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…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.26

LOEUF· LoF intol.

LOF

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in STXBP5L?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 51

1,489 rare PASS variants

Rare truncating (LoF)

1 in 1,800

135 rare PASS variants

Rare synonymous (reference)

1 in 93

568 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for STXBP5L. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 74	1 in 1,800
South Asian	~43k	1 in 46	1 in 1,900
Remaining (unassigned)	~30k	1 in 36	1 in 6,000
European (Finnish)	~27k	1 in 150	1 in 4,400
Admixed American	~22k	1 in 51	1 in 470
African / African American	~21k	1 in 56	1 in 2,800
East Asian	~20k	1 in 48	1 in 1,500
Ashkenazi Jewish	~13k	1 in 150	≈ 1 in 3,200
Middle Eastern	~2,884	1 in 50	≈ 1 in 750

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 21 of 26 coding exons well covered in gnomAD exomes; exons 7, 8, 10, 13, 20 marginal. Genomes: all 26.? see exons ↓