STX1A

Chr 7

syntaxin 1A

Also known as: HPC-1, P35-1, STX1, SYN1A

NCBI Gene: 6804 ENSG00000106089 UniProt: Q16623 OMIM: 186590

This protein is a key component of the SNARE complex that mediates calcium-dependent neurotransmitter release and synaptic vesicle fusion at presynaptic terminals. Mutations cause early infantile epileptic encephalopathy with autosomal dominant inheritance, typically presenting with seizures beginning in infancy and developmental delays. The gene is highly constrained against loss-of-function variants, reflecting its essential role in synaptic transmission.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the syntaxin superfamily. Syntaxins are nervous system-specific proteins implicated in the docking of synaptic vesicles with the presynaptic plasma membrane. Syntaxins possess a single C-terminal transmembrane domain, a SNARE [Soluble NSF (N-ethylmaleimide-sensitive fusion protein)-Attachment protein REceptor] domain (known as H3), and an N-terminal regulatory domain (Habc). Syntaxins bind synaptotagmin in a calcium-dependent fashion and interact with voltage dependent calcium and potassium channels via the C-terminal H3 domain. This gene product is a key molecule in ion channel regulation and synaptic exocytosis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.29

Clinical Summary— STX1A

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 25 VUS of 55 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.29LOEUF

pLI 0.979

Z-score 3.50

OE 0.06 (0.02–0.29)

Highly constrained

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

Missense Constraint?

2.40Z-score

OE missense 0.51 (0.43–0.61)

98 obs / 191.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.06 (0.02–0.29)

0≤0.351.4

Missense OE?0.51 (0.43–0.61)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 1 / 16.2Missense obs/exp: 98 / 191.4Syn Z: 0.95

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedSTX1A-related neurodevelopmental disorder without epilepsyOTHERAR

moderateSTX1A-related neurodevelopmental disorder with epilepsyOTHERAD

This gene — mechanism propensity

0.6648th %ile

GOF

0.6052th %ile

LOF

0.4825th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative 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.

LOF33% of P/LP variants are LoF · LOEUF 0.29

DNprediction 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

55 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic5

VUS25

Likely Benign15

Benign1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	0	0	1
Likely Pathogenic	1	4	0	0	5
VUS	1	24	0	0	25
Likely Benign	0	6	3	6	15
Benign	0	0	0	1	1
Total	3	34	3	7	47

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

View in ClinVar →

164 pathogenic / likely-pathogenic (of 170) ClinVar copy-number / structural variants overlap STX1A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →