STXBP1

Chr 9ADAR

syntaxin binding protein 1

Also known as: DEE4, MUNC18-1, N-Sec1, NSEC1, P67, RBSEC1, UNC18, unc-18A

NCBI Gene: 6812 ENSG00000136854 UniProt: P61764 OMIM: 602926

The syntaxin-binding protein regulates neurotransmitter release by controlling syntaxin, a transmembrane receptor protein essential for synaptic vesicle fusion. Mutations cause developmental and epileptic encephalopathy 4, inherited in autosomal dominant or recessive patterns, predominantly through loss-of-function mechanisms that disrupt synaptic transmission. The gene is highly intolerant to loss-of-function variants, consistent with haploinsufficiency as a primary disease mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

LOFmechanismAD/ARLOEUF 0.091 OMIM phenotype

Clinical Summary— STXBP1

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Gene-Disease Validity (ClinGen)

developmental and epileptic encephalopathy · 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 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

126 unique Pathogenic / Likely Pathogenic· 168 VUS of 500 total submissions

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Clinical Trials

4 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — STXBP1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.09LOEUF

pLI 1.000

Z-score 5.46

OE 0.00 (0.00–0.09)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint

4.26Z-score

OE missense 0.36 (0.31–0.42)

127 obs / 352.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.00 (0.00–0.09)

0≤0.351.4

Missense OE0.36 (0.31–0.42)

0≤0.61.4

Synonymous OE0.90

0≤1.21.6

LoF obs/exp: 0 / 34.7Missense obs/exp: 127 / 352.1Syn Z: 0.96

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSTXBP1-related epileptic encephalopathy early infantileLOFAD

0.2598th %ile

GOF

0.3590th %ile

LOF

0.71top 10%

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

LOFprediction above median · 1 literature citation · 44% of P/LP variants are LoF · LOEUF 0.09

GOF1 literature citation

Literature Evidence

GOFHomozygous STXBP1 variant causes encephalopathy and gain-of-function in synaptic transmission.PMID:31855252

LOFStxbp1/Munc18-1 haploinsufficiency impairs inhibition and mediates key neurological features of STXBP1 encephalopathy.PMID:32073399

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