SLC25A1

Chr 22AR

solute carrier family 25 member 1

Also known as: CIC, CMS23, CTP, D2L2AD, SEA, SLC20A3

NCBI Gene: 6576 ENSG00000100075 UniProt: P53007 OMIM: 190315

The protein transports citrate across the inner mitochondrial membrane as part of the citrate-malate antiporter system. Autosomal recessive mutations cause combined D-2- and L-2-hydroxyglutaric aciduria and congenital myasthenic syndrome type 23 with presynaptic dysfunction. The pathogenic mechanism appears to involve dominant-negative effects that disrupt normal mitochondrial citrate transport.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the mitochondrial carrier subfamily of solute carrier proteins. Members of this family include nuclear-encoded transporters that translocate small metabolites across the mitochondrial membrane. This protein regulates the movement of citrate across the inner membranes of the mitochondria. Mutations in this gene have been associated with combined D-2- and L-2-hydroxyglutaric aciduria. Pseudogenes of this gene have been identified on chromosomes 7, 11, 16, and 19. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.652 OMIM phenotypes

Clinical Summary— SLC25A1

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.31) despite low pLI — interpret in context.

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ClinVar Variants

25 unique Pathogenic / Likely Pathogenic· 90 VUS of 239 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SLC25A1

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?

0.65LOEUF

pLI 0.059

Z-score 2.58

OE 0.31 (0.16–0.65)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.24Z-score

OE missense 0.74 (0.64–0.85)

128 obs / 174.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.31 (0.16–0.65)

0≤0.351.4

Missense OE?0.74 (0.64–0.85)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 5 / 16.2Missense obs/exp: 128 / 174.0Syn Z: -1.01

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSLC25A1-related neurometabolic disorderLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.84top 10%

GOF

0.75top 25%

LOF

0.2971th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

239 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9

Likely Pathogenic16

VUS90

Likely Benign96

Benign11

Conflicting4

Pathogenic

Likely Pathogenic

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	1	1	0	9
Likely Pathogenic	7	9	0	0	16
VUS	2	74	9	5	90
Likely Benign	0	3	49	44	96
Benign	0	2	9	0	11
Conflicting	—				4
Total	16	89	68	49	226

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

View in ClinVar →

390 pathogenic / likely-pathogenic (of 416) ClinVar copy-number / structural variants overlap SLC25A1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →