MRAP2

Summary

MRAP2 (melanocortin 2 receptor accessory protein 2, HGNC:21232) is a protein-coding gene on chromosome 6q14.2, encoding Melanocortin-2 receptor accessory protein 2 (Q96G30). Modulator of melanocortin receptor 4 (MC4R), a receptor involved in energy homeostasis.

This gene encodes a protein that modulates melanocortin receptor signaling. The encoded protein has been shown to interact with all known melanocortin receptors and may regulate both receptor trafficking and activation in response to ligands. Mice lacking a functional copy of this gene exhibit severe obesity and a mutation in this gene may be associated with severe obesity in human patients.

Source: NCBI Gene 112609 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 109 total
• Phenotypes (HPO): 2
• MANE Select transcript: NM_138409

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21232
Approved symbol	MRAP2
Name	melanocortin 2 receptor accessory protein 2
Location	6q14.2
Locus type	gene with protein product
Status	Approved
Aliases	bA51G5.2
Ensembl gene	ENSG00000135324
Ensembl biotype	protein_coding
OMIM	615410
Entrez	112609

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 12 protein_coding

ENST00000257776, ENST00000855322, ENST00000855323, ENST00000855324, ENST00000855325, ENST00000855326, ENST00000855327, ENST00000930238, ENST00000930239, ENST00000930240, ENST00000968914, ENST00000968915

RefSeq mRNA: 5 — MANE Select: NM_138409 NM_001346541, NM_001346542, NM_001346543, NM_001346544, NM_138409

CCDS: CCDS5001

Canonical transcript exons

ENST00000257776 — 4 exons

Exon	Start	End
ENSE00000918626	84055312	84055445
ENSE00000918627	84062893	84062992
ENSE00000974754	84033772	84033883
ENSE00001012782	84089091	84090881

Expression profiles

Bgee: expression breadth ubiquitous, 203 present calls, max score 97.88.

FANTOM5 (CAGE): breadth broad, TPM avg 2.1211 / max 98.2626, expressed in 540 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
68788	1.6645	452
68787	0.3986	211
68786	0.0580	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	97.88	gold quality
descending thoracic aorta	UBERON:0002345	97.58	gold quality
thoracic aorta	UBERON:0001515	96.64	gold quality
ascending aorta	UBERON:0001496	96.53	gold quality
pancreatic ductal cell	CL:0002079	93.94	silver quality
aorta	UBERON:0000947	93.36	gold quality
endothelial cell	CL:0000115	92.38	gold quality
popliteal artery	UBERON:0002250	90.93	gold quality
tibial artery	UBERON:0007610	90.90	gold quality
right coronary artery	UBERON:0001625	90.62	gold quality
middle temporal gyrus	UBERON:0002771	89.95	gold quality
nasal cavity epithelium	UBERON:0005384	88.37	gold quality
islet of Langerhans	UBERON:0000006	88.36	gold quality
Brodmann (1909) area 23	UBERON:0013554	87.18	gold quality
prefrontal cortex	UBERON:0000451	86.74	gold quality
superior frontal gyrus	UBERON:0002661	86.22	gold quality
coronary artery	UBERON:0001621	85.94	gold quality
left coronary artery	UBERON:0001626	85.93	gold quality
cerebellar vermis	UBERON:0004720	85.73	gold quality
cartilage tissue	UBERON:0002418	85.59	gold quality
epithelium of nasopharynx	UBERON:0001951	85.23	gold quality
epithelial cell of pancreas	CL:0000083	85.19	silver quality
frontal cortex	UBERON:0001870	85.04	gold quality
ileal mucosa	UBERON:0000331	84.81	gold quality
Brodmann (1909) area 9	UBERON:0013540	84.33	gold quality
Brodmann (1909) area 46	UBERON:0006483	84.29	gold quality
oviduct epithelium	UBERON:0004804	84.25	gold quality
primary visual cortex	UBERON:0002436	84.14	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	83.99	gold quality
dorsal root ganglion	UBERON:0000044	83.71	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-81608	yes	4.88
E-ANND-3	no	3.30

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

66 targeting MRAP2, 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-8485	100.00	77.57	4731
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-187-5P	99.74	70.26	1404
HSA-MIR-1296-3P	99.72	64.04	636
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-452-5P	99.65	69.63	1762
HSA-MIR-4676-3P	99.65	69.31	1733
HSA-MIR-892C-3P	99.65	69.38	1745
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-4756-3P	99.62	66.30	1319
HSA-MIR-548AV-5P	99.60	70.84	2107
HSA-MIR-548K	99.60	70.84	2107
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-451B	99.55	68.28	1380

Literature-anchored findings (GeneRIF, showing 17)

• identify MRAP and MRAP2 as unique bidirectional regulators of the melanocortin receptor family (PMID:19329486)
• MRAP2 is an endogenous inhibitor that competes with MRAP for binding to MC2R and decreases the potency of adrenocorticotropic hormone (ACTH). (PMID:20371771)
• The MC2R/MRAP2 complex requires much higher concentrations of ACTH to activate compared with the MC2R/MRAP complex. (PMID:21367968)
• MRAP2 is positively regulated by ACTH and AngII in human adrenocortical tissues. (PMID:22419722)
• Data suggest that MRAP2 regulates expression of melanocortin receptors (MC1R-MC5R); MRAP2 is highly expressed in fetal adrenal glands; MRAP2 is also expressed in hypothalamus, a site that expresses high levels of MC3R and MC4R. [REVIEW] (PMID:23418361)
• In a study of humans with severe, early-onset obesity, they found four rare, potentially pathogenic genetic variants in MRAP2, suggesting that the gene may also contribute to body weight regulation in humans. (PMID:23869016)
• MC3R is a 2-exon gene that requires a 5’ UTR for translation, localization, and potential interaction with MRAP2 (PMID:25051171)
• Data show that co-expression with MRAPalpha, but not MRAP2, enhances MC4R constitutive activity. MRAPalpha-enhanced MC4R constitutive activity is not dependent on MC4R complex glycosylation but may result from MRAPalpha-induced changes in MC4R conformational states. (PMID:26469516)
• no gene harboring deletions were identified in the SIM1 and MRAP2 regions in the Prader Willi like (PWL) cohort; further functional analysis of p.P352S found in SIM1 and p.A40S found in MRAP2 is useful; this would provide further support for possible role of SIM1 and MRAP2 in the pathogenesis of the PWL phenotype in a limited number of patients (PMID:26795956)
• This was the first study describing an effect of a MRAP2 mutation on mediated by regulation of the melanocortin-4 receptor FUNCTION IN HUMAN. (PMID:27474872)
• The accepted idea that melanocortin Receptor Accessory Proteins (MRAPs) are specific regulators of melanocortin receptors was recently challenged by the discovery that MRAP2 inhibits the activity of prokineticin receptors. Recent studies are starting to explain the role of the unusual structure of MRAPs and to illustrate the importance of MRAP2 for the maintenance of both energy and glucose homeostasis. [review] (PMID:28499989)
• In this study we demonstrate a new role of MRAP2 in the regulation of the orexin receptor 1 (OX1R) and identify the specific regions of MRAP2 required for the regulation of OX1R and PKR1. Importantly, like MC4R and PKRs, OX1R is predominately expressed in the brain where it regulates food intake (PMID:28939058)
• Data found that MRAP2 was significantly up-regulated in women with unexplained infertility. The epithelium of the uterine glands showed hypertrophy in women with unexplained infertility. MRAP2 expression alteration in the endometrium on infertile women suggestes a potential role in regulating endometrial stability. (PMID:30951854)
• The pleiotropic metabolic effect of loss-of-function mutations in MRAP2 might be due to the failure of different MRAP2-regulated G-protein-coupled receptors in various tissues including pancreatic islets. (PMID:31700171)
• The GPCR accessory protein MRAP2 regulates both biased signaling and constitutive activity of the ghrelin receptor GHSR1a. (PMID:31911434)
• Study of LEP, MRAP2 and POMC genes as potential causes of severe obesity in Brazilian patients. (PMID:32578125)
• Membrane orientation and oligomerization of the melanocortin receptor accessory protein 2. (PMID:32943551)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	mrap2a	ENSDARG00000074763
mus_musculus	Mrap2	ENSMUSG00000042761
rattus_norvegicus	Mrap2	ENSRNOG00000010545

Protein

Protein identifiers

Melanocortin-2 receptor accessory protein 2 — Q96G30 (reviewed: Q96G30)

All UniProt accessions (1): Q96G30

UniProt curated annotations — full annotation on UniProt →

Function. Modulator of melanocortin receptor 4 (MC4R), a receptor involved in energy homeostasis. Plays a central role in the control of energy homeostasis and body weight regulation by increasing ligand-sensitivity of MC4R and MC4R-mediated generation of cAMP. May also act as a negative regulator of MC2R: competes with MRAP for binding to MC2R and impairs the binding of corticotropin (ACTH) to MC2R. May also regulate activity of other melanocortin receptors (MC1R, MC3R and MC5R); however, additional evidence is required in vivo.

Subunit / interactions. Homodimer and heterodimer. Forms antiparallel homodimers and heterodimers with MRAP. Interacts with MC1R, MC2R, MC3R, MC4R and MC5R.

Subcellular location. Cell membrane. Endoplasmic reticulum membrane.

Tissue specificity. Expressed in the adrenal gland and brain. Not expressed in other tissues.

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.

Polymorphism. Genetic variations in MRAP2 define the body mass index quantitative trait locus 18 (BMIQ18) [MIM:615457]. Variance in body mass index is a susceptibility factor for obesity.

Similarity. Belongs to the MRAP family.

RefSeq proteins (5): NP_001333470, NP_001333471, NP_001333472, NP_001333473, NP_612418* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR028111	MRAP	Family

Pfam: PF15183

UniProt features (9 total): sequence variant 3, chain 1, transmembrane region 1, modified residue 1, glycosylation site 1, mutagenesis site 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96G30-F1	57.58	0.10

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 (1): 89

Glycosylation sites (1): 9

Mutagenesis-validated functional residues (1):

Position	Phenotype
9	abolishes n-glycosylation.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 111 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, GOBP_BEHAVIOR, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_CELLULAR_LOCALIZATION, KONDO_COLON_CANCER_HCP_WITH_H3K27ME1, GOBP_MULTICELLULAR_ORGANISMAL_LEVEL_HOMEOSTASIS, GOBP_ENERGY_HOMEOSTASIS, GOMF_G_PROTEIN_COUPLED_RECEPTOR_BINDING, BASAKI_YBX1_TARGETS_DN, GOMF_SIGNALING_RECEPTOR_BINDING, GOBP_LOCALIZATION_WITHIN_MEMBRANE

GO Biological Process (8): energy reserve metabolic process (GO:0006112), feeding behavior (GO:0007631), protein localization to plasma membrane (GO:0072659), energy homeostasis (GO:0097009), regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0106070), positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0106071), negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0106072), negative regulation of protein localization to plasma membrane (GO:1903077)

GO Molecular Function (8): signaling receptor regulator activity (GO:0030545), corticotropin hormone receptor binding (GO:0031780), type 3 melanocortin receptor binding (GO:0031781), type 4 melanocortin receptor binding (GO:0031782), type 5 melanocortin receptor binding (GO:0031783), identical protein binding (GO:0042802), type 1 melanocortin receptor binding (GO:0070996), protein binding (GO:0005515)

GO Cellular Component (4): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
melanocortin receptor binding	5
adenylate cyclase-activating G protein-coupled receptor signaling pathway	3
regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway	2
energy derivation by oxidation of organic compounds	1
behavior	1
protein localization to membrane	1
protein localization to cell periphery	1
multicellular organismal-level homeostasis	1
regulation of G protein-coupled receptor signaling pathway	1
positive regulation of G protein-coupled receptor signaling pathway	1
negative regulation of G protein-coupled receptor signaling pathway	1
protein localization to plasma membrane	1
regulation of protein localization to plasma membrane	1
negative regulation of protein localization to cell periphery	1
negative regulation of protein localization to membrane	1
signaling receptor activity	1
molecular function regulator activity	1
protein binding	1
binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

632 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MRAP2	MC2R	Q01718	899
MRAP2	MC4R	P32245	807
MRAP2	MC5R	P33032	777
MRAP2	MC3R	P41968	775
MRAP2	PROKR1	Q8TCW9	752
MRAP2	POMC	P01189	630
MRAP2	MC1R	Q01726	602
MRAP2	GHSR	Q92847	601
MRAP2	AGRP	O00253	600
MRAP2	SIM1	P81133	564
MRAP2	PCSK1	P29120	476
MRAP2	SH2B1	Q9NRF2	469
MRAP2	RHO	P08100	464
MRAP2	PROK1	P58294	464
MRAP2	CYB5R4	Q7L1T6	460

IntAct

35 interactions, top by confidence:

A	B	Type	Score
MRAP2	MRAP2	psi-mi:“MI:0915”(physical association)	0.570
MRAP2	MRAP	psi-mi:“MI:0915”(physical association)	0.570
MC2R	MRAP2	psi-mi:“MI:0915”(physical association)	0.570
MRAP2	MC2R	psi-mi:“MI:0915”(physical association)	0.570
SGTA	MRAP2	psi-mi:“MI:0915”(physical association)	0.560
ISLR2	MRAP2	psi-mi:“MI:0915”(physical association)	0.560
APH1A	MRAP2	psi-mi:“MI:0915”(physical association)	0.560
MRAP2	TMEM80	psi-mi:“MI:0915”(physical association)	0.560
MRAP2	BDNF	psi-mi:“MI:0915”(physical association)	0.560
MRAP2	GOLIM4	psi-mi:“MI:0914”(association)	0.530
MRAP2	PODXL	psi-mi:“MI:0914”(association)	0.530
MRAP2	MC5R	psi-mi:“MI:0915”(physical association)	0.400
MRAP2	MC1R	psi-mi:“MI:0915”(physical association)	0.400
MRAP2	MC3R	psi-mi:“MI:0915”(physical association)	0.400
MRAP2	MC4R	psi-mi:“MI:0915”(physical association)	0.400
MRAP2	GOSR1	psi-mi:“MI:0914”(association)	0.350
MRAP2	A2ML1	psi-mi:“MI:0914”(association)	0.350
MRAP2	SGTA	psi-mi:“MI:0915”(physical association)	0.000
SGTA	MRAP2	psi-mi:“MI:0915”(physical association)	0.000
MRAP2	ISLR2	psi-mi:“MI:0915”(physical association)	0.000
MRAP2	APH1A	psi-mi:“MI:0915”(physical association)	0.000
MRAP2	TMEM80	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (118): SLC25A51 (Affinity Capture-MS), TEX2 (Affinity Capture-MS), PODXL (Affinity Capture-MS), UST (Affinity Capture-MS), FGFR4 (Affinity Capture-MS), BMPR2 (Affinity Capture-MS), CC2D1A (Affinity Capture-MS), UGCG (Affinity Capture-MS), LRP12 (Affinity Capture-MS), WDR41 (Affinity Capture-MS), ABCB6 (Affinity Capture-MS), SNX27 (Affinity Capture-MS), FGFR2 (Affinity Capture-MS), BMPR1A (Affinity Capture-MS), MFAP3 (Affinity Capture-MS)

ESM2 similar proteins: A4IG66, A5PLA0, A9ZLX4, D3Z1Q2, D3ZZP4, D5K8A9, F1M2Z5, O14525, P0C2L3, P0DKX4, Q08DP3, Q08EA8, Q13145, Q1LVN1, Q1RMT2, Q2F7Z7, Q3MHM8, Q3T0Q2, Q3URD2, Q4R8C8, Q502I1, Q58CU5, Q5BJN9, Q5R800, Q5RA41, Q5XJS0, Q5ZKK0, Q61137, Q6GM22, Q6PBK8, Q8BPM6, Q8C4Q9, Q8HYZ0, Q8IUW5, Q8K2J7, Q8N4K4, Q8N6S5, Q8NEA5, Q91XN4, Q96G30

Diamond homologs: D3Z1Q2, F8W4H9, P0DM64, Q68UT4, Q8TCY5, Q96G30, Q9D159

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
MRAP2	“up-regulates activity”	MC2R	binding
MRAP2	“down-regulates activity”	MC4R	binding
MRAP2	“down-regulates activity”	MC1R	binding
MRAP2	“down-regulates activity”	MC3R	binding
MRAP2	“down-regulates activity”	MC5R	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 15 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Class A/1 (Rhodopsin-like receptors)	5	37.1×	3e-06
Peptide ligand-binding receptors	5	37.1×	3e-06
G alpha (s) signalling events	5	36.6×	3e-06
GPCR ligand binding	5	32.1×	3e-06
GPCR downstream signalling	5	21.7×	2e-05
Signaling by GPCR	5	20.0×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
adenylate cyclase-activating G protein-coupled receptor signaling pathway	5	40.4×	4e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	71
Likely benign	26
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

1351 predictions. Top by Δscore:

Variant	Effect	Δscore
6:84033880:GCCG:G	donor_gain	1.0000
6:84062991:GA:G	donor_gain	1.0000
6:84062993:G:GG	donor_gain	1.0000
6:84080732:ACAG:A	donor_gain	1.0000
6:84055446:G:GG	donor_gain	0.9900
6:84062990:AGA:A	donor_gain	0.9900
6:84062991:GAG:G	donor_gain	0.9900
6:84066697:A:G	donor_gain	0.9900
6:84089085:A:AG	acceptor_gain	0.9900
6:84089086:A:G	acceptor_gain	0.9900
6:84089089:A:AG	acceptor_gain	0.9900
6:84089090:G:GG	acceptor_gain	0.9900
6:84033882:CGGTA:C	donor_loss	0.9800
6:84033883:GGTAA:G	donor_loss	0.9800
6:84033884:G:GC	donor_loss	0.9800
6:84089090:GCA:G	acceptor_gain	0.9800
6:84051900:G:A	acceptor_gain	0.9700
6:84055444:AT:A	donor_gain	0.9700
6:84062989:AAGAG:A	donor_loss	0.9700
6:84062990:AGAG:A	donor_loss	0.9700
6:84062991:GAGTA:G	donor_loss	0.9700
6:84062992:AGTAA:A	donor_loss	0.9700
6:84062993:G:A	donor_loss	0.9700
6:84062994:T:G	donor_loss	0.9700
6:84062995:A:AT	donor_loss	0.9700
6:84062996:AGTT:A	donor_loss	0.9700
6:84089088:T:G	acceptor_gain	0.9700
6:84089090:GC:G	acceptor_gain	0.9700
6:84089090:GCAAT:G	acceptor_gain	0.9700
6:84033912:G:GT	donor_gain	0.9600

AlphaMissense

1359 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:84062913:T:A	W50R	0.999
6:84062913:T:C	W50R	0.999
6:84062908:G:A	G48E	0.998
6:84062919:G:C	G52R	0.997
6:84062920:G:A	G52D	0.997
6:84062923:T:C	L53P	0.996
6:84062907:G:A	G48R	0.995
6:84062907:G:C	G48R	0.995
6:84062956:T:C	L64P	0.995
6:84062923:T:A	L53H	0.994
6:84062931:T:C	F56L	0.994
6:84062933:C:A	F56L	0.994
6:84062933:C:G	F56L	0.994
6:84062944:T:A	M60K	0.994
6:84062926:C:A	A54E	0.993
6:84062944:T:G	M60R	0.993
6:84062929:T:A	V55D	0.992
6:84062910:T:C	F49L	0.991
6:84062911:T:C	F49S	0.991
6:84062912:T:A	F49L	0.991
6:84062912:T:G	F49L	0.991
6:84055385:T:A	W23R	0.990
6:84055385:T:C	W23R	0.990
6:84055421:T:C	F35L	0.990
6:84055423:T:A	F35L	0.990
6:84055423:T:G	F35L	0.990
6:84062915:G:C	W50C	0.990
6:84062915:G:T	W50C	0.990
6:84062917:T:A	V51D	0.990
6:84062905:T:A	I47N	0.989

dbSNP variants (sampled 300 via entrez): RS1000001373 (6:84145626 C>T), RS1000052493 (6:84070107 T>A,C), RS1000083753 (6:84140560 C>A,T), RS1000139514 (6:84031233 T>A), RS1000150662 (6:84115584 G>A), RS1000166656 (6:84110779 A>C), RS1000179736 (6:84111586 AC>A), RS1000180140 (6:84093383 C>A), RS1000182257 (6:84115790 C>A), RS1000200567 (6:84134070 C>A), RS1000228542 (6:84046062 G>A,C), RS1000248432 (6:84106100 G>A), RS1000252397 (6:84087099 G>A), RS1000325338 (6:84052454 G>C), RS1000331194 (6:84140207 G>A)

Disease associations

OMIM: gene MIM:615410 | disease phenotypes: MIM:601665

GenCC curated gene-disease

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

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

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001513	Obesity

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004946_136	Schizophrenia	2.000000e-13
GCST009200_6	Whole brain grey matter density	4.000000e-06
GCST009391_2103	Metabolite levels	5.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0010306	Grey matter density measurement
EFO:0010373	phosphatidylcholine 32:1 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects binding, increases expression, affects cotreatment	2
Nickel	decreases expression	2
sotorasib	affects cotreatment, increases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
deoxynivalenol	decreases expression	1
sodium arsenate	decreases expression, increases abundance	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
abrine	decreases expression	1
trametinib	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
theaflavin-3,3’-digallate	affects expression	1
Antineoplastic Agents, Immunological	decreases expression, decreases response to substance	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic Trioxide	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Air Pollutants	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	decreases expression, increases abundance	1
Carbamazepine	affects expression	1
Diazinon	increases methylation	1
Methapyrilene	increases methylation	1
Methylmercury Compounds	increases response to substance	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	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