SLC25A12

Chr 2AR

solute carrier family 25 member 12

Also known as: AGC1, ARALAR, DEE39, EIEE39

NCBI Gene: 8604ENSG00000115840UniProt: O75746

This gene encodes a calcium-binding mitochondrial carrier protein. The encoded protein localizes to the mitochondria and is involved in the exchange of aspartate for glutamate across the inner mitochondrial membrane. Polymorphisms in this gene may be associated with autism, and mutations in this gene may also be a cause of global cerebral hypomyelination. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Apr 2012]

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 39MIM #612949
AR
580
ClinVar variants
47
Pathogenic / LP
0.22
pLI score
0
Active trials
Clinical Summary— SLC25A12
🧬
Gene-Disease Validity (ClinGen)
mitochondrial disease · ARModerate

Moderate evidence — consider for supplementary testing

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.
📋
ClinVar Variants
47 Pathogenic / Likely Pathogenic· 241 VUS of 580 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.42LOEUF
pLI 0.216
Z-score 4.34
OE 0.24 (0.14–0.42)
Moderately constrained

More LoF-intolerant than ~75% of genes

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.
2.71Z-score
OE missense 0.61 (0.54–0.68)
226 obs / 373.5 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.24 (0.14–0.42)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.61 (0.54–0.68)
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.1.08
0≤1.21.6
LoF obs/exp: 9 / 37.8Missense obs/exp: 226 / 373.5Syn Z: -0.72

ClinVar Variant Classifications

580 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic37
Likely Pathogenic10
VUS241
Likely Benign262
Benign22
Conflicting8
37
Pathogenic
10
Likely Pathogenic
241
VUS
262
Likely Benign
22
Benign
8
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
2
29
0
37
Likely Pathogenic
6
2
2
0
10
VUS
3
204
31
3
241
Likely Benign
0
1
130
131
262
Benign
0
2
16
4
22
Conflicting
—8
Total15211208138580

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

View in ClinVar →

Protein Context — Lollipop Plot

SLC25A12 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Developmental and epileptic encephalopathy 39

MIM #612949

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre.
Pronicka E et al.·J Transl Med
2016
Mitochondrial Aspartate/Glutamate Carrier SLC25A12 and Autism Spectrum Disorder: a Meta-Analysis.
Aoki Y et al.·Mol Neurobiol
2016Meta-analysis
SLC gene mutations and pediatric neurological disorders: diverse clinical phenotypes in a Saudi Arabian population.
Mir A et al.·Hum Genet
2022
SLC25A12 Missense Variant in Nova Scotia Duck Tolling Retrievers Affected by Cerebellar Degeneration-Myositis Complex (CDMC).
Christen M et al.·Genes (Basel)
2022
Longitudinal MRI findings in patient with SLC25A12 pathogenic variants inform disease progression and classification.
Kavanaugh BC et al.·Am J Med Genet A
2019Case report
[Analysis of a child with developmental disorder and epilepsy due to a homozygous variant of SLC25A12 gene].
Wei S et al.·Zhonghua Yi Xue Yi Chuan Xue Za Zhi
2024Case report
Combined ketone body and glutamine supplementation restores aerobic energy production in AGC1-deficient neuronal progenitors.
Barile SN et al.·Cell Death Dis
2025
Pathogenic variants of the mitochondrial aspartate/glutamate carrier causing citrin deficiency.
Tavoulari S et al.·Trends Endocrinol Metab
2022Review
[Prognostic Value of SLC25A12 Expression in Patients with Acute Myeloid Leukemia Based on Integrated Analysis of Multi-dimensional Clinical Data].
Liu YC et al.·Zhongguo Shi Yan Xue Ye Xue Za Zhi
2020Cohort
A pilot study on glutamate receptor and carrier gene variants and risk of childhood autism spectrum.
Liu J et al.·Metab Brain Dis
2023
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