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…

DN/LOFmechanismAD/ARLOEUF 0.643 OMIM phenotypes

Clinical Summary— SLC25A4

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Gene-Disease Validity (ClinGen)

Leigh syndrome · ADLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.20) despite low pLI — interpret in context.

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ClinVar Variants

23 unique Pathogenic / Likely Pathogenic· 158 VUS of 309 total submissions

Explore recent and relevant literature in Research Assistant →

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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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSLC25A4-related mitochondrial diseaseOTHERAR

strongSLC25A4-related Fontaine progeroid syndromeOTHERAD

strongSLC25A4-related severe early-onset mitochondrial disease and loss of mitochondrial DNA copy numberOTHERAD

Mechanism Note (variant-dependent)

DNLOF— mechanism depends on specific variant

Mitochondrial ADP/ATP carrier. Dominant DN variants cause adPEO with mtDNA deletions. Recessive LOF causes mitochondrial myopathy and cardiomyopathy. Mechanism depends on inheritance pattern.1

This gene — mechanism propensity

0.82top 10%

GOF

0.7126th %ile

LOF

0.3550th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNHowever, expression of aac2(A128P) results in depolarization, structural swelling and disintegration of mitochondria, and ultimately an arrest of cell growth in a dominant-negative manner.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

ClinVar Variant Classifications

309 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13

Likely Pathogenic10

VUS158

Likely Benign85

Benign35

Conflicting3

Pathogenic

Likely Pathogenic

158

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	7	6	0	0	13
Likely Pathogenic	4	6	0	0	10
VUS	3	107	47	1	158
Likely Benign	0	3	21	61	85
Benign	0	0	33	2	35
Conflicting	—				3
Total	14	122	101	64	304

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

113 pathogenic / likely-pathogenic (of 142) ClinVar copy-number / structural variants overlap SLC25A4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →