STX1B

Chr 16AD

syntaxin 1B

Also known as: GEFSP9, STX1B1, STX1B2

NCBI Gene: 112755 ENSG00000099365 UniProt: P61266 OMIM: 601485

STX1B encodes syntaxin-1B, a membrane protein that mediates synaptic vesicle exocytosis and neurotransmitter release at synapses. Autosomal dominant mutations cause generalized epilepsy with febrile seizures plus, type 9, likely through impaired synaptic transmission. The high pLI score (0.99) indicates the gene is highly intolerant to loss-of-function variants.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene belongs to a family of proteins thought to play a role in the exocytosis of synaptic vesicles. Vesicle exocytosis releases vesicular contents and is important to various cellular functions. For instance, the secretion of transmitters from neurons plays an important role in synaptic transmission. After exocytosis, the membrane and proteins from the vesicle are retrieved from the plasma membrane through the process of endocytosis. Mutations in this gene have been identified as one cause of fever-associated epilepsy syndromes. A possible link between this gene and Parkinson's disease has also been suggested. [provided by RefSeq, Jan 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.271 OMIM phenotype

Clinical Summary— STX1B

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Gene-Disease Validity (ClinGen)

generalized epilepsy with febrile seizures plus · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

73 unique Pathogenic / Likely Pathogenic· 167 VUS of 448 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — STX1B

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.27LOEUF

pLI 0.988

Z-score 3.68

OE 0.06 (0.02–0.27)

Highly constrained

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

Missense Constraint?

2.94Z-score

OE missense 0.38 (0.31–0.47)

68 obs / 178.7 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.06 (0.02–0.27)

0≤0.351.4

Missense OE?0.38 (0.31–0.47)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 1 / 17.7Missense obs/exp: 68 / 178.7Syn Z: 0.30

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongSTX1B-related generalized epilepsy with febrile seizures plusLOFAD

This gene — mechanism propensity

0.6646th %ile

GOF

0.6150th %ile

LOF

0.4627th %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.

LOF1 literature citation · 75% of P/LP variants are LoF · LOEUF 0.27

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.

Literature Evidence

LOFInactivation of syntaxin 1B likely accounts for the patient's cortical hyperexcitability because mutations of syntaxin 1B cause febrile seizures with or without epilepsy, haploinsufficiency of the STX1B is associated with myoclonic astatic epilepsy, and antisense knockdown of stx1b in zebrafish larv1

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

References

1.PMID 27648472 ↗

ClinVar Variant Classifications

448 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic37

Likely Pathogenic36

VUS167

Likely Benign170

Benign24

Conflicting10

Pathogenic

Likely Pathogenic

167

VUS

170

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	29	5	3	0	37
Likely Pathogenic	26	9	1	0	36
VUS	2	139	23	3	167
Likely Benign	0	2	101	67	170
Benign	0	0	20	4	24
Conflicting	—				10
Total	57	155	148	74	444

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

View in ClinVar →

15 pathogenic / likely-pathogenic (of 26) ClinVar copy-number / structural variants overlap STX1B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →