STXBP5L

Chr 3

syntaxin binding protein 5L

Also known as: LLGL4

NCBI Gene: 9515 ENSG00000145087 UniProt: Q9Y2K9 OMIM: 609381

The protein inhibits exocytosis in neurosecretory cells by regulating SNARE proteins involved in vesicle fusion, including inhibition of insulin secretion in pancreatic beta-cells and modulation of neurotransmitter release at synapses. Mutations cause infantile-onset neurodegenerative disorder with autosomal recessive inheritance. This gene is highly constrained against loss-of-function variants, indicating that functional copies are critical for normal development and cellular function.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is similar to syntaxin-binding protein 5 and contains ten N-terminal WD40 repeats, four variable region WD40 repeats, and a C-terminal R-SNARE domain. Studies of the orthologous proteins in mouse and rat have shown that the encoded protein may inhibit exocytosis in neurosecretory cells, and may negatively regulate the secretion of insulin. A missense variant in this gene is likely the cause of an infantile-onset neurodegenerative disorder diagnosed in two siblings of consanguineous parents. [provided by RefSeq, Jan 2017]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.26

Clinical Summary— STXBP5L

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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

147 VUS of 176 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.26LOEUF

pLI 0.999

Z-score 6.32

OE 0.15 (0.09–0.26)

Highly constrained

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

Missense Constraint?

1.71Z-score

OE missense 0.81 (0.75–0.87)

511 obs / 631.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.15 (0.09–0.26)

0≤0.351.4

Missense OE?0.81 (0.75–0.87)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 10 / 64.9Missense obs/exp: 511 / 631.9Syn Z: -0.23

This gene — mechanism propensity

0.4190th %ile

GOF

0.3788th %ile

LOF

0.71top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.26

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

176 submitted variants in ClinVar

ClinVar

Classification Summary

VUS147

Likely Benign11

Benign2

Conflicting1

147

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	2	145	0	0	147
Likely Benign	0	4	2	5	11
Benign	0	1	1	0	2
Conflicting	—				1
Total	2	150	3	5	161

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 23) ClinVar copy-number / structural variants overlap STXBP5L — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →