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…

Primary Disease Associations & Inheritance

Combined D-2- and L-2-hydroxyglutaric aciduriaMIM #615182

Myasthenic syndrome, congenital, 23, presynapticMIM #618197

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · mitochondrial disease · AR · ClinGen 2023

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.65

LOEUF

LOF

Mechanism· G2P

📖

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

Background carrier burden — how many people carry a rare variant somewhere in SLC25A1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 170

405 rare PASS variants

Rare truncating (LoF)

1 in 2,100

67 rare PASS variants

Rare synonymous (reference)

1 in 290

223 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SLC25A1. 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 2,200
South Asian	~43k	1 in 220	1 in 4,300
Remaining (unassigned)	~30k	1 in 160	1 in 4,000
European (Finnish)	~27k	1 in 2,000	≈ 1 in 26,000
Admixed American	~22k	1 in 230	1 in 1,900
African / African American	~21k	1 in 170	1 in 4,100
East Asian	~20k	1 in 220	≈ 1 in 6,600
Ashkenazi Jewish	~13k	1 in 310	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 370	≈ 1 in 2,900

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): 8 of 9 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 9.? see exons ↓