AGRP

Summary

AGRP (agouti related neuropeptide, HGNC:330) is a protein-coding gene on chromosome 16q22.1, encoding Agouti-related protein (O00253). Signaling protein that functions as an antagonist of melanocyte-stimulating-hormone receptors MC3R and MC4R by precluding agonist-induced signaling, thereby inhibiting cAMP production within the hypothalamus and adrenal gland.

This gene encodes an antagonist of the melanocortin-3 and melanocortin-4 receptor. It appears to regulate hypothalamic control of feeding behavior via melanocortin receptor and/or intracellular calcium regulation, and thus plays a role in weight homeostasis. Mutations in this gene have been associated with late on-set obesity.

Source: NCBI Gene 181 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 25 total — 1 pathogenic
• Phenotypes (HPO): 6
• MANE Select transcript: NM_001138

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:330
Approved symbol	AGRP
Name	agouti related neuropeptide
Location	16q22.1
Locus type	gene with protein product
Status	Approved
Aliases	Agrt, ART, ASIP2
Ensembl gene	ENSG00000159723
Ensembl biotype	protein_coding
OMIM	602311
Entrez	181

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000290953, ENST00000968437, ENST00000968438

RefSeq mRNA: 1 — MANE Select: NM_001138 NM_001138

CCDS: CCDS10839

Canonical transcript exons

ENST00000290953 — 4 exons

Exon	Start	End
ENSE00001047346	67483517	67483547
ENSE00001047348	67483269	67483401
ENSE00001047349	67483025	67483110
ENSE00001884910	67482571	67482818

Expression profiles

Bgee: expression breadth ubiquitous, 148 present calls, max score 84.49.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0654 / max 57.3512, expressed in 10 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
157790	0.0654	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left adrenal gland	UBERON:0001234	84.49	gold quality
left adrenal gland cortex	UBERON:0035825	83.89	gold quality
right adrenal gland	UBERON:0001233	81.42	gold quality
right adrenal gland cortex	UBERON:0035827	81.27	gold quality
adrenal cortex	UBERON:0001235	80.67	gold quality
adrenal gland	UBERON:0002369	80.32	gold quality
adrenal tissue	UBERON:0018303	79.31	gold quality
corpus epididymis	UBERON:0004359	73.50	gold quality
cauda epididymis	UBERON:0004360	71.98	silver quality
right lung	UBERON:0002167	71.40	gold quality
caput epididymis	UBERON:0004358	70.88	gold quality
upper lobe of left lung	UBERON:0008952	69.39	gold quality
upper lobe of lung	UBERON:0008948	66.75	gold quality
monocyte	CL:0000576	65.40	gold quality
mononuclear cell	CL:0000842	65.25	gold quality
leukocyte	CL:0000738	64.83	gold quality
hypothalamus	UBERON:0001898	62.96	gold quality
granulocyte	CL:0000094	61.12	gold quality
tibialis anterior	UBERON:0001385	60.20	silver quality
C1 segment of cervical spinal cord	UBERON:0006469	58.74	gold quality
spinal cord	UBERON:0002240	57.05	gold quality
lung	UBERON:0002048	56.54	gold quality
spleen	UBERON:0002106	56.43	gold quality
ileal mucosa	UBERON:0000331	56.08	silver quality
nucleus accumbens	UBERON:0001882	54.67	gold quality
adult mammalian kidney	UBERON:0000082	54.60	gold quality
pituitary gland	UBERON:0000007	54.34	gold quality
adenohypophysis	UBERON:0002196	54.29	gold quality
deltoid	UBERON:0001476	54.10	gold quality
cerebellar hemisphere	UBERON:0002245	53.89	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.22

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF3, BSX, FOXO1, KLF4, RORA, STAT3

Literature-anchored findings (GeneRIF, showing 39)

• The high expressing C/C genotype of AGRP was significantly associated with high BMI and type 2 diabetes in Africans. (PMID:11554767)
• A polymorphism, 199G>A, resulted in substitution of the amino acid at position 67 from alanine to threonine. (PMID:11602360)
• NMR structural studies show that the loop in the first 16 residues of the C-terminal domain of AGRP confers distinct selectivity for melanocortin receptors MC3R and MC4R. (PMID:11747427)
• the c.199G–>A polymorphism in hAGRP could play a role in the development of human obesity in an age-dependent fashion (PMID:12213871)
• Ala67Thr polymorphism in the Agouti-related peptide gene is associated with inherited leanness in humans (PMID:15054840)
• Two single nucleotide polymorphisms in the AGRP promotor showed opposite effects on promotor activity. (PMID:15121772)
• Serum levels could serve as useful peripheral markers of changes in energy homeostasis. (PMID:15546902)
• the C-terminus of AgRP can participate in the insulin secretion in pancreatic beta cells, through the modulation of calcium release (PMID:15978665)
• Single-nucleotide polymorphisms found in anorexia nervosa. (PMID:16314751)
• AgRP may have a novel inhibitory paracrine role in the human adrenal gland (PMID:16320160)
• analysis of molecular basis of melanocortin-4 receptor for AGRP inverse agonism (PMID:16820227)
• Plasma Agouti-related protein (AGRP)elevation may be related to energy homeostasis disturbance in anorexia nervosa, and in addition to leptin, peripheral AGRP levels could be used as a nutritional marker in AN patients. (PMID:16904835)
• in addition to its inverse agonistic activities, Agrp exhibits agonistic properties on the endocytosis pathway of melanocortin-3 and -4 receptors (PMID:17041250)
• a rare mutation, +79G>A, was identified in the AGRP minimal promoter; the +79G>A mutation could predispose to body weight gain (PMID:17180153)
• two adjacent enhancers inside the first intron of the neighboring (1.4 kb downstream) ATPase gene (ATP6V0D1) modulate the human AgRP promoter with profound spatiotemporal variation (PMID:19285986)
• This study presents an association of rare allele of AGRP polymorphism in heterozygous state with increased body mass index (PMID:19602223)
• This review defines how peripheral signals (particularly leptin, insulin and glucose) converge on a molecular level in proopiomelanocortin (POMC)- and agouti-related protein (AgRP)-expressing arcuate nucleus neurons to control energy homeostasis. (PMID:19770186)
• Agouti-related protein is neatively correlated with nonalcolic fatty liver disease in obese adolescents. (PMID:19942238)
• Only the patients with nonalcoholic fatty liver presented a positive correlation between the saturated fatty acids intake and the orexigenic neuropeptides NPY and agouti related protein, and carbohydrate with NPY (PMID:20164781)
• AgRP may provide an important signal in the immune environment and the lymphocyte may be considered as an extra-hypothalamic source of plasma AgRP following exercise stress (PMID:20404050)
• Cognitive flexibility plays an important role in anorexia nervosa and may be modulated by abnormal levels of the appetite-regulating peptide AGRP. (PMID:21531082)
• Data suggest that prolonged steady-state exercise/physical activity at moderate intensity elicits substantial increases in blood lactate and cortisol concentrations without a significant change in AgRP; study was pilot project involving men. (PMID:22477065)
• AgRP and NPY are correlated with body weight changes, rather than the presence of type 2 diabetes, whereas changes in alphaMSH immunoreactivity are related to the presence of type 2 diabetes, indicating separate hypothalamic mechanisms. (PMID:22492775)
• Despite peripheral hyperleptinemia, positive energy balance is achieved during pregnancy by a relative decrease in central leptin concentrations and resistance to leptin’s effects on target neuropeptides that regulate energy balance. (PMID:23118421)
• Variations in genes AGRP, CPE, GHRL, GLP1R, HTR2A, NPY1R, NPY5R, SOCS3 and STAT3 showed modest associations with BMI in European Americans. (PMID:23900445)
• AGRP SNP (rs1338993) was not associated with antipsychotic-induced weight gain in schizophrenia patients. (PMID:24564533)
• Elevations in AgRP also favor the diagnosis of ectopic ACTH syndrome, suggesting AgRP should be further evaluated as a potential neuroendocrine tumor marker. (PMID:25013995)
• human agouti-related protein has a role in enhancing expression and stability of human melanocortin-4 receptor (PMID:25446108)
• CSF AgRP was not different in lean vs. overweight/obese subjects; however, plasma AgRP was higher in lean subjects. (PMID:26152765)
• The aim of this survey is to evaluate the association of genetic variants of melanocortin-4-receptor (MC4R), pro-opiomelanocortin (POMC), apolipoprotein E (APOE) and agouti-related protein (AGRP) with obesity in the North Indian population. (PMID:26226973)
• AgRP acted as a biased agonist in MC3R, decreasing cAMP activity of constitutively active mutant (F347A) MC3R but stimulating ERK1/2 activation in both wild type and F347A MC3Rs. (PMID:27208795)
• AgRP is not associated with changes in hunger or satiety, and can change without corresponding changes in leptin. This suggests that AgRP may not be involved in the episodic control of appetite and the release of AgRP may involve signals other than leptin. (PMID:27476955)
• data provide compelling evidence that AgRP is a heparan sulfate-binding protein and localizes critical regions in the AgRP structure required for this interaction. (PMID:28264929)
• Plasma agouti-related protein (AgRP) level is elevated in Cushing disease, tightly correlates with cortisol concentration, and decline with surgical cure. These data support the regulation of AgRP by glucocorticoids in humans. (PMID:30597030)
• The plasma AgRP levels were higher in those with active acromegaly than in the matched healthy subjects, and decreased after treatment with pegvisomant or with surgery. (PMID:31361303)
• Mitochondrial Dynamics and Microglia as New Targets in Metabolism Regulation. (PMID:32414136)
• Discovery of Molecular Interactions of the Human Melanocortin-4 Receptor (hMC4R) Asp189 (D189) Amino Acid with the Endogenous G-Protein-Coupled Receptor (GPCR) Antagonist Agouti-Related Protein (AGRP) Provides Insights to AGRP’s Inverse Agonist Pharmacology at the hMC4R. (PMID:33470098)
• AgRP neurons coordinate the mitigation of activity-based anorexia. (PMID:36577844)
• Nuclear receptor 5A2 regulation of Agrp underlies olanzapine-induced hyperphagia. (PMID:36765131)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	agrp	ENSDARG00000069089
mus_musculus	Agrp	ENSMUSG00000005705
rattus_norvegicus	Agrp	ENSRNOG00000039001

Paralogs (1): ASIP (ENSG00000101440)

Protein

Protein identifiers

Agouti-related protein — O00253 (reviewed: O00253)

All UniProt accessions (2): O00253, C6SUN5

UniProt curated annotations — full annotation on UniProt →

Function. Signaling protein that functions as an antagonist of melanocyte-stimulating-hormone receptors MC3R and MC4R by precluding agonist-induced signaling, thereby inhibiting cAMP production within the hypothalamus and adrenal gland. Involved in the control of feeding behavior via the central melanocortin system. Has very low activity towards MC5R. Also promotes endocytosis of MC3R and MC4R in an arrestin-dependent mechanism.

Subunit / interactions. Interacts with melanocortin receptors MC3R, MC4R and MC5R.

Subcellular location. Secreted. Golgi apparatus lumen.

Tissue specificity. Expressed primarily in the adrenal gland, subthalamic nucleus, and hypothalamus, with a lower level of expression occurring in testis, lung, and kidney.

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 is associated with variants affecting the gene represented in this entry.

Domain organisation. The presence of a ‘disulfide through disulfide knot’ structurally defines this protein as a knottin.

RefSeq proteins (1): NP_001129* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007733	Agouti	Family
IPR027300	Agouti_dom	Domain
IPR036836	Agouti_dom_sf	Homologous_superfamily

Pfam: PF05039

UniProt features (22 total): disulfide bond 5, strand 5, mutagenesis site 4, signal peptide 1, propeptide 1, sequence variant 1, sequence conflict 1, chain 1, domain 1, region of interest 1, site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1HYK	SOLUTION NMR
1MR0	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00253-F1	69.91	0.23

Functional residue map

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

Catalytic / active sites (1): 82–83 (cleavage; by pcsk1)

Disulfide bonds (5): 110–117, 87–102, 94–108, 101–119, 105–129

Mutagenesis-validated functional residues (4):

Position	Phenotype
79–82	cleavage is blocked.
85–86	no effect on cleavage.
86–89	no effect on cleavage.
111	abolishes inhibition of camp production in response to melanocortin receptor stimulation.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-9615017	FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes
R-HSA-212436	Generic Transcription Pathway
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-9614085	FOXO-mediated transcription

MSigDB gene sets: 139 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_CIRCADIAN_RHYTHM, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_BEHAVIOR, KEGG_ADIPOCYTOKINE_SIGNALING_PATHWAY, chr16q22, GGGNRMNNYCAT_UNKNOWN, GOBP_PHOTOPERIODISM, GOBP_ADULT_BEHAVIOR, MODULE_64, GOBP_POSITIVE_REGULATION_OF_BEHAVIOR, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOBP_HORMONE_MEDIATED_SIGNALING_PATHWAY, YGACNNYACAR_UNKNOWN, GOBP_REGULATION_OF_BEHAVIOR

GO Biological Process (13): neuropeptide signaling pathway (GO:0007218), circadian rhythm (GO:0007623), feeding behavior (GO:0007631), adult feeding behavior (GO:0008343), hormone-mediated signaling pathway (GO:0009755), response to insulin (GO:0032868), eating behavior (GO:0042755), long-day photoperiodism (GO:0048571), maternal process involved in female pregnancy (GO:0060135), regulation of feeding behavior (GO:0060259), negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0106072), positive regulation of eating behavior (GO:1904000), positive regulation of feeding behavior (GO:2000253)

GO Molecular Function (4): signaling receptor binding (GO:0005102), neuropeptide hormone activity (GO:0005184), receptor antagonist activity (GO:0048019), type 1 melanocortin receptor binding (GO:0070996)

GO Cellular Component (5): obsolete extracellular space (GO:0005615), Golgi lumen (GO:0005796), neuronal cell body (GO:0043025), extracellular region (GO:0005576), Golgi apparatus (GO:0005794)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
FOXO-mediated transcription	1
RNA Polymerase II Transcription	1
Gene expression (Transcription)	1
Generic Transcription Pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
feeding behavior	4
G protein-coupled receptor signaling pathway	1
rhythmic process	1
behavior	1
adult behavior	1
signal transduction	1
cellular response to hormone stimulus	1
response to peptide hormone	1
photoperiodism	1
female pregnancy	1
multicellular organismal reproductive process	1
regulation of behavior	1
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1
negative regulation of G protein-coupled receptor signaling pathway	1
regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway	1
eating behavior	1
regulation of eating behavior	1
positive regulation of feeding behavior	1
positive regulation of behavior	1
regulation of feeding behavior	1
protein binding	1
hormone activity	1
neuropeptide activity	1
signaling receptor binding	1
signaling receptor inhibitor activity	1
melanocortin receptor binding	1
Golgi apparatus	1
intracellular organelle lumen	1
somatodendritic compartment	1
cell body	1
cellular anatomical structure	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1268 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AGRP	MC4R	P32245	997
AGRP	MC3R	P41968	996
AGRP	POMC	P01189	978
AGRP	GHRL	Q9UBU3	977
AGRP	NPY	P01303	976
AGRP	LEP	P41159	975
AGRP	INS	P01308	932
AGRP	CARTPT	Q16568	882
AGRP	LEPR	P48357	881
AGRP	HCRT	O43612	877
AGRP	PMCH	P20382	850
AGRP	PYY	P10082	840
AGRP	ASIP	P42127	825
AGRP	GHSR	Q92847	814
AGRP	CRH	P06850	804

IntAct

5 interactions, top by confidence:

A	B	Type	Score
AGRP	TK1	psi-mi:“MI:0914”(association)	0.640
ERAP1	AGRP	psi-mi:“MI:0914”(association)	0.350

BioGRID (18): ASB7 (Affinity Capture-MS), TK1 (Affinity Capture-MS), BIRC6 (Affinity Capture-MS), GRN (Affinity Capture-MS), NHLRC3 (Affinity Capture-MS), NOTCH2 (Affinity Capture-MS), KCTD10 (Affinity Capture-MS), FBLN1 (Affinity Capture-MS), MC4R (Reconstituted Complex), NHLRC3 (Affinity Capture-MS), BIRC6 (Affinity Capture-MS), ASB7 (Affinity Capture-MS), NOTCH2 (Affinity Capture-MS), ZER1 (Affinity Capture-MS), TK1 (Affinity Capture-MS)

ESM2 similar proteins: B2RZ42, E9PY61, F8W2C9, J3QPP8, O00253, O02695, O77559, O95157, P01311, P01313, P01322, P01323, P01325, P06306, P15473, P17936, P20959, P21743, P24591, P47876, P47878, P49192, P55107, P55108, P56388, P56722, P97737, Q08DX6, Q16568, Q16849, Q4RU86, Q58CS8, Q60673, Q62587, Q62865, Q68RJ9, Q6PRD1, Q6Q484, Q6S5C2, Q6UX46

Diamond homologs: A1YL66, A1YL67, A1YL68, A1YL69, A1YL70, A1YL72, A1YL74, A1YL77, A1YL78, A1YL79, A1YL80, A1YL81, A1YL82, A8CEM0, A8CEM1, A8CEM4, A8CEM5, A8CEM7, A8CEM8, A8CEM9, A8CEN1, A8CEN3, O00253, P42127, P56413, P56473, P79407, Q03288, Q1XGU5, Q1XGU6, Q1XGU7, Q1XGU8, Q1XGU9, Q1XGV0, Q1XGV1, Q1XGV2, Q1XGV3, Q1XGV4, Q1XGV5, Q1XGV6

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
AGRP	“down-regulates activity”	MC4R	binding
AGRP	“down-regulates activity”	MC3R	binding
FOXO1	“up-regulates quantity by expression”	AGRP	“transcriptional regulation”
AGRP	“down-regulates activity”	MC2R	binding
AGRP	“down-regulates activity”	MC1R	binding
AGRP	“down-regulates activity”	MC5R	binding
AGRP	down-regulates	MC3R	binding
AGRP	down-regulates	MC4R	binding
LEPR	“down-regulates quantity”	AGRP

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	18
Likely benign	1
Benign	3

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
625609	GRCh37/hg19 16q22.1(chr16:67132790-68166320)	Pathogenic

SpliceAI

392 predictions. Top by Δscore:

Variant	Effect	Δscore
16:67483024:CCT:C	donor_gain	0.9900
16:67483164:C:T	acceptor_gain	0.9900
16:67483175:T:TC	acceptor_gain	0.9900
16:67483262:CA:C	donor_gain	0.9900
16:67482816:TACC:T	acceptor_loss	0.9800
16:67482819:CTGCA:C	acceptor_loss	0.9800
16:67482820:T:A	acceptor_loss	0.9800
16:67483020:GTTA:G	donor_loss	0.9800
16:67483021:TTACC:T	donor_loss	0.9800
16:67483022:TAC:T	donor_loss	0.9800
16:67483023:ACCTC:A	donor_loss	0.9800
16:67483024:CC:C	donor_loss	0.9800
16:67483044:T:TA	donor_gain	0.9800
16:67483175:T:C	acceptor_gain	0.9800
16:67483265:TGA:T	donor_loss	0.9800
16:67483266:GA:G	donor_loss	0.9800
16:67483268:C:G	donor_loss	0.9800
16:67483106:CAGGC:C	acceptor_gain	0.9700
16:67483109:GCC:G	acceptor_loss	0.9700
16:67483112:T:A	acceptor_loss	0.9700
16:67483111:C:CC	acceptor_gain	0.9600
16:67483409:A:T	acceptor_gain	0.9600
16:67483164:C:CT	acceptor_gain	0.9500
16:67483108:GGC:G	acceptor_gain	0.9400
16:67483011:C:A	donor_gain	0.9300
16:67483107:AGGC:A	acceptor_gain	0.9300
16:67483161:TCCCA:T	acceptor_gain	0.9300
16:67483165:A:T	acceptor_gain	0.9300
16:67483267:A:AC	donor_gain	0.9300
16:67483268:C:CC	donor_gain	0.9300

AlphaMissense

832 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:67482696:G:C	F113L	0.996
16:67482696:G:T	F113L	0.996
16:67482697:A:C	F113C	0.996
16:67482698:A:G	F113L	0.996
16:67482698:A:T	F113I	0.995
16:67482700:A:C	F112C	0.995
16:67482685:C:T	C117Y	0.991
16:67482698:A:C	F113V	0.991
16:67482704:G:T	R111S	0.991
16:67482706:C:T	C110Y	0.991
16:67482754:C:G	C94S	0.991
16:67482755:A:T	C94S	0.991
16:67482677:G:T	R120S	0.990
16:67482685:C:G	C117S	0.990
16:67482686:A:T	C117S	0.990
16:67482684:G:C	C117W	0.989
16:67482699:G:C	F112L	0.989
16:67482699:G:T	F112L	0.989
16:67482700:A:G	F112S	0.989
16:67482701:A:G	F112L	0.989
16:67482676:C:G	R120P	0.988
16:67482703:C:G	R111P	0.988
16:67482706:C:G	C110S	0.988
16:67482707:A:T	C110S	0.988
16:67482754:C:T	C94Y	0.988
16:67482685:C:A	C117F	0.987
16:67482686:A:G	C117R	0.987
16:67482755:A:G	C94R	0.987
16:67482679:C:G	C119S	0.986
16:67482680:A:T	C119S	0.986

dbSNP variants (sampled 300 via entrez): RS1000799819 (16:67484502 A>G), RS1001189708 (16:67484943 CA>C), RS1001766410 (16:67482477 A>C), RS1002582805 (16:67484037 G>T), RS1003169484 (16:67483698 C>A,T), RS1004434970 (16:67483649 G>A), RS1004700425 (16:67482309 A>G), RS1006450278 (16:67482933 G>A), RS1007731209 (16:67483606 C>T), RS1008037744 (16:67484979 T>G), RS1008109751 (16:67485241 C>A,T), RS1008956628 (16:67484992 G>A), RS1009183542 (16:67485270 C>G), RS1009185197 (16:67484334 G>A), RS1009672011 (16:67484474 G>C)

Disease associations

OMIM: gene MIM:602311 | disease phenotypes: MIM:601665

GenCC curated gene-disease

Mondo (1): inherited obesity (MONDO:0019182)

Orphanet (1): Genetic obesity (Orphanet:77828)

HPO phenotypes

6 total (6 of 6 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0001513	Obesity
HP:0010982	Polygenic inheritance
HP:0012340	Decreased resting energy expenditure
HP:0031819	Increased waist to hip ratio

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST006585_1321	Blood protein levels	2.000000e-18
GCST010002_113	Refractive error	2.000000e-14
GCST90002390_93	Mean corpuscular hemoglobin	8.000000e-14
GCST90002392_508	Mean corpuscular volume	8.000000e-15
GCST90002396_592	Mean reticulocyte volume	2.000000e-19
GCST90002397_244	Mean spheric corpuscular volume	1.000000e-19

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004527	mean corpuscular hemoglobin
EFO:0010701	mean reticulocyte volume

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Rosiglitazone	increases expression	1
Allergens	decreases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases expression	1
Cadmium	increases abundance, increases expression	1
Camptothecin	decreases response to substance	1
Dimethyl Sulfoxide	affects expression	1
Cadmium Chloride	increases abundance, increases expression	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05093634	PHASE3	ACTIVE_NOT_RECRUITING	EMANATE: A Study of Setmelanotide in Patients With Specific Gene Variants in the MC4R Pathway
NCT07220772	PHASE3	RECRUITING	A Study Evaluating Mibavademab Treatment of Obesity Due to Leptin (LEP) Gene Mutations in Children, Adolescents and Adults
NCT03013543	PHASE2	COMPLETED	Setmelanotide Phase 2 Treatment Trial in Participants With Rare Genetic Disorders of Obesity
NCT04963231	PHASE2	COMPLETED	DAYBREAK: A Study of Setmelanotide in Participants With Specific Gene Variants in the Melanocortin-4 Receptor (MC4R) Pathway
NCT04710056	Not specified	AVAILABLE	Expanded Access to REGN4461 for Patients With Diseases Associated With Deficient Leptin Signaling
NCT05362565	Not specified	UNKNOWN	Genetic Research of Monogenic Obesity in a Pediatric Cohort With Severe and Early Onset Obesity
NCT06113523	Not specified	UNKNOWN	Genetic Research of Monogenic Obesity in a Pediatric Cohort With Severe and Early Onset Obesity (GENOBE)
NCT06380426	Not specified	RECRUITING	Real-life Evaluation of WEGOVY (Semaglutide) Treatment in Adults With Monogenic Obesity (ObGeSema)
NCT07296900	Not specified	RECRUITING	International Genetic Obesity Registry
NCT07302802	Not specified	RECRUITING	Efficacy of Semaglutide s.c. Once-weekly on Weight Loss and Management in Adolescents With Monogenic Obesity in Clinical Practice