SLC25A1

Chr 22AR

solute carrier family 25 member 1

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

NCBI Gene: 6576ENSG00000100075UniProt: P53007

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]

Primary Disease Associations & Inheritance

Combined D-2- and L-2-hydroxyglutaric aciduriaMIM #615182
AR
Myasthenic syndrome, congenital, 23, presynapticMIM #618197
AR
524
ClinVar variants
319
Pathogenic / LP
0.06
pLI score
0
Active trials
Clinical Summary— SLC25A1
🧬
Gene-Disease Validity (ClinGen)
mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.31) despite low pLI — interpret in context.
📋
ClinVar Variants
319 Pathogenic / Likely Pathogenic· 104 VUS of 524 total submissions

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.
0.65LOEUF
pLI 0.059
Z-score 2.58
OE 0.31 (0.16–0.65)
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.
1.24Z-score
OE missense 0.74 (0.64–0.85)
128 obs / 174.0 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.0.31 (0.16–0.65)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.74 (0.64–0.85)
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.1.15
0≤1.21.6
LoF obs/exp: 5 / 16.2Missense obs/exp: 128 / 174.0Syn Z: -1.01

ClinVar Variant Classifications

524 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic298
Likely Pathogenic21
VUS104
Likely Benign86
Benign12
Conflicting3
298
Pathogenic
21
Likely Pathogenic
104
VUS
86
Likely Benign
12
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
4
0
294
0
298
Likely Pathogenic
6
8
7
0
21
VUS
1
69
29
5
104
Likely Benign
0
3
44
39
86
Benign
0
2
10
0
12
Conflicting
—3
Total118238444524

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

View in ClinVar →

Protein Context — Lollipop Plot

SLC25A1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SLC25A1-related neurometabolic disorder

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Combined D-2- and L-2-hydroxyglutaric aciduria

MIM #615182

Molecular basis of disorder known

Autosomal recessive

Myasthenic syndrome, congenital, 23, presynaptic

MIM #618197

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — SLC25A1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review.
Ohno K et al.·Int J Mol Sci
2023Review
Inactivation of the SLC25A1 gene during embryogenesis induces a unique senescence program controlled by p53.
Kasprzyk-Pawelec A et al.·Cell Death Differ
2025
Opportunities and Challenges for Inhibitors Targeting Citrate Transport and Metabolism in Drug Discovery.
Zhang L et al.·J Med Chem
2023Review
[Congenital myasthenic syndrome related to SLC25A1 gene variant: two cases report and literature review].
Li WH et al.·Zhonghua Er Ke Za Zhi
2021Review
Targeting mitochondrial transporters and metabolic reprogramming for disease treatment.
Anselme M et al.·J Transl Med
2025Review
The genetic interaction map of the human solute carrier superfamily.
Wolf G et al.·Mol Syst Biol
2025
SLC25A1 promotes tumor growth and survival by reprogramming energy metabolism in colorectal cancer.
Yang Y et al.·Cell Death Dis
2021
Increased expression of SLC25A1/CIC causes an autistic-like phenotype with altered neuron morphology.
Rigby MJ et al.·Brain
2022
DMC-BH derivative DMC-GF inhibits the growth of glioma stem cells by targeting the TRIM33/SLC25A1/mitochondrial oxidative phosphorylation pathway.
Shi L et al.·J Transl Med
2025
Deficiency in SLC25A1, encoding the mitochondrial citrate carrier, causes combined D-2- and L-2-hydroxyglutaric aciduria.
Nota B et al.·Am J Hum Genet
2013
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