UCP2

Chr 11

uncoupling protein 2

Also known as: BMIQ4, SLC25A8, UCPH

NCBI Gene: 7351 ENSG00000175567 UniProt: P55851

UCP2 encodes a mitochondrial uncoupling protein that functions as an antiporter, exporting dicarboxylate intermediates from the Krebs cycle in exchange for phosphate and protons across the inner mitochondrial membrane, thereby regulating cellular metabolism, glucose homeostasis, and reactive oxygen species levels. Mutations in UCP2 cause autosomal recessive hyperinsulinemic hypoglycemia, typically presenting in the neonatal period with severe hypoglycemia. The gene shows very low constraint against loss-of-function variants (LOEUF 1.549), suggesting tolerance to complete protein loss.

GeneReviews ResearchSummary from RefSeq, UniProt

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. 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 in many tissues, with the greatest expression in skeletal muscle. It is thought to play a role in nonshivering thermogenesis, obesity and diabetes. Chromosomal order is 5'-UCP3-UCP2-3'. [provided by RefSeq, Jul 2008]

GeneReviews ResearchGenerating clinical summary…

Active trials

201

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.55

LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — UCP2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.55LOEUF

pLI 0.000

Z-score -0.04

OE 1.01 (0.68–1.55)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.00Z-score

OE missense 1.00 (0.89–1.13)

197 obs / 197.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.01 (0.68–1.55)

0≤0.351.4

Missense OE?1.00 (0.89–1.13)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 15 / 14.8Missense obs/exp: 197 / 197.1Syn Z: 0.96

Background carrier burden — how many people carry a rare variant somewhere in UCP2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 110

413 rare PASS variants

Rare truncating (LoF)

1 in 920

80 rare PASS variants

Rare synonymous (reference)

1 in 630

142 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for UCP2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 190	1 in 920
South Asian	~43k	1 in 94	1 in 630
Remaining (unassigned)	~30k	1 in 82	1 in 1,200
European (Finnish)	~27k	1 in 420	≈ 1 in 13,000
Admixed American	~22k	1 in 99	1 in 830
African / African American	~21k	1 in 90	1 in 1,100
East Asian	~20k	1 in 94	1 in 470
Ashkenazi Jewish	~13k	1 in 500	none seen
Middle Eastern	~2,884	1 in 160	1 in 480

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 6 coding exons well covered in gnomAD exomes and genomes.? see exons ↓