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

This gene encodes a syntaxin-binding protein. The encoded protein appears to play a role in release of neurotransmitters via regulation of syntaxin, a transmembrane attachment protein receptor. Mutations in this gene have been associated with infantile epileptic encephalopathy-4. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.091 OMIM phenotype

Clinical Summary— STXBP1

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Gene-Disease Validity (ClinGen)

genetic 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

425 unique Pathogenic / Likely Pathogenic· 312 VUS of 1302 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 OE?0.00 (0.00–0.09)

0≤0.351.4

Missense OE?0.36 (0.31–0.42)

0≤0.61.4

Synonymous OE?0.90

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

This gene — mechanism propensity

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 · 56% of P/LP variants are LoF · LOEUF 0.09 · ClinGen HI: Sufficient evidence for dosage pathogenicity

GOF1 literature citation

Literature Evidence

GOFHomozygous STXBP1 variant causes encephalopathy and gain-of-function in synaptic transmission.1

LOFStxbp1/Munc18-1 haploinsufficiency impairs inhibition and mediates key neurological features of STXBP1 encephalopathy.2

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

References

ClinVar Variant Classifications

1302 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic279

Likely Pathogenic146

VUS312

Likely Benign426

Benign74

Conflicting55

279

Pathogenic

146

Likely Pathogenic

312

VUS

426

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	200	47	31	1	279
Likely Pathogenic	40	92	14	0	146
VUS	6	274	26	6	312
Likely Benign	1	39	215	171	426
Benign	0	16	52	6	74
Conflicting	—				55
Total	247	468	338	184	1,292

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

View in ClinVar →

52 pathogenic / likely-pathogenic (of 55) ClinVar copy-number / structural variants overlap STXBP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →