SLC25A4

Chr 4ADAR

solute carrier family 25 member 4

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

NCBI Gene: 291ENSG00000151729UniProt: P12235

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]

Primary Disease Associations & Inheritance

Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type) ADMIM #617184
AD
Mitochondrial DNA depletion syndrome 12B (cardiomyopathic type) ARMIM #615418
AR
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2MIM #609283
AD
0
ClinVar variants
0
Pathogenic / LP
0.45
pLI score
0
Active trials
Clinical Summary— SLC25A4
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.20) despite low pLI — interpret in context.
Some data sources returned errors (1)

clinvarCount: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.64LOEUF
pLI 0.453
Z-score 2.33
OE 0.20 (0.08–0.64)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.87Z-score
OE missense 0.60 (0.51–0.71)
105 obs / 174.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.20 (0.08–0.64)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.60 (0.51–0.71)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.02
0≤1.21.6
LoF obs/exp: 2 / 9.9Missense obs/exp: 105 / 174.7Syn Z: -0.15

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

SLC25A4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

SLC25A4-related mitochondrial disease

definitive
ARUndeterminedAbsent Gene Product, Altered Gene Product Structure
Cardiac
G2P ↗
splice donor variantmissense variantframeshift variant NMD triggering

SLC25A4-related Fontaine progeroid syndrome

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

SLC25A4-related severe early-onset mitochondrial disease and loss of mitochondrial DNA copy number

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type) AD

MIM #617184

Molecular basis of disorder known

Autosomal dominant

Mitochondrial DNA depletion syndrome 12B (cardiomyopathic type) AR

MIM #615418

Molecular basis of disorder known

Autosomal recessive

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2

MIM #609283

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Mitochondrial DNA maintenance defects.
El-Hattab AW et al.·Biochim Biophys Acta Mol Basis Dis
2017Review
Two new cases of mitochondrial myopathy with exercise intolerance, hyperlactatemia and cardiomyopathy, caused by recessive SLC25A4 mutations.
Tosserams A et al.·Mitochondrion
2018Review
Kearns-Sayre syndrome with rare imaging finding of SLC25A4 Mutation.
Zhao H et al.·Neurosciences (Riyadh)
2022Case report
[Expression of genes psma6 and slc25a4 in patients with acute monocytic leukemia].
Chen YX et al.·Zhongguo Shi Yan Xue Ye Xue Za Zhi
2009Cohort
Porcine β-defensin 2 confers enhanced resistance to swine flu infection in transgenic pigs and alleviates swine influenza virus-induced apoptosis possibly through interacting with host SLC25A4.
Huang J et al.·Antiviral Res
2022
Mitochondrial pathology in inclusion body myositis.
Lindgren U et al.·Neuromuscul Disord
2015
The SLC Family Are Candidate Diagnostic and Prognostic Biomarkers in Clear Cell Renal Cell Carcinoma.
Kang W et al.·Biomed Res Int
2020
An integrated bioinformatic investigation of succinic acid metabolism related genes in ccRCC followed by preliminary validation of SLC25A4 in tumorigenesis.
Yue D et al.·Sci Rep
2025
Recurrent De Novo Dominant Mutations in SLC25A4 Cause Severe Early-Onset Mitochondrial Disease and Loss of Mitochondrial DNA Copy Number.
Thompson K et al.·Am J Hum Genet
2016Case report
Molecular analysis of inherited cardiomyopathy using next generation semiconductor sequencing technologies.
Lu C et al.·J Transl Med
2018
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools