SLC25A11

Chr 17AD

solute carrier family 25 member 11

Also known as: OGC, PGL6, PPGL6, SLC20A4

NCBI Gene: 8402 ENSG00000108528 UniProt: Q02978 OMIM: 604165

The oxoglutarate/malate carrier catalyzes the transport of 2-oxoglutarate across the inner mitochondrial membrane in exchange for malate and other dicarboxylic acids, contributing to key metabolic processes including the malate-aspartate shuttle, gluconeogenesis, and nitrogen metabolism. Mutations cause pheochromocytoma/paraganglioma syndrome 6 with autosomal dominant inheritance. The gene shows significant constraint against loss-of-function variants (LOEUF 0.512), indicating intolerance to complete protein loss.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The oxoglutarate/malate carrier transports 2-oxoglutarate across the inner membranes of mitochondria in an electroneutral exchange for malate or other dicarboxylic acids (summary by Iacobazzi et al., 1992 [PubMed 1457818]).[supplied by OMIM, Jan 2011]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.511 OMIM phenotype

Clinical Summary— SLC25A11

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.53) — some intolerance to loss-of-function variants.

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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 45 VUS of 93 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?

0.51LOEUF

pLI 0.535

Z-score 2.89

OE 0.20 (0.09–0.51)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.49Z-score

OE missense 0.51 (0.43–0.60)

105 obs / 205.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.20 (0.09–0.51)

0≤0.351.4

Missense OE?0.51 (0.43–0.60)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 3 / 15.2Missense obs/exp: 105 / 205.4Syn Z: -0.52

This gene — mechanism propensity

0.7326th %ile

GOF

0.6542th %ile

LOF

0.4234th %ile

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

DNprediction above median

GOFprediction above median

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.

ClinVar Variant Classifications

93 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

VUS45

Likely Benign34

Benign3

Conflicting4

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	1	3	0	1	5
Likely Pathogenic	0	0	0	0	0
VUS	1	40	0	4	45
Likely Benign	0	0	18	16	34
Benign	0	0	3	0	3
Conflicting	—				4
Total	2	43	21	21	91

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

View in ClinVar →

25 pathogenic / likely-pathogenic (of 39) ClinVar copy-number / structural variants overlap SLC25A11 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →