UCP3

Summary

UCP3 (uncoupling protein 3, HGNC:12519) is a protein-coding gene on chromosome 11q13.4, encoding Putative mitochondrial transporter UCP3 (P55916). Putative transmembrane transporter that plays a role in mitochondrial metabolism via an as yet unclear mechanism.

Mitochondrial uncoupling proteins (UCP) are members of the larger family of mitochondrial anion carrier proteins (MACP). UCPs separate oxidative phosphorylation from ATP synthesis with energy dissipated as heat, also referred to as the mitochondrial proton leak. UCPs facilitate the transfer of anions from the inner to the outer mitochondrial membrane and the return transfer of protons from the outer to the inner mitochondrial membrane. They also reduce the mitochondrial membrane potential in mammalian cells. The different UCPs have tissue-specific expression; this gene is primarily expressed in skeletal muscle. This gene’s protein product is postulated to protect mitochondria against lipid-induced oxidative stress. Expression levels of this gene increase when fatty acid supplies to mitochondria exceed their oxidation capacity and the protein enables the export of fatty acids from mitochondria. UCPs contain the three solcar protein domains typically found in MACPs. Two splice variants have been found for this gene.

Source: NCBI Gene 7352 — RefSeq curated summary.

At a glance

• Gene–disease (curated): inherited obesity (Limited, GenCC)
• Clinical variants (ClinVar): 211 total
• Phenotypes (HPO): 6
• MANE Select transcript: NM_003356

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12519
Approved symbol	UCP3
Name	uncoupling protein 3
Location	11q13.4
Locus type	gene with protein product
Status	Approved
Aliases	SLC25A9
Ensembl gene	ENSG00000175564
Ensembl biotype	protein_coding
OMIM	602044
Entrez	7352

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000314032, ENST00000426995, ENST00000544614, ENST00000545271, ENST00000963037

RefSeq mRNA: 2 — MANE Select: NM_003356 NM_003356, NM_022803

CCDS: CCDS44677, CCDS8229

Canonical transcript exons

ENST00000314032 — 7 exons

Exon	Start	End
ENSE00001184314	74003827	74004007
ENSE00001184320	74004484	74004585
ENSE00001184324	74005730	74005933
ENSE00001184329	74006169	74006379
ENSE00001389673	74006917	74007137
ENSE00002251985	74000277	74001526
ENSE00002261443	74008978	74009085

Expression profiles

Bgee: expression breadth ubiquitous, 224 present calls, max score 98.66.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3128 / max 204.2532, expressed in 23 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
121298	0.2987	19
121299	0.0141	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	98.66	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.68	gold quality
muscle of leg	UBERON:0001383	97.15	gold quality
triceps brachii	UBERON:0001509	96.79	gold quality
skeletal muscle organ	UBERON:0014892	96.69	gold quality
muscle organ	UBERON:0001630	96.68	gold quality
diaphragm	UBERON:0001103	96.08	gold quality
gluteal muscle	UBERON:0002000	95.93	gold quality
skeletal muscle tissue	UBERON:0001134	95.72	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	95.61	gold quality
quadriceps femoris	UBERON:0001377	95.44	gold quality
vastus lateralis	UBERON:0001379	95.41	gold quality
biceps brachii	UBERON:0001507	93.19	gold quality
deltoid	UBERON:0001476	92.73	gold quality
muscle tissue	UBERON:0002385	91.88	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	91.69	gold quality
tibialis anterior	UBERON:0001385	86.98	silver quality
body of tongue	UBERON:0011876	86.75	gold quality
type B pancreatic cell	CL:0000169	86.37	silver quality
olfactory bulb	UBERON:0002264	86.02	silver quality
heart right ventricle	UBERON:0002080	84.01	silver quality
tongue squamous epithelium	UBERON:0006919	82.64	silver quality
tongue	UBERON:0001723	82.23	gold quality
cervix squamous epithelium	UBERON:0006922	82.07	gold quality
granulocyte	CL:0000094	80.82	gold quality
left ventricle myocardium	UBERON:0006566	78.72	gold quality
vena cava	UBERON:0004087	78.51	silver quality
lateral nuclear group of thalamus	UBERON:0002736	77.77	silver quality
superior surface of tongue	UBERON:0007371	77.31	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.80	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.52

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF1, FLCN, HAND2, MYC, MYOD1, MYOG, NCOA2, NR3C2, PPARA, PPARD, PPARG, PRKAA1, RXRA, SIRT1, SP1, SP3, THRA

miRNA regulators (miRDB)

71 targeting UCP3, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-548AJ-5P	99.78	71.12	3085

Literature-anchored findings (GeneRIF, showing 40)

• Uncoupling protein 3 gene is associated with body composition changes with training. (PMID:11842047)
• mitochondrial uncoupling protein, involved in thermogenesis. mRNA levels elevated in weight loss associated with gastrointestinal adenocarcioma. (PMID:11875702)
• microsatellite markers at the UCP2/UCP3 locus on chromosome 11q13 in anorexia nervosa (PMID:11920154)
• Fasting activates the gene expression of UCP3 independent of lipid transport and oxidation genes in skeletal muscle suggesting a role in regulation of FA homeostasis during fasting (PMID:12051710)
• UCP3 protein content is related to energy metabolism in humans and might help in the metabolic adaptation to cold exposure (PMID:12075570)
• Decreased mitochondrial proton leak and reduced expression in skeletal muscle of obese diet-resistant women (PMID:12145158)
• Depressed UCP3 expression may be an important mechanism for reducing the formation of oxygen-derived free radicals. (PMID:12145475)
• Metabolic and anthropometric factors related to skeletal muscle UCP3 gene expression in healthy human adults. (PMID:12217879)
• expression of UCP3 mRNA was dependent on human muscle differentiation (PMID:12351640)
• role of UCP3 in postnatal activation of lipid oxidation in skeletal muscle and suggest the involvement of UCP3 in the delayed activation of mitochondrial energy conversion in very immature preterm neonates. (PMID:12612210)
• Training status did not change skeletal muscle fiber hierarchical UCP3 protein expression in different fiber types. It affected UCP3 content more in type I and type IIa than in type IIx muscle fibers. (PMID:12634927)
• purine nucleotides must be the physiological inhibitors of UCP3-mediated uncoupling in vivo. (PMID:12670931)
• UCPs in adipose tissue may play a role in the reduction in 24-h energy expenditure observed in post-obese individuals. (PMID:12720538)
• study of isolation, refolding, transport properties, and regulation of recombinant UCP3 (PMID:12734183)
• Uncoupling protein 3 polymorphisms are associated with waist-to-hip ratio. (PMID:12756473)
• This is the first study to demonstrate a downregulation of skeletal muscle UCP3 mRNA expression after the lowering of plasma free fatty acids concentrations in humans, despite an increase in energy expenditure upon beta2-adrenergic stimulation. (PMID:12824081)
• convergence of MyoD and PPAR-dependent pathways provides a molecular mechanism for skeletal muscle specificity and fatty acid regulation of the human UCP3 gene. (PMID:12843208)
• Up-regulation of UCP3 in riboflavin-responsive, multiple acylcoenzyme A dehydrogenase deficiency is due to accumulation of muscle fatty acid/acylCoA. (PMID:14671191)
• Results support a role for UCP3 in fuel substrate management and energy metabolism, which may influence body weight regulation. (PMID:15045692)
• Association between BMI and the UCP3 -55 C–>T polymorphism in diabetic nephropathy. (PMID:15120704)
• IGF-1 may protect from hyperglycemia-induced oxidative stress and neuronal injuries by regulating mitochondrial membrane potential, possibly by the involvement of UCP3. (PMID:15211595)
• No association was found between the -55 C/T polymorphism within the uncoupling protein 3 gene and the ultra-endurance performance of triathletes. (PMID:15346230)
• UCP3 gene transcription is activated by thyroid hormone treatment in vivo, and this activation is mediated by a TRE (thyroid hormone response element) in the proximal promoter region (PMID:15496137)
• The hypothesis that differences in the UCP-3 genes influence the susceptibility to anorexia nervossa was not supported. (PMID:15564896)
• In summary, our results suggest that UCP3 gene polymorphisms may contribute to body mass index variation in this Caucasian population. (PMID:15870396)
• Our results suggest that the LEP and UCP2/UCP3 genes are unlikely to have a substantial effect on variation in obesity phenotypes in this particular US Caucasian population. (PMID:15910756)
• results are consistent with uncoupling protein (UCP)3 functioning to facilitate fatty acid oxidation and minimize reactive oxygen species (ROS) production (PMID:16046300)
• When glycolysis and mitochondria generate ATP, and in the absence of appropriate activators of proton transport, UCPs do not transport protons (uncoupling), but rather other ions of physiological relevance that control mitochondrial activity. (PMID:16178820)
• The level of difference in Resting energy expenditure caused by the polymorphism of promoter region of uncoupling protein 3 gene -55(C>T) may play a role in energy metabolism in Chinese. (PMID:16215931)
• Overexpression of UCP3 gene in human myotube cell culture leads to significant activation of different proteolytic systems involved in muscle myofibrillar protein breakdown. These results suggest possible relation involved in muscle wasting during cancer. (PMID:16337086)
• Data comply with the hypothesis that UCP3 may protect against lipotoxicity. (PMID:16352674)
• C-55T polymorphism in the UCP3 gene is associated with a reduced risk of diabetic neuropathy in type 1 diabetes (PMID:16373902)
• Functional promoter variants UCP2 and UCP3 increase the prospective risk of type 2 diabetes, and is exacerbated by obesity. (PMID:16644712)
• Skeletal muscle mRNA expression of UCP3 increased in type 2 diabetic patients with an improved clinical profile following low-intensity exercise, but were unchanged in patients who did not show exercise-mediated improvements in clinical parameters. (PMID:16752430)
• Results suggest involvement of AMP-activated protein kinase in the control of expression of both metabolic genes, UCP3 and GLUT4, in the skeletal muscle of mice and of human newborns. (PMID:16966355)
• Results show that in individuals that were UCP3 T-carriers the Odds Ratio increased from 1 in the youngest to 10.84 (95% CI 4.54-25.85) in the oldest. (PMID:17150099)
• Results show that UCP3 is essential for mitochondrial Ca(2+) sequestration in response to cell stimulation under physiological conditions. (PMID:17351641)
• +4589C>T (Y210Y) in UCP3, a silent variation of Tyr210Tyr in exon 5, was significantly associated with HDL cholesterol in Korean women (PMID:17512314)
• UCP2-3 polymorphisms were important genetic factor for the very low calorie diet-induced reduction of body fat mass (PMID:17544366)
• increasing mitochondrial uncoupling in skeletal muscle may be an excellent therapeutic target for type 2 diabetes mellitus (PMID:17571165)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ucp3	ENSMUSG00000032942
rattus_norvegicus	Ucp3	ENSRNOG00000017716

Paralogs (49): SLC25A13 (ENSG00000004864), SLC25A5 (ENSG00000005022), SLC25A39 (ENSG00000013306), SLC25A40 (ENSG00000075303), SLC25A3 (ENSG00000075415), SLC25A43 (ENSG00000077713), SLC25A24 (ENSG00000085491), SLC25A1 (ENSG00000100075), SLC25A17 (ENSG00000100372), SLC25A14 (ENSG00000102078), SLC25A15 (ENSG00000102743), SLC25A11 (ENSG00000108528), UCP1 (ENSG00000109424), SLC25A36 (ENSG00000114120), SLC25A12 (ENSG00000115840), SLC25A2 (ENSG00000120329), SLC25A51 (ENSG00000122696), SLC25A16 (ENSG00000122912), SLC25A35 (ENSG00000125434), SLC25A19 (ENSG00000125454), SLC25A23 (ENSG00000125648), SLC25A47 (ENSG00000140107), SLC25A52 (ENSG00000141437), SLC25A38 (ENSG00000144659), SLC25A26 (ENSG00000144741), SLC25A48 (ENSG00000145832), SLC25A37 (ENSG00000147454), SLC25A25 (ENSG00000148339), SLC25A31 (ENSG00000151475), SLC25A4 (ENSG00000151729), SLC25A27 (ENSG00000153291), SLC25A28 (ENSG00000155287), SLC25A44 (ENSG00000160785), SLC25A45 (ENSG00000162241), SLC25A34 (ENSG00000162461), SLC25A32 (ENSG00000164933), SLC25A6 (ENSG00000169100), SLC25A33 (ENSG00000171612), SLC25A30 (ENSG00000174032), UCP2 (ENSG00000175567)

Protein

Protein identifiers

Putative mitochondrial transporter UCP3 — P55916 (reviewed: P55916)

Alternative names: Solute carrier family 25 member 9, Uncoupling protein-3

All UniProt accessions (3): P55916, A0A0S2Z4G5, F5H3N5

UniProt curated annotations — full annotation on UniProt →

Function. Putative transmembrane transporter that plays a role in mitochondrial metabolism via an as yet unclear mechanism. Originally, this mitochondrial protein was thought to act as a proton transmembrane transporter from the mitochondrial intermembrane space into the matrix, causing proton leaks through the inner mitochondrial membrane, thereby uncoupling mitochondrial membrane potential generation from ATP synthesis. However, this function is controversial and uncoupling may not be the function, or at least not the main function, but rather a consequence of more conventional metabolite transporter activity.

Subunit / interactions. Interacts with HAX1; the interaction is direct and calcium-dependent.

Subcellular location. Mitochondrion inner membrane.

Tissue specificity. Only in skeletal muscle and heart. Also expressed in white and brown adipose tissues. Is more expressed in glycolytic than in oxidative skeletal muscles.

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. The gene represented in this entry may be involved in disease pathogenesis.

Activity regulation. The proton transporter activity is activated by fatty acids (in vitro). The proton transporter activity is inhibited by ATP and ADP (in vitro). The effect of Ubiquinone/coenzyme Q10 on the proton transporter activity in reconstituted membranes is unclear (in vitro).

Induction. Up-regulated by beta3-adrenergic stimulation, starvation, glucocorticoids and leptin.

Similarity. Belongs to the mitochondrial carrier (TC 2.A.29) family.

Isoforms (3)

UniProt ID	Names	Canonical?
P55916-1	UCP3L	yes
P55916-2	UCP3S
P55916-3	3

RefSeq proteins (2): NP_003347, NP_073714 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002067	MCP	Family
IPR018108	MCP_transmembrane	Repeat
IPR023395	MCP_dom_sf	Homologous_superfamily
IPR050391	Mito_Metabolite_Transporter	Family

Pfam: PF00153

UniProt features (24 total): topological domain 7, transmembrane region 6, repeat 3, sequence variant 3, splice variant 2, chain 1, region of interest 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P55916-F1	62.65	0.00

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-167826	The fatty acid cycling model

MSigDB gene sets: 138 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPIRATORY_GASEOUS_EXCHANGE_BY_RESPIRATORY_SYSTEM, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_RESPONSE_TO_COLD, GOBP_RESPONSE_TO_CORTICOSTEROID, GOZGIT_ESR1_TARGETS_DN, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, chr11q13, GOBP_MITOCHONDRIAL_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_MITOCHONDRIAL_TRANSMEMBRANE_TRANSPORT, BROWNE_HCMV_INFECTION_48HR_DN, MARTINEZ_RB1_TARGETS_UP, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS

GO Biological Process (18): response to superoxide (GO:0000303), response to hypoxia (GO:0001666), lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631), response to nutrient (GO:0007584), respiratory gaseous exchange by respiratory system (GO:0007585), response to cold (GO:0009409), response to activity (GO:0014823), response to insulin (GO:0032868), cellular response to hormone stimulus (GO:0032870), response to glucocorticoid (GO:0051384), lipid hydroperoxide transport (GO:1901373), response to fenofibrate (GO:1901557), proton transmembrane transport (GO:1902600), mitochondrial transmembrane transport (GO:1990542), adaptive thermogenesis (GO:1990845), response to steroid hormone (GO:0048545), transmembrane transport (GO:0055085)

GO Molecular Function (3): proton transmembrane transporter activity (GO:0015078), oxidative phosphorylation uncoupler activity (GO:0017077), protein binding (GO:0005515)

GO Cellular Component (3): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Mitochondrial Uncoupling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to stress	2
response to hormone	2
proton transmembrane transport	2
response to oxygen radical	1
response to decreased oxygen levels	1
primary metabolic process	1
lipid metabolic process	1
monocarboxylic acid metabolic process	1
response to nutrient levels	1
response to chemical	1
multicellular organismal process	1
response to temperature stimulus	1
response to stimulus	1
response to peptide hormone	1
cellular response to chemical stimulus	1
cellular response to endogenous stimulus	1
response to corticosteroid	1
lipid transport	1
response to ether	1
response to ketone	1
monoatomic cation transmembrane transport	1
mitochondrial transport	1
transmembrane transport	1
temperature homeostasis	1
response to lipid	1
transport	1
cellular process	1
monoatomic cation transmembrane transporter activity	1
transmembrane transporter activity	1
binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1420 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UCP3	PPARGC1A	Q9UBK2	916
UCP3	CPT1B	Q92523	842
UCP3	CPT1C	Q8TCG5	807
UCP3	PPARD	Q03181	769
UCP3	PPARG	P37231	755
UCP3	PDK4	Q16654	735
UCP3	CPT1A	P50416	718
UCP3	PPARA	Q07869	709
UCP3	ADRB3	P13945	704
UCP3	GHRL	Q9UBU3	696
UCP3	COX4I1	P13073	694
UCP3	SLC2A4	P14672	664
UCP3	INS	P01308	637
UCP3	COX4I2	Q96KJ9	629
UCP3	LEP	P41159	609

IntAct

4 interactions, top by confidence:

A	B	Type	Score
UCP3	NS	psi-mi:“MI:0915”(physical association)	0.510
UCP3	UCP2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (18): RC3H1 (Reconstituted Complex), ZC3H7A (Affinity Capture-MS), STRBP (Affinity Capture-MS), GEMIN5 (Affinity Capture-MS), DDX1 (Affinity Capture-MS), MEX3A (Affinity Capture-MS), RTCB (Affinity Capture-MS), RBM47 (Affinity Capture-MS), RALY (Affinity Capture-MS), RC3H2 (Affinity Capture-MS), RC3H1 (Affinity Capture-MS), UCP3 (Protein-RNA), UCP3 (Protein-RNA), YWHAB (Two-hybrid), YWHAZ (Two-hybrid)

ESM2 similar proteins: A0A0G2K5L2, A0JN87, G3XP90, G3YAF3, O04619, O77792, O95847, O97562, P55851, P55916, P56499, P56500, P56501, P70406, Q08DK4, Q1LZB3, Q29RM1, Q2YDD9, Q3SZI5, Q3TZX3, Q3V132, Q4V9P0, Q505J6, Q5IS35, Q5NVC1, Q5R5A8, Q5RD81, Q5RFB7, Q5ZKP7, Q6DG32, Q6P036, Q6PGY3, Q7K566, Q8BZ09, Q922G0, Q96CQ1, Q99JD3, Q9BQT8, Q9BSK2, Q9C5M0

Diamond homologs: A0PC02, A6SL61, A6ZXL1, A7ER02, A7TIQ0, B0G143, B3LH09, F1RFX9, G3Y1Q5, G5EE96, K3VFR5, O74439, O77792, O81845, O89035, O95258, O95847, O97562, O97649, P04575, P04633, P10861, P12242, P14271, P22292, P25874, P32332, P55851, P55916, P56499, P56500, P56501, P70406, P90992, P97700, Q02978, Q06143, Q07534, Q08DK7, Q18P97

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PRKAA1	“up-regulates quantity by expression”	UCP3	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	130
Likely benign	58
Benign	12

Top pathogenic / likely-pathogenic (0)

SpliceAI

802 predictions. Top by Δscore:

Variant	Effect	Δscore
11:74003825:ACC:A	donor_gain	1.0000
11:74003826:CCC:C	donor_gain	1.0000
11:74004003:GTTGT:G	acceptor_gain	1.0000
11:74004004:TTGT:T	acceptor_gain	1.0000
11:74004005:TGT:T	acceptor_gain	1.0000
11:74004006:GT:G	acceptor_gain	1.0000
11:74004007:TC:T	acceptor_loss	1.0000
11:74004008:C:CA	acceptor_loss	1.0000
11:74004008:C:CC	acceptor_gain	1.0000
11:74004009:T:C	acceptor_loss	1.0000
11:74004478:CCTCA:C	donor_loss	1.0000
11:74004479:CTCAC:C	donor_loss	1.0000
11:74004482:A:AC	donor_gain	1.0000
11:74004482:A:C	donor_loss	1.0000
11:74004483:C:CC	donor_gain	1.0000
11:74004483:C:T	donor_loss	1.0000
11:74004581:AGTTC:A	acceptor_gain	1.0000
11:74004582:GTTC:G	acceptor_gain	1.0000
11:74004583:TTCC:T	acceptor_loss	1.0000
11:74004584:TC:T	acceptor_gain	1.0000
11:74004585:CC:C	acceptor_gain	1.0000
11:74004586:C:CC	acceptor_gain	1.0000
11:74004587:T:A	acceptor_loss	1.0000
11:74006167:A:AC	donor_gain	1.0000
11:74006167:ACTGT:A	donor_gain	1.0000
11:74006168:C:CA	donor_gain	1.0000
11:74006168:CTGT:C	donor_gain	1.0000
11:74006168:CTGTC:C	donor_gain	1.0000
11:74006380:C:CC	acceptor_gain	1.0000
11:74006381:T:C	acceptor_loss	1.0000

AlphaMissense

2023 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:74004515:C:A	K204N	0.997
11:74004515:C:G	K204N	0.997
11:74005906:G:T	A122D	0.997
11:74006233:G:C	F91L	0.997
11:74006233:G:T	F91L	0.997
11:74006235:A:G	F91L	0.997
11:74003936:C:G	D239H	0.996
11:74005882:G:T	A130E	0.996
11:74006267:C:T	G80E	0.996
11:74003828:C:G	G275R	0.995
11:74003828:C:T	G275R	0.995
11:74003925:C:A	K242N	0.995
11:74003925:C:G	K242N	0.995
11:74003980:G:T	A224D	0.995
11:74004564:C:A	R188M	0.995
11:74005891:C:T	G127E	0.995
11:74005901:A:G	C124R	0.995
11:74005903:C:T	G123D	0.995
11:74006222:C:G	R95P	0.995
11:74001478:G:C	F291L	0.994
11:74001478:G:T	F291L	0.994
11:74001480:A:G	F291L	0.994
11:74003827:C:T	G275E	0.994
11:74003920:C:G	R244P	0.994
11:74003935:T:A	D239V	0.994
11:74003935:T:C	D239G	0.994
11:74004547:A:G	C194R	0.994
11:74004548:G:C	N193K	0.994
11:74004548:G:T	N193K	0.994
11:74005730:C:G	G181R	0.994

dbSNP variants (sampled 300 via entrez): RS1000070968 (11:74003328 T>C), RS1000458261 (11:74009278 G>A), RS1001093265 (11:74001887 G>A), RS1001513921 (11:74008118 G>A), RS1001539562 (11:74005322 C>A,T), RS1002088889 (11:74009564 G>A), RS1002092762 (11:74000305 G>A), RS1002106586 (11:74006623 G>A), RS1003080480 (11:74005337 A>G), RS1003113012 (11:74005666 T>A), RS1003524779 (11:74002213 A>G), RS1003602930 (11:74010063 T>C), RS1003727242 (11:74007725 G>A), RS1003863394 (11:74000577 C>T), RS1003977045 (11:74009723 G>A)

Disease associations

OMIM: gene MIM:602044 | disease phenotypes: MIM:601665, MIM:616300

GenCC curated gene-disease

Disease	Classification	Inheritance
inherited obesity	Limited	Autosomal dominant

Mondo (4): obesity disorder (MONDO:0011122), inherited obesity (MONDO:0019182), short-rib thoracic dysplasia 13 with or without polydactyly (MONDO:0014577), morbid obesity (MONDO:0005139)

Orphanet (4): Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), Genetic obesity (Orphanet:77828), Jeune syndrome (Orphanet:474), NON RARE IN EUROPE: Non rare obesity (Orphanet:521399)

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

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009767	Obesity, Morbid	C18.654.726.750.500.700; C23.888.144.699.500.500

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
rs668514	UCP3		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — Mitochondrial uncoupling proteins

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
ochratoxin A	increases expression	2
acipimox	decreases expression, affects cotreatment	2
aristolochic acid I	increases expression	1
beauvericin	affects cotreatment, decreases expression	1
propionaldehyde	decreases expression	1
kaempferol	increases expression	1
bisphenol A	decreases methylation	1
cordycepin	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
enniatins	affects cotreatment, decreases expression	1
abrine	decreases expression	1
licochalcone B	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Adenosine Triphosphate	decreases reaction, increases transport	1
Albuterol	affects cotreatment, decreases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Copper	decreases expression, affects cotreatment	1
Glucose	decreases expression, increases reaction, increases secretion	1
Isoproterenol	decreases expression, increases expression	1
Protons	decreases reaction, increases transport	1
Smoke	decreases expression	1
Testosterone	increases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1
Zinc	affects cotreatment, increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D4FR	1321N1-UCP3-KO-c13	Cancer cell line	Male
CVCL_D4FS	1321N1-UCP3-KO-c16	Cancer cell line	Male

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