UCP1

Summary

UCP1 (uncoupling protein 1, HGNC:12517) is a protein-coding gene on chromosome 4q31.1, encoding Mitochondrial brown fat uncoupling protein 1 (P25874). Mitochondrial protein responsible for thermogenic respiration, a specialized capacity of brown adipose tissue and beige fat that participates in non-shivering adaptive thermogenesis to temperature and diet variations and more generally to the regulation of energy balance.

Mitochondrial uncoupling proteins (UCP) are members of the 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. Tissue specificity occurs for the different UCPs and the exact methods of how UCPs transfer H+/OH- are not known. UCPs contain the three homologous protein domains of MACPs. This gene is expressed only in brown adipose tissue, a specialized tissue which functions to produce heat.

Source: NCBI Gene 7350 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 54 total
• MANE Select transcript: NM_021833

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12517
Approved symbol	UCP1
Name	uncoupling protein 1
Location	4q31.1
Locus type	gene with protein product
Status	Approved
Aliases	SLC25A7
Ensembl gene	ENSG00000109424
Ensembl biotype	protein_coding
OMIM	113730
Entrez	7350

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000262999, ENST00000956211

RefSeq mRNA: 1 — MANE Select: NM_021833 NM_021833

CCDS: CCDS3753

Canonical transcript exons

ENST00000262999 — 6 exons

Exon	Start	End
ENSE00001009006	140567779	140567977
ENSE00001081759	140563318	140563518
ENSE00001081760	140559431	140560010
ENSE00001081761	140568604	140568961
ENSE00001081762	140563110	140563211
ENSE00001081763	140562193	140562373

Expression profiles

Bgee: expression breadth broad, 58 present calls, max score 88.13.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1389 / max 26.5969, expressed in 33 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
54128	0.1389	33

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.13	gold quality
buccal mucosa cell	CL:0002336	79.25	gold quality
vena cava	UBERON:0004087	64.35	silver quality
parotid gland	UBERON:0001831	61.63	gold quality
nasal cavity epithelium	UBERON:0005384	55.05	gold quality
myocardium	UBERON:0002349	55.00	gold quality
gingival epithelium	UBERON:0001949	54.49	gold quality
deltoid	UBERON:0001476	53.88	gold quality
tibialis anterior	UBERON:0001385	53.70	silver quality
triceps brachii	UBERON:0001509	53.21	gold quality
decidua	UBERON:0002450	51.49	gold quality
gingiva	UBERON:0001828	50.28	gold quality
male germ cell	CL:0000015	49.98	gold quality
sperm	CL:0000019	49.61	gold quality
quadriceps femoris	UBERON:0001377	49.55	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
hair follicle	UBERON:0002073	49.18	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
vastus lateralis	UBERON:0001379	48.83	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
epithelial cell of pancreas	CL:0000083	48.25	gold quality
left ventricle myocardium	UBERON:0006566	48.24	gold quality
orbitofrontal cortex	UBERON:0004167	48.20	gold quality
upper arm skin	UBERON:0004263	48.06	gold quality
cervix epithelium	UBERON:0004801	48.04	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.78

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BMP7, CEBPA, CEBPB, CEBPD, CEBPG, CREB1, EGR1, ELF1, ESRRA, FOXA3, FOXO1, JUN, KDM3B, KLF11, KLF15, MYC, NCOA1, NR1H3, NR3C1, NR3C2, NR4A1, NRF1, PAX1, PPARA, PPARD, PPARG, PPARGC1A, RARA, RXRA, SRF, STAT5A, TCF3, TFAM, THRA, THRB, TRPV4, VDR

Literature-anchored findings (GeneRIF, showing 40)

• a new polymorphic site disrupts a consensus site for the binding of ATF/CREB transcription factor family and inhibits the factor binding in vitro (PMID:12032762)
• Regulatory motifs for CREB-binding protein and Nfe2l2 transcription factors in the upstream enhancer of the mitochondrial uncoupling protein 1 gene. (PMID:12084707)
• The -3826A > G polymorphism of UCP1 does not play a major role in the development of obesity and/or disturbances of glucose metabolism. (PMID:12375583)
• Data describe the expression of peroxisome proliferator-activated receptor gamma (PPAR gamma) co-activator 1, PPAR gamma, insulin receptor substrate-1, glucose transporter isoform-4, and mitochondrial uncoupling protein-1 in adipose tissue. (PMID:12565902)
• Uncoupling protein 1 polymorphisms are associated with waist-to-hip ratio. (PMID:12756473)
• the polymorphism -3826 A/G of the UCP1 gene is associated with a greater degree of obesity and very high figures of arterial tension. (PMID:12951617)
• GG allele carriers have lowered capacity of thermic effect of a meal in response to fat intake. Impaired UCP1-linked thermogenesis can have adverse effects on regulation of body weight. (PMID:14671150)
• No association between the different polymorphisms and diabetic nephropathy. (PMID:15120704)
• the GG type of the UCP-1 gene has a strong association with increased LDL cholesterol level and might be a significant risk factor for hyper-LDL cholesterolemia among Korean obese subjects (PMID:15281018)
• Polymorphisms in uncoupling protein 1 is associated with Type 2 Diabetes Mellitus (PMID:15355441)
• Our results agree with the previously reported association between UCP1 -3826G allele and obesity and point to a gender-related effect. (PMID:15536594)
• results of the present study provided insufficient evidence of the existence of a major [cleft lip/palate] susceptibility locus in the 4q region (PMID:15865460)
• UCP1 has a new genetic polymorphism, with effects on body fat accumulation. (PMID:15955458)
• UCP-1 polymorphisms have roles in body fat accumulation in Korean female subjects (PMID:16084837)
• Nuclear magnetic resonance study of this protein. (PMID:16132835)
• Ectopic UCP1 gene expression in HepG2 cells affects ATP production. (PMID:16180337)
• These results suggest that insulin resistance caused by the -112C allele influences the susceptibility to type 2 diabetes. (PMID:16338218)
• Our results indicated that young healthy Japanese men with the AG heterozygote of the A-3826G polymorphism in the UCP-1 gene showed higher BMI than those with other genotypes. (PMID:16953057)
• human uncoupling proteins 1 and 2 are activated by polyunsaturated fatty acids in planar lipid bilayers (PMID:17242157)
• Possible involvement of the A-3826G polymorphism in the regulation of body composition. (PMID:17516293)
• the GG genotype of UCP1 may be associated with the presence of hypertension in Japanese males and older subjects (PMID:17635070)
• These results suggest that the GG genotype may be an independent protective factor associated with low HDL-cholesterolemia in this population, although the role of the UCP-1 A-3826G polymorphism in HDL-C is complex and remains controversial. (PMID:18068010)
• The expression of UCP1 mRNA was found in the human epidermis and was upregulated in differentiated keratinocytes. (PMID:18305572)
• UCP1 genetic polymorphisms are associated with blood pressure among Korean female subjects (PMID:18955781)
• no significant associations between these UCP1 genetic polymorphisms and thigh fat areas, visceral fat areas, or blood biochemical profiles, in Korean women (PMID:19076691)
• Polymorphic UCP1 (AG+GG) obese patients with low adiponectin levels appear to be high-risk subjects for worsening of liver steatosis, a NAFLD, possibly requiring a second-step evaluation by liver biopsy. (PMID:19474520)
• UCP-1 expression was similar in patients without and with severe coronary atherosclerosis and metabolic syndrome or type 2 diabetes. (PMID:19567523)
• The -3826A/G allele is associated with an increased risk of type 2 diabetes in a northwestern Colombian population. (PMID:19753844)
• 3826A/G polymorphism in the promoter of the uncoupling protein-1 gene was not associated with obesity in Chinese. (PMID:19806581)
• UCP1 gene is associated with hearing disorders among Japanese elderly. (PMID:19895332)
• the haplotype, A-C-Met, in the UCP1 gene is significantly associated with the increased genetic risk for developing type 2 diabetes in Asian Indians (PMID:19943796)
• These results suggest that the G allele at -3826 in the UCP1 gene may ameliorate the reduction in serum HDL-C levels in obese women during low-calorie diet. (PMID:19966534)
• KLF11, but not KLF15, was essential for UCP1 expression during brown adipocyte differentiation of muBM3.1. (PMID:20709022)
• Associations between UCP1 polymorphism and a resistance to weight loss has been documented. (PMID:20803423)
• Diminished resting energy expenditure (REE) in G-allele carriers as well as reduced thermoregulatory SNS activity for the G/G genotype, suggest that attenuated UCP1-linked thermogenesis has an adverse effect on the regulation of energy balance. (PMID:21189472)
• Data show that the abnormally expressed adipogenic UCP1 protein may serve as a unique marker. (PMID:21355075)
• The UCP1 gene -3826 G allele may result in smaller weight loss after a short-term, controlled-energy diet in young, lean women. (PMID:21530798)
• Two variants located in the upstream enhancer region of human UCP1 gene affect gene expression and are correlated with human longevity. (PMID:21827845)
• In human multipotent adipose-derived stem cells differentiated into functional brown adipocytes, activation of either beta(1)-adrenergic receptors or beta(3)-adrenergic receptors was able to increase UCP1 mRNA and protein levels. (PMID:21878665)
• The present study demonstrated the interaction among beta3AR Trp64Arg, beta2AR Arg16Gly and UCP1 -3826A>G for the accumulation of visceral fat. (PMID:21959333)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ucp1	ENSDARG00000023151
mus_musculus	Ucp1	ENSMUSG00000031710
rattus_norvegicus	Ucp1	ENSRNOG00000003580

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), 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), UCP3 (ENSG00000175564), UCP2 (ENSG00000175567)

Protein

Protein identifiers

Mitochondrial brown fat uncoupling protein 1 — P25874 (reviewed: P25874)

Alternative names: Solute carrier family 25 member 7, Thermogenin

All UniProt accessions (2): P25874, Q4KMT7

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial protein responsible for thermogenic respiration, a specialized capacity of brown adipose tissue and beige fat that participates in non-shivering adaptive thermogenesis to temperature and diet variations and more generally to the regulation of energy balance. Functions as a long-chain fatty acid/LCFA and proton symporter, simultaneously transporting one LCFA and one proton through the inner mitochondrial membrane. However, LCFAs remaining associated with the transporter via their hydrophobic tails, it results in an apparent transport of protons activated by LCFAs. Thereby, dissipates the mitochondrial proton gradient and converts the energy of substrate oxydation into heat instead of ATP. Regulates the production of reactive oxygen species/ROS by mitochondria.

Subunit / interactions. Most probably functions as a monomer. Binds one purine nucleotide per monomer. However, has also been suggested to function as a homodimer or a homotetramer. Tightly associates with cardiolipin in the mitochondrion inner membrane; may stabilize and regulate its activity.

Subcellular location. Mitochondrion inner membrane.

Tissue specificity. Brown adipose tissue.

Post-translational modifications. May undergo sulfenylation upon cold exposure. May increase the sensitivity of UCP1 thermogenic function to the activation by noradrenaline probably through structural effects. May undergo ubiquitin-mediated proteasomal degradation.

Activity regulation. Has no constitutive proton transporter activity and has to be activated by long-chain fatty acids/LCFAs. Inhibited by purine nucleotides. Both purine nucleotides and LCFAs bind the cytosolic side of the transporter and directly compete to activate or inhibit it. Activated by noradrenaline and reactive oxygen species. Despite lacking canonical translational encoding for selenocysteine, a small pool of the protein has been observed to selectively incorporate selenocysteine at ‘Cys-254’. Selenocysteine-modified protein is highly sensitive to redox modification and may constitute a pool of protein highly sensitive to activation by elevated levels of reactive oxygen species (ROS).

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

RefSeq proteins (1): NP_068605* (*=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

Catalyzed reactions (Rhea), 1 shown:

• H(+)(in) = H(+)(out) (RHEA:34979)

UniProt features (43 total): helix 11, topological domain 7, transmembrane region 6, mutagenesis site 4, repeat 3, turn 3, binding site 2, sequence variant 2, strand 2, chain 1, modified residue 1, sequence conflict 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
8HBV	ELECTRON MICROSCOPY	2.51
8J1N	ELECTRON MICROSCOPY	2.51
8HBW	ELECTRON MICROSCOPY	2.57
9FZQ	ELECTRON MICROSCOPY	3.03
12PB	ELECTRON MICROSCOPY	3.1
12OZ	ELECTRON MICROSCOPY	3.3
12OY	ELECTRON MICROSCOPY	3.6
8G8W	ELECTRON MICROSCOPY	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P25874-F1	76.46	0.00

Antibody-complex structures (SAbDab): 5 — 8G8W, 8HBV, 8HBW, 8J1N, 9FZQ

Functional residue map

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

Ligand- & substrate-binding residues (2): 56; 269

Post-translational modifications (1): 254

Mutagenesis-validated functional residues (4):

Position	Phenotype
38	does not affect h(+) transmembrane transport activity.
54	does not affect h(+) transmembrane transport activity.
56	severely reduced h(+) transmembrane transport activity.
269	severely reduced h(+) transmembrane transport activity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-166187	Mitochondrial Uncoupling
R-HSA-167826	The fatty acid cycling model
R-HSA-9844594	Transcriptional regulation of brown and beige adipocyte differentiation by EBF2

MSigDB gene sets: 157 (showing top): BENPORATH_ES_WITH_H3K27ME3, GOBP_RESPONSE_TO_COLD, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_RESPONSE_TO_DIETARY_EXCESS, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_MITOCHONDRIAL_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_MITOCHONDRIAL_TRANSMEMBRANE_TRANSPORT, GOBP_REACTIVE_OXYGEN_SPECIES_BIOSYNTHETIC_PROCESS, MCBRYAN_PUBERTAL_BREAST_4_5WK_DN, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, MARTINEZ_RB1_TARGETS_DN, GOBP_RESPONSE_TO_KETONE, KEGG_PPAR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_REACTIVE_OXYGEN_SPECIES_METABOLIC_PROCESS

GO Biological Process (20): diet induced thermogenesis (GO:0002024), regulation of transcription by RNA polymerase II (GO:0006357), response to temperature stimulus (GO:0009266), response to cold (GO:0009409), response to nutrient levels (GO:0031667), cellular response to hormone stimulus (GO:0032870), cellular response to reactive oxygen species (GO:0034614), brown fat cell differentiation (GO:0050873), cellular response to cold (GO:0070417), cellular response to fatty acid (GO:0071398), positive regulation of cold-induced thermogenesis (GO:0120162), proton transmembrane transport (GO:1902600), regulation of reactive oxygen species biosynthetic process (GO:1903426), cellular response to dehydroepiandrosterone (GO:1903495), mitochondrial transmembrane transport (GO:1990542), adaptive thermogenesis (GO:1990845), monoatomic ion transport (GO:0006811), mitochondrial transport (GO:0006839), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085)

GO Molecular Function (10): GTP binding (GO:0005525), proton transmembrane transporter activity (GO:0015078), oxidative phosphorylation uncoupler activity (GO:0017077), GDP binding (GO:0019003), transmembrane transporter activity (GO:0022857), purine ribonucleotide binding (GO:0032555), long-chain fatty acid binding (GO:0036041), cardiolipin binding (GO:1901612), protein binding (GO:0005515), anion binding (GO:0043168)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial envelope (GO:0005740), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Aerobic respiration and respiratory electron transport	1
Mitochondrial Uncoupling	1
Transcriptional regulation of brown and beige adipocyte differentiation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transmembrane transport	3
cellular response to oxygen-containing compound	2
cellular response to lipid	2
transport	2
guanyl ribonucleotide binding	2
proton transmembrane transport	2
response to dietary excess	1
adaptive thermogenesis	1
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
response to abiotic stimulus	1
response to stress	1
response to temperature stimulus	1
response to stimulus	1
response to hormone	1
cellular response to chemical stimulus	1
cellular response to endogenous stimulus	1
response to reactive oxygen species	1
cellular response to oxidative stress	1
fat cell differentiation	1
response to cold	1
cellular response to stress	1
response to fatty acid	1
positive regulation of multicellular organismal process	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	1
monoatomic cation transmembrane transport	1
regulation of biosynthetic process	1
reactive oxygen species biosynthetic process	1
regulation of reactive oxygen species metabolic process	1
cellular response to alcohol	1
cellular response to ketone	1
response to dehydroepiandrosterone	1
mitochondrial transport	1
temperature homeostasis	1
intracellular transport	1
monoatomic ion transport	1
cellular process	1
purine ribonucleoside triphosphate binding	1
monoatomic cation transmembrane transporter activity	1

Protein interactions and networks

STRING

2288 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UCP1	PRDM16	Q9HAZ2	946
UCP1	PPARGC1A	Q9UBK2	943
UCP1	ADRB3	P13945	937
UCP1	CIDEA	O60543	933
UCP1	PPARG	P37231	918
UCP1	PPARA	Q07869	914
UCP1	LEP	P41159	873
UCP1	INS	P01308	867
UCP1	DIO2	Q92813	845
UCP1	TMEM26	Q6ZUK4	817
UCP1	ADIPOQ	Q15848	802
UCP1	ELOVL3	Q9HB03	794
UCP1	FNDC5	Q8NAU1	793
UCP1	FGF21	Q9NSA1	793
UCP1	LIPE	Q05469	792

IntAct

4 interactions, top by confidence:

A	B	Type	Score
UCP1	NME2P1	psi-mi:“MI:0915”(physical association)	0.590
UCP1	CD44	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (7): NME2P1 (Affinity Capture-MS), GSTM1 (Affinity Capture-MS), NME2P1 (Affinity Capture-MS), UCP1 (Reconstituted Complex), UCP1 (Negative Genetic), NME2P1 (Affinity Capture-MS), CD44 (Affinity Capture-MS)

ESM2 similar proteins: A0A0U2IR85, A0A3G9HRV8, A0PC02, A5DIS9, F4HW79, G3YFS7, K3VFR5, O14281, O81845, O94370, P23500, P25874, P32331, P32332, P38087, P38152, P38921, P40035, Q03028, Q06143, Q10248, Q12375, Q18P97, Q1ECW7, Q3MHI3, Q54B67, Q54BM3, Q54FE6, Q54W11, Q55DY8, Q55GE2, Q6C107, Q6CQR3, Q6DHS9, Q6FTN2, Q6ZT89, Q7DNC3, Q84UC7, Q8BW66, Q8CFJ7

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

5 interactions.

A	Effect	B	Mechanism
BMP7	“up-regulates quantity by expression”	UCP1	“transcriptional regulation”
BMP7	up-regulates	UCP1	“transcriptional regulation”
TRPV4	“down-regulates quantity by repression”	UCP1	“transcriptional regulation”
PPARG	“up-regulates quantity by expression”	UCP1	“transcriptional regulation”
KDM3B	“up-regulates quantity by expression”	UCP1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	44
Likely benign	3
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

699 predictions. Top by Δscore:

Variant	Effect	Δscore
4:140560692:T:A	donor_gain	1.0000
4:140562187:TCTTA:T	donor_loss	1.0000
4:140562188:CTTAC:C	donor_loss	1.0000
4:140562189:TTACC:T	donor_loss	1.0000
4:140562190:TAC:T	donor_loss	1.0000
4:140562191:A:AC	donor_gain	1.0000
4:140562191:AC:A	donor_gain	1.0000
4:140562191:ACC:A	donor_gain	1.0000
4:140562191:ACCC:A	donor_gain	1.0000
4:140562192:C:CC	donor_gain	1.0000
4:140562192:C:G	donor_loss	1.0000
4:140562192:CC:C	donor_gain	1.0000
4:140562192:CCC:C	donor_gain	1.0000
4:140562192:CCCC:C	donor_gain	1.0000
4:140562370:TCATC:T	acceptor_loss	1.0000
4:140562371:CAT:C	acceptor_gain	1.0000
4:140562372:ATC:A	acceptor_loss	1.0000
4:140562373:TC:T	acceptor_loss	1.0000
4:140562374:C:CC	acceptor_gain	1.0000
4:140562374:CTAAA:C	acceptor_loss	1.0000
4:140562375:T:C	acceptor_loss	1.0000
4:140562379:A:AC	acceptor_gain	1.0000
4:140563105:GTTAC:G	donor_loss	1.0000
4:140563106:TTACC:T	donor_loss	1.0000
4:140563107:TACC:T	donor_loss	1.0000
4:140563108:A:C	donor_loss	1.0000
4:140563109:CCTG:C	donor_gain	1.0000
4:140563109:CCTGC:C	donor_loss	1.0000
4:140563207:AGTCC:A	acceptor_gain	1.0000
4:140563208:GTCC:G	acceptor_gain	1.0000

AlphaMissense

1974 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:140563141:C:A	K199N	0.985
4:140563141:C:G	K199N	0.985
4:140563173:A:G	C189R	0.974
4:140563196:A:G	L181P	0.974
4:140562291:T:A	K237N	0.972
4:140562291:T:G	K237N	0.972
4:140559962:A:C	F286L	0.965
4:140559962:A:T	F286L	0.965
4:140559964:A:G	F286L	0.965
4:140568616:T:A	K38N	0.964
4:140568616:T:G	K38N	0.964
4:140563318:C:G	G176R	0.962
4:140563318:C:T	G176R	0.962
4:140562194:C:G	G270R	0.959
4:140562194:C:T	G270R	0.959
4:140562292:T:A	K237I	0.959
4:140563318:C:A	G176W	0.958
4:140563142:T:G	K199T	0.957
4:140568617:T:A	K38I	0.957
4:140563431:T:A	K138I	0.955
4:140563430:T:A	K138N	0.952
4:140563430:T:G	K138N	0.952
4:140563142:T:A	K199M	0.951
4:140563485:C:T	G120D	0.951
4:140563488:G:T	A119D	0.950
4:140568662:G:T	A23E	0.949
4:140562302:C:G	D234H	0.947
4:140562346:G:T	A219D	0.947
4:140563211:C:T	G176E	0.947
4:140567853:C:G	R84P	0.946

dbSNP variants (sampled 300 via entrez): RS1000016299 (4:140568792 C>A,G), RS1000081543 (4:140567204 C>G,T), RS1000121916 (4:140568168 C>A,G), RS1000305568 (4:140562797 A>G), RS1000573339 (4:140563164 G>T), RS1000625632 (4:140562939 A>G), RS1000905884 (4:140561491 C>G,T), RS1000907297 (4:140568783 A>C), RS10011540 (4:140568842 T>G), RS1001253372 (4:140561683 A>C), RS1001738600 (4:140569762 T>G), RS1001806288 (4:140560093 C>T), RS1002247237 (4:140564766 G>A), RS1002298394 (4:140564463 A>G), RS1002328531 (4:140559633 G>A)

Disease associations

OMIM: gene MIM:113730 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST010725_4	Malaria	4.000000e-10
GCST010725_84	Malaria	7.000000e-11
GCST010725_89	Malaria	7.000000e-11

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — Mitochondrial uncoupling proteins

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects reaction, increases expression, affects expression	5
Rosiglitazone	increases abundance, affects cotreatment, decreases reaction, increases expression, decreases abundance (+1 more)	3
Benzo(a)pyrene	decreases methylation, increases expression, affects methylation, decreases expression	3
Dexamethasone	increases expression, affects cotreatment, decreases reaction	3
enniatins	increases expression	2
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases reaction, increases expression	2
cyclopamine	decreases reaction, increases expression	1
methylmercuric chloride	increases expression	1
pirinixic acid	increases activity, affects binding, decreases expression	1
bisphenol A	decreases methylation	1
nuciferine	increases expression, decreases reaction	1
ethyl-p-hydroxybenzoate	increases expression	1
terbufos	increases methylation	1
trichostatin A	increases expression	1
sodium arsenite	increases expression	1
ochratoxin A	decreases expression	1
15-acetyldeoxynivalenol	increases expression	1
CGP 52608	affects binding, increases reaction	1
tofacitinib	decreases expression, decreases reaction, increases expression	1
mirdametinib	decreases reaction, increases expression	1
N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine	decreases reaction, increases expression, decreases expression	1
dorsomorphin	decreases reaction, increases expression	1
ruxolitinib	increases expression	1
2-((4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy)methyl)quinoline	increases expression	1
bisphenol AF	decreases reaction, increases expression, affects cotreatment	1
Arsenic Trioxide	increases expression	1
Orlistat	affects cotreatment, decreases reaction, increases expression	1
Rosmarinic Acid	increases expression, affects cotreatment, decreases reaction	1
Abacavir	increases expression	1
Adenosine Triphosphate	decreases abundance, increases reaction	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D4UY	HuH7-UCP1-KO-c11	Cancer cell line	Male
CVCL_D4UZ	HuH7-UCP1-KO-c9	Cancer cell line	Male
CVCL_TW16	HAP1 UCP1 (-) 1	Cancer cell line	Male
CVCL_TW17	HAP1 UCP1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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