SLC32A1

Chr 20

solute carrier family 32 member 1

Also known as: DEE114, GEFSP12, VGAT, VIAAT, VIAAT GEFSP12

NCBI Gene: 140679 ENSG00000101438 UniProt: Q9H598

The encoded protein transports GABA and glycine into synaptic vesicles as an integral membrane protein. Mutations cause developmental and epileptic encephalopathy 114 and generalized epilepsy with febrile seizures plus type 12 through an autosomal dominant inheritance pattern. The pathogenic mechanism involves gain-of-function mutations that disrupt normal inhibitory neurotransmitter packaging.

ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene is an integral membrane protein involved in gamma-aminobutyric acid (GABA) and glycine uptake into synaptic vesicles. The encoded protein is a member of amino acid/polyamine transporter family II. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.32

Clinical Summary— SLC32A1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 83 VUS of 95 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

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.32LOEUF

pLI 0.967

Z-score 3.35

OE 0.07 (0.02–0.32)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.30Z-score

OE missense 0.63 (0.56–0.71)

188 obs / 300.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.07 (0.02–0.32)

0≤0.351.4

Missense OE?0.63 (0.56–0.71)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 1 / 15.0Missense obs/exp: 188 / 300.3Syn Z: -0.43

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateSLC32A1-related developmental and epileptic encephalopathyOTHERAD

This gene — mechanism propensity

0.5576th %ile

GOF

0.75top 25%

LOF

0.4726th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.32

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

95 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic5

VUS83

Likely Benign4

Benign1

Conflicting1

Pathogenic

Likely 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	0	1	0	0	1
Likely Pathogenic	0	5	0	0	5
VUS	3	80	0	0	83
Likely Benign	0	0	0	4	4
Benign	0	1	0	0	1
Conflicting	—				1
Total	3	87	0	4	95

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

View in ClinVar →

7 pathogenic / likely-pathogenic (of 10) ClinVar copy-number / structural variants overlap SLC32A1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →