SLC25A12

Chr 2AR

solute carrier family 25 member 12

Also known as: AGC1, ARALAR, DEE39, EIEE39

NCBI Gene: 8604 ENSG00000115840 UniProt: O75746 OMIM: 603667

This gene encodes a calcium-binding mitochondrial carrier protein that exchanges aspartate for glutamate across the inner mitochondrial membrane. Mutations cause developmental and epileptic encephalopathy 39 through an autosomal recessive inheritance pattern, with a predicted gain-of-function mechanism. The protein dysfunction may also result in global cerebral hypomyelination.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.421 OMIM phenotype

Clinical Summary— SLC25A12

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ARModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.

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ClinVar Variants

23 unique Pathogenic / Likely Pathogenic· 235 VUS of 566 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

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?

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?

LoF OE?0.24 (0.14–0.42)

0≤0.351.4

Missense OE?0.61 (0.54–0.68)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 9 / 37.8Missense obs/exp: 226 / 373.5Syn Z: -0.72

This gene — mechanism propensity

0.74top 25%

GOF

0.82top 10%

LOF

0.3164th %ile

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

GOFprediction above median

DNprediction above median

LOF74% of P/LP variants are LoF · LOEUF 0.42

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.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

566 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13

Likely Pathogenic10

VUS235

Likely Benign263

Benign22

Conflicting8

Pathogenic

Likely Pathogenic

235

VUS

263

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	9	2	2	0	13
Likely Pathogenic	8	2	0	0	10
VUS	3	209	20	3	235
Likely Benign	0	1	130	132	263
Benign	0	2	16	4	22
Conflicting	—				8
Total	20	216	168	139	551

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

View in ClinVar →

24 pathogenic / likely-pathogenic (of 30) ClinVar copy-number / structural variants overlap SLC25A12 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →