenic peptide. Involved in the regulation exocrine gland function through MC5R activation. Functions as a ligand for the melanocortin receptors MC1R, MC3R, MC4R and MC5R. Activation of MC1R increases melanogenesis in melanocytes found in the skin and hair. Contributes to the regulation of energy homeostasis through activation of MC3R. Binds to MC4R with low potency. Involved in the regulation exocrine gland function through MC5R activation. Endogenous orexigenic opiate. Endogenous opiate.

Subcellular location. Secreted.

Tissue specificity. ACTH and MSH are produced by the pituitary gland.

Post-translational modifications. Specific enzymatic cleavages at paired basic residues yield the different active peptides. O-glycosylated; reducing sugar is probably N-acetylgalactosamine.

Disease relevance. Obesity (OBESITY) [MIM:601665] A condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat. Disease susceptibility may be associated with variants affecting the gene represented in this entry. Obesity, early-onset, with adrenal insufficiency and red hair (OBAIRH) [MIM:609734] An autosomal recessive disorder characterized by early-onset obesity due to severe hyperphagia, pigmentary abnormalities, mainly pale skin and red hair, and secondary hypocortisolism. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the POMC family.

RefSeq proteins (4): NP_000930, NP_001030333, NP_001306133, NP_001306134 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001941	PMOC	Family
IPR013531	Mcrtin_ACTH_cent	Domain
IPR013532	Opioid_neuropept	Domain
IPR013593	Melanocortin_N	Domain
IPR050878	POMC-derived_peptides	Family

Pfam: PF00976, PF08035, PF08384

UniProt features (41 total): peptide 11, sequence variant 9, modified residue 5, strand 4, region of interest 3, compositionally biased region 2, glycosylation site 2, sequence conflict 2, signal peptide 1, disulfide bond 1, helix 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
4XNH	X-RAY DIFFRACTION	2.1
8INR	ELECTRON MICROSCOPY	2.73
4XPD	X-RAY DIFFRACTION	2.81
7PIV	ELECTRON MICROSCOPY	2.86
8IOC	ELECTRON MICROSCOPY	2.86
8W8W	ELECTRON MICROSCOPY	2.9
8W8X	ELECTRON MICROSCOPY	2.9
8W8Y	ELECTRON MICROSCOPY	2.9
7F53	ELECTRON MICROSCOPY	3
7F54	ELECTRON MICROSCOPY	3
8F7Q	ELECTRON MICROSCOPY	3.22
4Y49	X-RAY DIFFRACTION	3.95
6TUB	SOLID-STATE NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01189-F1	58.47	0.00

Antibody-complex structures (SAbDab): 8 — 7F53, 7F54, 7PIV, 8F7Q, 8IOC, 8W8W, 8W8X, 8W8Y

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (5): 87, 134, 138, 150, 168

Disulfide bonds (1): 28–50

Glycosylation sites (2): 71, 91

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-111885	Opioid Signalling
R-HSA-193048	Androgen biosynthesis
R-HSA-194002	Glucocorticoid biosynthesis
R-HSA-202040	G-protein activation
R-HSA-209952	Peptide hormone biosynthesis
R-HSA-211976	Endogenous sterols
R-HSA-375276	Peptide ligand-binding receptors
R-HSA-418555	G alpha (s) signalling events
R-HSA-418594	G alpha (i) signalling events
R-HSA-5579031	Defective ACTH causes obesity and POMCD
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling
R-HSA-9615017	FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes
R-HSA-9856649	Transcriptional and post-translational regulation of MITF-M expression and activity

MSigDB gene sets: 349 (showing top): GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, REACTOME_BIOLOGICAL_OXIDATIONS, BENPORATH_ES_WITH_H3K27ME3, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOBP_PHENOL_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_BEHAVIOR, KEGG_ADIPOCYTOKINE_SIGNALING_PATHWAY, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, NKX25_02, GOCC_SECRETORY_GRANULE, GOBP_GLUCOCORTICOID_METABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS

GO Biological Process (16): generation of precursor metabolites and energy (GO:0006091), signal transduction (GO:0007165), neuropeptide signaling pathway (GO:0007218), cell-cell signaling (GO:0007267), regulation of blood pressure (GO:0008217), calcium-mediated signaling (GO:0019722), regulation of appetite (GO:0032098), negative regulation of tumor necrosis factor production (GO:0032720), cellular pigmentation (GO:0033059), glucose homeostasis (GO:0042593), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of glycogen metabolic process (GO:0070873), positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0106071), positive regulation of oxytocin production (GO:0140668), response to melanocyte-stimulating hormone (GO:1990680), regulation of corticosterone secretion (GO:2000852)

GO Molecular Function (7): G protein-coupled receptor binding (GO:0001664), signaling receptor binding (GO:0005102), hormone activity (GO:0005179), type 3 melanocortin receptor binding (GO:0031781), type 4 melanocortin receptor binding (GO:0031782), type 1 melanocortin receptor binding (GO:0070996), protein binding (GO:0005515)

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), secretory granule (GO:0030141), secretory granule lumen (GO:0034774)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Metabolism of steroid hormones	2
GPCR downstream signalling	2
G alpha (i) signalling events	1
Opioid Signalling	1
Peptide hormone metabolism	1
Cytochrome P450 - arranged by substrate type	1
Class A/1 (Rhodopsin-like receptors)	1
Diseases of metabolism	1
Signaling by Interleukins	1
FOXO-mediated transcription	1
MITF-M-regulated melanocyte development	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
melanocortin receptor binding	3
cell communication	2
cellular process	2
signaling	2
regulation of biological quality	2
cellular anatomical structure	2
metabolic process	1
regulation of cellular process	1
cellular response to stimulus	1
G protein-coupled receptor signaling pathway	1
blood circulation	1
intracellular signaling cassette	1
response to nutrient levels	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
negative regulation of tumor necrosis factor superfamily cytokine production	1
pigmentation	1
carbohydrate homeostasis	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
glycogen metabolic process	1
regulation of polysaccharide metabolic process	1
regulation of generation of precursor metabolites and energy	1
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1
positive regulation of G protein-coupled receptor signaling pathway	1
regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway	1
positive regulation of gene expression	1
oxytocin production	1
regulation of oxytocin production	1
response to peptide hormone	1
corticosterone secretion	1
regulation of glucocorticoid secretion	1
signaling receptor binding	1
protein binding	1
receptor ligand activity	1
binding	1
intracellular anatomical structure	1
endomembrane system	1
secretory vesicle	1

Protein interactions and networks

STRING

3552 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POMC	MC4R	P32245	999
POMC	MC2R	Q01718	999
POMC	MC1R	Q01726	999
POMC	MC3R	P41968	998
POMC	MC5R	P33032	997
POMC	OPRM1	P35372	996
POMC	LEP	P41159	992
POMC	CRH	P06850	987
POMC	AGRP	O00253	978
POMC	NPY	P01303	973
POMC	CPE	P16870	965
POMC	ATP7A	Q04656	964
POMC	PRL	P01236	959
POMC	PDYN	P01213	949
POMC	INS	P01308	947

IntAct

57 interactions, top by confidence:

A	B	Type	Score
HSF2BP	POMC	psi-mi:“MI:0915”(physical association)	0.560
POMC	GLYCTK	psi-mi:“MI:0915”(physical association)	0.560
POMC	ATP6V0D2	psi-mi:“MI:0915”(physical association)	0.560
POMC	ABI2	psi-mi:“MI:0915”(physical association)	0.560
POMC	BHLHA9	psi-mi:“MI:0915”(physical association)	0.560
POMC	NFKBID	psi-mi:“MI:0915”(physical association)	0.560
POMC	AIRIM	psi-mi:“MI:0915”(physical association)	0.560
POMC	CCDC102B	psi-mi:“MI:0915”(physical association)	0.560
POMC	TXN2	psi-mi:“MI:0915”(physical association)	0.560
POMC	SUOX	psi-mi:“MI:0915”(physical association)	0.560
POMC	ESRRG	psi-mi:“MI:0915”(physical association)	0.560
POMC	MKRN3	psi-mi:“MI:0915”(physical association)	0.560
POMC	HDDC2	psi-mi:“MI:0915”(physical association)	0.560
POMC	OAZ3	psi-mi:“MI:0915”(physical association)	0.560
POMC	KLHL42	psi-mi:“MI:0915”(physical association)	0.560
POMC	NTAQ1	psi-mi:“MI:0915”(physical association)	0.560
TSPAN11	IGLL5	psi-mi:“MI:0914”(association)	0.530
POMC	AMD1	psi-mi:“MI:0914”(association)	0.530
PRSS33	SAC3D1	psi-mi:“MI:0914”(association)	0.350
POMC	HSF2BP	psi-mi:“MI:0915”(physical association)	0.000
GLYCTK	POMC	psi-mi:“MI:0915”(physical association)	0.000
ATP6V0D2	POMC	psi-mi:“MI:0915”(physical association)	0.000
KLHL42	POMC	psi-mi:“MI:0915”(physical association)	0.000
NTAQ1	POMC	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (46): POMC (Affinity Capture-MS), TTL (Affinity Capture-MS), E2F4 (Affinity Capture-MS), UBR4 (Affinity Capture-MS), KLHL15 (Affinity Capture-MS), AMD1 (Affinity Capture-MS), POMC (Negative Genetic), POMC (Negative Genetic), POMC (Negative Genetic), POMC (Negative Genetic), POMC (Negative Genetic), TPSAB1 (Negative Genetic), POMC (Negative Genetic), POMC (Two-hybrid), POMC (Two-hybrid)

ESM2 similar proteins: A0A1L2F565, B3IWF8, O09163, O57312, O73812, O93464, P01189, P01193, P01194, P01256, P01355, P01356, P04089, P06307, P06881, P07660, P09240, P10092, P10093, P10286, P12760, P23362, P37042, P41520, P45656, P48645, P55247, P81564, P81872, P87352, Q28588, Q75V93, Q75V94, Q766Y6, Q766Y7, Q805D3, Q862B1, Q90Y63, Q91082, Q99JA0

Diamond homologs: P01189, P01190, P01191, P01192, P01193, P01194, P01196, P01197, P01201, P01202, P01203, P06297, P06298, P06299, P10000, P11280, P11885, P19402, P21252, P22923, P68000, P68001, P87352, Q04617, Q04618, Q91082, Q9YGK2, Q9YGK4, Q9YGK5, P01205

SIGNOR signaling

20 interactions.

A	Effect	B	Mechanism
POMC	up-regulates	MC5R	binding
USF1	“up-regulates quantity by expression”	POMC	“transcriptional regulation”
POMC	“up-regulates activity”	MC1R	binding
POMC	“down-regulates activity”	NFKB1
POMC	“up-regulates activity”	MC4R	binding
POMC	“up-regulates quantity by expression”	CDKN2A	“transcriptional regulation”
STAT3	“up-regulates quantity by expression”	POMC	“transcriptional regulation”
FOXO1	“down-regulates quantity by repression”	POMC	“transcriptional regulation”
CRHR1	“up-regulates quantity by expression”	POMC	“transcriptional regulation”
CREB1	“up-regulates quantity by expression”	POMC	“transcriptional regulation”
POMC	“up-regulates activity”	MC3R	binding
POMC	“up-regulates activity”	MC5R	binding
PRCP	“down-regulates activity”	POMC
LEPR	“up-regulates quantity”	POMC
POMC	“up-regulates activity”	OPRD1	“chemical activation”
POMC	“up-regulates activity”	OPRK1	“chemical activation”
POMC	“up-regulates activity”	MC2R	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

188 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	16
Likely pathogenic	3
Uncertain significance	114
Likely benign	36
Benign	8

Top pathogenic / likely-pathogenic (19)

Variant ID	HGVS	Classification
13353	NM_000939.4(POMC):c.313G>T (p.Glu105Ter)	Pathogenic
13354	NM_000939.4(POMC):c.433del (p.Arg145fs)	Pathogenic
13355	NM_000939.4(POMC):c.-11C>A	Pathogenic
13357	NM_000939.4(POMC):c.403_404dup (p.Lys136fs)	Pathogenic
13359	POMC, 1-BP DEL, NT6996	Pathogenic
1338533	NM_000939.4(POMC):c.34del (p.Leu12fs)	Pathogenic
208711	NM_001035256.2(POMC):c.20_21ins25	Pathogenic
2989528	NM_000939.4(POMC):c.48del (p.Leu16fs)	Pathogenic
3767318	NM_000939.4(POMC):c.132+1G>A	Pathogenic
436364	NM_000939.4(POMC):c.133-2A>C	Pathogenic
492966	POMC, 1-BP INS, 6922C	Pathogenic
520619	NM_000939.4(POMC):c.20_21insGGGCCCTCGGGGGCCCCTCGGGTGG (p.Ser7fs)	Pathogenic
596627	NM_000939.4(POMC):c.251G>A (p.Trp84Ter)	Pathogenic
596630	NM_000939.4(POMC):c.225del (p.Lys76fs)	Pathogenic
666581	NM_000939.4(POMC):c.416dup (p.Tyr139Ter)	Pathogenic
666582	NM_000939.4(POMC):c.84C>A (p.Cys28Ter)	Pathogenic
3355722	NM_000939.4(POMC):c.434G>T (p.Arg145Leu)	Likely pathogenic
4812832	NM_000939.4(POMC):c.214G>T (p.Glu72Ter)	Likely pathogenic
596628	NM_000939.4(POMC):c.55C>T (p.Gln19Ter)	Likely pathogenic

SpliceAI

724 predictions. Top by Δscore:

Variant	Effect	Δscore
2:25161748:CACTC:C	acceptor_gain	1.0000
2:25161750:CTC:C	acceptor_gain	1.0000
2:25161751:TCC:T	acceptor_loss	1.0000
2:25161753:C:CC	acceptor_gain	1.0000
2:25161753:CTGGG:C	acceptor_loss	1.0000
2:25161754:T:G	acceptor_loss	1.0000
2:25164637:GTACC:G	donor_loss	1.0000
2:25164638:TAC:T	donor_loss	1.0000
2:25164639:A:AC	donor_gain	1.0000
2:25164639:AC:A	donor_gain	1.0000
2:25164639:ACCAG:A	donor_gain	1.0000
2:25164640:C:CC	donor_gain	1.0000
2:25164640:CC:C	donor_gain	1.0000
2:25164640:CCA:C	donor_gain	1.0000
2:25164640:CCAG:C	donor_gain	1.0000
2:25164640:CCAGC:C	donor_gain	1.0000
2:25164654:T:A	donor_gain	1.0000
2:25168492:CCTTA:C	donor_loss	1.0000
2:25168493:CTTAC:C	donor_loss	1.0000
2:25168494:TTACC:T	donor_loss	1.0000
2:25168495:TAC:T	donor_loss	1.0000
2:25168497:CCTGT:C	donor_gain	1.0000
2:25161751:TC:T	acceptor_gain	0.9900
2:25161752:CC:C	acceptor_gain	0.9900
2:25164705:T:TA	donor_gain	0.9900
2:25164791:CT:C	acceptor_gain	0.9900
2:25164793:C:CC	acceptor_gain	0.9900
2:25167047:A:AC	donor_gain	0.9900
2:25167106:A:AC	donor_gain	0.9900
2:25167107:C:CC	donor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000129389 (2:25170543 G>C), RS1000176429 (2:25166753 T>C), RS1000208527 (2:25163351 G>C,T), RS1000224681 (2:25170142 T>G), RS1000414528 (2:25167730 C>A), RS1000466933 (2:25167487 C>T), RS1000943222 (2:25164977 G>A), RS1001135762 (2:25168966 T>C), RS1003570825 (2:25167203 C>G,T), RS1003715161 (2:25164216 T>G), RS1003798730 (2:25170441 GTTTTGTTTTTGT>G,GTTTTGT,GTTTTGTTTTTGTTTTTGT,GTTTTGTTTTTGTTTTTGTTTTTGT), RS1004195530 (2:25168470 G>T), RS1004248287 (2:25168143 A>C), RS1004431069 (2:25161967 C>G), RS1004458683 (2:25167605 C>G,T)

Disease associations

OMIM: gene MIM:176830 | disease phenotypes: MIM:609734, MIM:601665

GenCC curated gene-disease

Disease	Classification	Inheritance
inherited obesity	Strong	Semidominant
obesity due to pro-opiomelanocortin deficiency	Strong	Autosomal recessive

Mondo (3): obesity due to pro-opiomelanocortin deficiency (MONDO:0012335), obesity disorder (MONDO:0011122), inherited obesity (MONDO:0019182)

Orphanet (4): Obesity due to pro-opiomelanocortin deficiency (Orphanet:71526), Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), Genetic obesity (Orphanet:77828), NON RARE IN EUROPE: Non rare obesity (Orphanet:521399)

HPO phenotypes

31 total (30 of 31 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000823	Delayed puberty
HP:0000824	Decreased response to growth hormone stimulation test
HP:0000835	Adrenal hypoplasia
HP:0000842	Hyperinsulinemia
HP:0000846	Adrenal insufficiency
HP:0000956	Acanthosis nigricans
HP:0001010	Hypopigmentation of the skin
HP:0001396	Cholestasis
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001513	Obesity
HP:0002173	Hypoglycemic seizures
HP:0002297	Red hair
HP:0002591	Polyphagia
HP:0002750	Delayed skeletal maturation
HP:0002904	Hyperbilirubinemia
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0008163	Decreased circulating cortisol level
HP:0008213	Gonadotropin deficiency
HP:0008245	Pituitary hypothyroidism
HP:0008915	Childhood-onset truncal obesity
HP:0009126	Increased adipose tissue
HP:0010982	Polygenic inheritance
HP:0011734	Central adrenal insufficiency
HP:0011748	Adrenocorticotropic hormone deficiency
HP:0012340	Decreased resting energy expenditure
HP:0031819	Increased waist to hip ratio

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST000175_18	Height	8.000000e-07
GCST000830_38	Body mass index	6.000000e-22
GCST001255_1	Type 1 diabetes	4.000000e-09
GCST001876_3	Pubertal anthropometrics	1.000000e-08
GCST001953_30	Obesity	1.000000e-17
GCST001953_54	Obesity	3.000000e-14
GCST001956_23	Height	6.000000e-12
GCST001956_74	Height	1.000000e-13
GCST002021_4	Body mass index	5.000000e-08
GCST004131_107	Inflammatory bowel disease	3.000000e-07
GCST004132_38	Crohn’s disease	9.000000e-08
GCST005950_4	Body mass index x sex x age interaction (4df test)	5.000000e-26
GCST005951_195	Body mass index	3.000000e-24
GCST005952_4	Body mass index (age>50)	5.000000e-09
GCST005953_10	Body mass index (age <50)	6.000000e-20
GCST006986_9	Red vs. brown/black hair color	1.000000e-10
GCST008163_483	Height	1.000000e-06
GCST90020028_431	Hip circumference adjusted for BMI	2.000000e-12

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0001382	puberty
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0003924	hair color
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C565726	Proopiomelanocortin Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs934778	POMC		0.00	0

CTD chemical–gene interactions

62 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Hydrocortisone	decreases reaction, increases secretion, increases abundance, increases response to substance	6
Dexamethasone	decreases reaction, increases secretion, increases abundance, decreases expression, decreases secretion (+1 more)	5
Naloxone	affects binding, increases activity, increases expression, increases response to substance	3
Aldosterone	decreases reaction, increases abundance, decreases abundance	2
Clonidine	increases expression, increases response to substance	2
Melatonin	increases abundance, decreases response to substance, decreases reaction	2
Phenylephrine	increases response to substance	2
GSK-J4	decreases expression	1
bisphenol A	decreases methylation	1
aflatoxin B2	increases methylation	1
18-hydroxycortisol	increases abundance	1
epigallocatechin gallate	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
pomiferin	decreases expression	1
osajin	decreases expression	1
rosavin	decreases expression	1
bisphenol S	affects cotreatment, increases methylation	1
Fulvestrant	affects cotreatment, increases methylation	1
Fomepizole	decreases expression, decreases reaction	1
Acetaminophen	decreases expression	1
Ethanol	decreases expression, decreases reaction	1
Aspartame	increases expression	1
Hexachlorocyclohexane	affects cotreatment, increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Bromocriptine	increases expression	1
Buspirone	increases expression, decreases reaction	1
Carbamazepine	affects expression	1
Cocaine	increases secretion	1
Cyproheptadine	decreases secretion	1

Clinical trials (associated diseases)

310 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00076362	PHASE4	COMPLETED	Pediatric Hypothalamic Obesity
NCT00079547	PHASE4	COMPLETED	The Safety and Effectiveness of Low and High Carbohydrate Diets
NCT00115063	PHASE4	TERMINATED	LOSS- Louisiana Obese Subjects Study
NCT00134303	PHASE4	COMPLETED	Trial Comparing Metformin Versus Placebo in Non Alcoholic Steatohepatitis (NASH) Patients Receiving Bariatric Surgery for Obesity
NCT00143936	PHASE4	COMPLETED	The Safety and Efficacy of Low and High Carbohydrate Diets
NCT00143962	PHASE4	COMPLETED	Comparison of Two Approaches to Weight Loss Follow-Up Study
NCT00152360	PHASE4	COMPLETED	The Effect of Xenical on Weight and Risk Factors
NCT00176306	PHASE4	COMPLETED	Levofloxacin Pharmacokinetics (PK) in the Severely Obese
NCT00203450	PHASE4	COMPLETED	Zonegran for the Treatment of Weight Gain Associated With Psychotropic Medication Use: A Placebo-Controlled Trial
NCT00205504	PHASE4	COMPLETED	Oral Contraceptives in the Metabolic Syndrome
NCT00229229	PHASE4	TERMINATED	Comparison of 4 Diets in the Management of Overweight Patients With Vascular Disease
NCT00234988	PHASE4	COMPLETED	A Phase IV, Multi-Center, Open-Label Trial of Sibutramine in Combination With a Hypocaloric Diet in Obese and Overweight Thai Subjects.
NCT00264589	PHASE4	COMPLETED	Exercise Training and Cardiovascular Function in Obesity and in Type 2 Diabetes
NCT00288873	PHASE4	COMPLETED	Characterization of Hyperparathyroidism and Vitamin D Deficiency in Obesity
NCT00298857	PHASE4	TERMINATED	A Pharmacokinetic Study to Compare the Dosing of Valproic Acid in Subjects With Different Body Weights
NCT00315146	PHASE4	COMPLETED	Optimizing Body Composition for Function in Older Adults
NCT00319202	PHASE4	TERMINATED	Clinical Trial to Assess the Effects of Candesartan on the Carbohydrate Metabolism of Obese Subjects
NCT00327912	PHASE4	UNKNOWN	Laparoscopic Roux-en-Y Gastric Bypass Versus Laparoscopic Biliopancreatic Diversion (BPD)- Duodenal Switch for Superobesity
NCT00352287	PHASE4	COMPLETED	Study to Determine the Effects of Human Growth Hormone and Pioglitazone in Overweight, Prediabetic Adults
NCT00353054	PHASE4	COMPLETED	Effect of Calcium/Vitamin D Supplementation on Body Weight and Fat Loss.
NCT00390637	PHASE4	COMPLETED	Diet, Obesity and Genes (DiOGenes)
NCT00415688	PHASE4	COMPLETED	Lifestyle Modification for Obesity-Related Type 2 Diabetes
NCT00433641	PHASE4	COMPLETED	Weight Loss in Response to Sibutramine (MERIDIA) is Influenced by the Inherited Genes
NCT00440375	PHASE4	COMPLETED	Effects of Rosiglitazone on Bone in Postmenopausal Diabetic Women
NCT00453557	PHASE4	COMPLETED	Mechanism of Growth Hormone Effects on Adipose Tissue
NCT00456885	PHASE4	COMPLETED	The Effect of Exenatide on Weight and Hunger in Obese, Healthy Women
NCT00463112	PHASE4	COMPLETED	Effect of Diet Plus Sibutramine on Hormonal and Metabolic Features in Overweight and Obese Women With PCOS
NCT00512187	PHASE4	COMPLETED	Moderate Weight Loss Makes Obese Patients With Severe Chronic Plaque Psoriasis Responsive to Sub-Optimal Dose of Cyclosporine: an Investigator Blinded, Controlled, Randomized Clinical Trial
NCT00516919	PHASE4	COMPLETED	Study of Behavioral Weight Loss Therapy for Obesity and Binge Eating in Monolingual Hispanic Persons
NCT00522470	PHASE4	COMPLETED	Effects of Rosiglitazone on Serum Ghrelin and Peptide YY Levels
NCT00537810	PHASE4	COMPLETED	Treatment of Binge Eating in Obese Patients in Primary Care
NCT00538486	PHASE4	COMPLETED	A Randomized, Double-Blind, Active Control Trial Comparing Effects of Telmisartan, Candesartan and Amlodipine, Alone or Plus Metformin, on Non-Diabetic, Obese Hypertensive Patients
NCT00584389	PHASE4	TERMINATED	The Effect of Rimonabant on Energy Expenditure, Fat Metabolism and Body Composition
NCT00585182	PHASE4	COMPLETED	Study to Evaluate Weight-based Enoxaparin Dosing in Obese Medical Patients at Risk for DVT
NCT00632840	PHASE4	COMPLETED	Pharmacological Regulation of Fat Transport in Metabolic Syndrome
NCT00636142	PHASE4	COMPLETED	Effects of Infliximab on Insulin Sensitivity and Beta Cell Function in Insulin Resistant Human Obesity
NCT00675987	PHASE4	COMPLETED	A Randomized Clinical Trial To Study Losartan On Endothelial Dysfunction and Insulin Resistance In Obese Patients
NCT00694811	PHASE4	COMPLETED	Effects of Re-Feeding Duration on Weight Maintenance After Weight Loss With Very-Low-Energy Diets (VLEDs)
NCT00699413	PHASE4	TERMINATED	Supplements for Controlling Resistance to Insulin
NCT00729963	PHASE4	COMPLETED	Sibutramine Versus Continuous Positive Airway Pressure (CPAP)in Obstructive Sleep Apnea (OSA) Patients