STXBP1

Chr 9ADAR

syntaxin binding protein 1

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

NCBI Gene: 6812ENSG00000136854UniProt: P61764

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]

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 4MIM #612164
ADAR
691
ClinVar variants
217
Pathogenic / LP
1.00
pLI score· haploinsufficient
4
Active trials
Clinical Summary— STXBP1
🧬
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.
📋
ClinVar Variants
217 Pathogenic / Likely Pathogenic· 193 VUS of 691 total submissions
💊
Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.09)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.36 (0.31–0.42)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.90
0≤1.21.6
LoF obs/exp: 0 / 34.7Missense obs/exp: 127 / 352.1Syn Z: 0.96

ClinVar Variant Classifications

691 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic144
Likely Pathogenic73
VUS193
Likely Benign215
Benign41
Conflicting25
144
Pathogenic
73
Likely Pathogenic
193
VUS
215
Likely Benign
41
Benign
25
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
62
21
61
0
144
Likely Pathogenic
20
37
16
0
73
VUS
4
163
23
3
193
Likely Benign
0
13
121
81
215
Benign
0
13
27
1
41
Conflicting
—25
Total8624724885691

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

View 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.

Gene2Phenotype Curations

STXBP1-related epileptic encephalopathy early infantile

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Developmental and epileptic encephalopathy 4

MIM #612164

Molecular basis of disorder known

Autosomal dominantAutosomal recessive
📖
GeneReview available — STXBP1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy.
Stamberger H et al.·Neurology
2016Review
STXBP1 encephalopathies: Clinical spectrum, disease mechanisms, and therapeutic strategies.
Abramov D et al.·J Neurochem
2021Review
De novo genic mutations among a Chinese autism spectrum disorder cohort.
Wang T et al.·Nat Commun
2016Cohort
Assessing the landscape of STXBP1-related disorders in 534 individuals.
Xian J et al.·Brain
2022
Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders.
Lindy AS et al.·Epilepsia
2018Cohort
Clinical and genetic characteristics and prenatal diagnosis of patients presented GDD/ID with rare monogenic causes.
Lin L et al.·Orphanet J Rare Dis
2020Cohort
STXBP1-Related Disorders: Clinical Presentation, Molecular Function, Treatment, and Future Directions.
Freibauer A et al.·Genes (Basel)
2023Review
Genetic determinants of global developmental delay and intellectual disability in Ukrainian children.
Shchubelka K et al.·J Neurodev Disord
2024
Delineating clinical and developmental outcomes in STXBP1-related disorders.
Xian J et al.·Brain
2023
Current and Emerging Precision Therapies for Developmental and Epileptic Encephalopathies.
Samanta D et al.·Pediatr Neurol
2025Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10
STXBP1 Encephalopathy With Epilepsy

Phenotyping and Identification of Biological Markers in STXBP1 Encephalopathy

NOT YET RECRUITING
NCT06356233Fundación Iniciativa para las Neurociencias (FINCE)Started 2024-05-01
No intervention will be performed
STXBP1 Encephalopathy With Epilepsy

A Multicentric European Study to Promote Clinical Trial Readiness for STXBP1-related Disorders

RECRUITING
NCT06625112European STXBP1 ConsortiumStarted 2025-11-04
STXBP1 Encephalopathy With Epilepsy, SLC6A1 Neurodevelopmental DisorderDevelopmental and Epileptic Encephalopathy

Phenylbutyrate for Monogenetic Developmental and Epileptic Encephalopathy

ACTIVE NOT RECRUITING
NCT04937062Phase EARLY_PHASE1Weill Medical College of Cornell UniversityStarted 2021-03-01
Glycerol Phenylbutyrate 1100 MG/ML [Ravicti]

External Resources

Links to major genomics databases and tools