SLC25A4

Chr 4ADAR

solute carrier family 25 member 4

Also known as: AAC1, ANT, ANT 1, ANT1, MTDPS12, MTDPS12A, PEO2, PEO3

NCBI Gene: 291 ENSG00000151729 UniProt: P12235 OMIM: 103220

The protein functions as a gated pore in the inner mitochondrial membrane that translocates ADP from the cytoplasm into the mitochondrial matrix and ATP from the mitochondrial matrix into the cytoplasm, forming a homodimer essential for cellular energy metabolism. Mutations cause mitochondrial DNA depletion syndrome with cardiomyopathy (both autosomal dominant and recessive forms) and autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions. The disease mechanism can vary by variant type, with some mutations likely acting through dominant-negative effects that disrupt the homodimer function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene is a member of the mitochondrial carrier subfamily of solute carrier protein genes. The product of this gene functions as a gated pore that translocates ADP from the cytoplasm into the mitochondrial matrix and ATP from the mitochondrial matrix into the cytoplasm. The protein forms a homodimer embedded in the inner mitochondria membrane. Mutations in this gene have been shown to result in autosomal dominant progressive external opthalmoplegia and familial hypertrophic cardiomyopathy. [provided by RefSeq, Jun 2013]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type) ADMIM #617184

Mitochondrial DNA depletion syndrome 12B (cardiomyopathic type) ARMIM #615418

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2MIM #609283

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessive · AR · ClinGen 2017
Definitive · mitochondrial disease · AR · G2P
Strong · mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominant · AD · Labcorp Genetics (formerly Invitae)
Strong · progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2 · AD · Labcorp Genetics (formerly Invitae)
Limited · Leigh syndrome · AD · ClinGen 2021 — not for standalone diagnostic reporting

+3 more curated pairs

Interpreting a novel variant

Both dominant negative and loss of function mechanisms are described for this gene and which one applies is variant-dependent. Do not assume a null variant is — or isn't — the pathogenic class without checking the specific variant against curated evidence.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

—

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.64

LOEUF

DN/LOF*

Mechanism· annotated

📖

GeneReview available — SLC25A4

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.64LOEUF

pLI 0.453

Z-score 2.33

OE 0.20 (0.08–0.64)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.87Z-score

OE missense 0.60 (0.51–0.71)

105 obs / 174.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.20 (0.08–0.64)

0≤0.351.4

Missense OE?0.60 (0.51–0.71)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 2 / 9.9Missense obs/exp: 105 / 174.7Syn Z: -0.15

Background carrier burden — how many people carry a rare variant somewhere in SLC25A4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 520

290 rare PASS variants

Rare truncating (LoF)

1 in 5,400

44 rare PASS variants

Rare synonymous (reference)

1 in 490

136 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SLC25A4. 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 650	1 in 4,200
South Asian	~43k	1 in 550	≈ 1 in 14,000
Remaining (unassigned)	~30k	1 in 530	≈ 1 in 7,400
European (Finnish)	~27k	1 in 1,800	≈ 1 in 8,900
Admixed American	~22k	1 in 360	≈ 1 in 5,200
African / African American	~21k	1 in 460	≈ 1 in 8,400
East Asian	~20k	1 in 250	1 in 3,500
Ashkenazi Jewish	~13k	1 in 810	none seen
Middle Eastern	~2,884	1 in 480	≈ 1 in 2,800

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.