SLC25A35

Chr 17

solute carrier family 25 member 35

NCBI Gene: 399512 ENSG00000125434 UniProt: Q3KQZ1

SLC25A35 encodes a mitochondrial carrier protein that exchanges dicarboxylates and sulfur oxoanions across the inner mitochondrial membrane. Mutations cause autosomal recessive developmental and epileptic encephalopathy with microcephaly, affecting the nervous system with seizures typically beginning in early infancy. The gene shows minimal constraint against loss-of-function variants in the general population.

ResearchSummary from RefSeq, UniProt

SLC25A35 belongs to the SLC25 family of mitochondrial carrier proteins (Haitina et al., 2006 [PubMed 16949250]).[supplied by OMIM, Mar 2008]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.38

Clinical Summary— SLC25A35

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

145 VUS of 246 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.38LOEUF

pLI 0.000

Z-score 0.48

OE 0.87 (0.56–1.38)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.27Z-score

OE missense 0.94 (0.83–1.07)

164 obs / 174.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.87 (0.56–1.38)

0≤0.351.4

Missense OE?0.94 (0.83–1.07)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 13 / 15.0Missense obs/exp: 164 / 174.0Syn Z: 0.03

This gene — mechanism propensity

0.75top 25%

GOF

0.72top 25%

LOF

0.3259th %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

246 submitted variants in ClinVar

ClinVar

Classification Summary

VUS145

Likely Benign82

Benign9

Conflicting2

145

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	12	124	6	3	145
Likely Benign	5	12	34	31	82
Benign	0	0	6	3	9
Conflicting	—				2
Total	17	136	46	37	238

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap SLC25A35 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →