STXBP1

Chr 9ADAR

syntaxin binding protein 1

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

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.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
LOFmechanismAD/ARLOEUF 0.091 OMIM phenotype
Clinical SummarySTXBP1
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Gene-Disease Validity (ClinGen)
developmental and epileptic encephalopathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available
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GeneReview available — STXBP1
Authoritative clinical overview · Recommended first read
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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Dual constrained — LoF & missense intolerant
LoF Constraint
0.09LOEUF
pLI 1.000
Z-score 5.46
OE 0.00 (0.000.09)
Highly constrained

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

Missense Constraint
4.26Z-score
OE missense 0.36 (0.310.42)
127 obs / 352.1 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios
LoF OE0.00 (0.000.09)
00.351.4
Missense OE0.36 (0.310.42)
00.61.4
Synonymous OE0.90
01.21.6
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
DN
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 · 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.

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

STXBP1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold
Clinical Literature
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