VAMP1

Chr 12ARAD

vesicle associated membrane protein 1

Also known as: CMS25, SAX1, SPAX1, SYB1, VAMP-1

NCBI Gene: 6843 ENSG00000139190 UniProt: P23763 OMIM: 185880

The VAMP1 protein is a key component of the synaptic vesicle docking and fusion machinery at presynaptic nerve terminals, working alongside syntaxins and SNAP25 to enable neurotransmitter release. Mutations cause either autosomal dominant spastic ataxia 1 or autosomal recessive congenital myasthenic syndrome, affecting the central nervous system and neuromuscular junction respectively. The gene shows tolerance to loss-of-function variation (pLI 0.004, LOEUF 1.145), suggesting different pathogenic mechanisms may underlie these distinct clinical presentations.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

Synapotobrevins, syntaxins, and the synaptosomal-associated protein SNAP25 are the main components of a protein complex involved in the docking and/or fusion of synaptic vesicles with the presynaptic membrane. The protein encoded by this gene is a member of the vesicle-associated membrane protein (VAMP)/synaptobrevin family. Mutations in this gene are associated with autosomal dominant spastic ataxia 1. Multiple alternative splice variants have been described, but the full-length nature of some variants has not been defined. [provided by RefSeq, Jul 2014]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Myasthenic syndrome, congenital, 25MIM #618323

Spastic ataxia 1, autosomal dominantMIM #108600

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Myasthenic syndrome, congenital; Spastic ataxia 1, autosomal dominant; no ClinGen or GenCC tier

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.15

LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — VAMP1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.15LOEUF

pLI 0.004

Z-score 1.28

OE 0.54 (0.28–1.15)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.23Z-score

OE missense 0.57 (0.44–0.75)

38 obs / 66.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.54 (0.28–1.15)

0≤0.351.4

Missense OE?0.57 (0.44–0.75)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 5 / 9.2Missense obs/exp: 38 / 66.3Syn Z: 0.47

Background carrier burden — how many people carry a rare variant somewhere in VAMP1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 970

132 rare PASS variants

Rare truncating (LoF)

1 in 5,900

39 rare PASS variants

Rare synonymous (reference)

1 in 1,200

44 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for VAMP1. 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 1,500	1 in 7,800
South Asian	~43k	1 in 270	≈ 1 in 10,000
Remaining (unassigned)	~30k	1 in 1,000	1 in 5,000
European (Finnish)	~27k	1 in 1,500	none seen
Admixed American	~22k	1 in 420	1 in 3,700
African / African American	~21k	1 in 350	≈ 1 in 6,400
East Asian	~20k	1 in 350	1 in 1,600
Ashkenazi Jewish	~13k	≈ 1 in 3,300	≈ 1 in 6,500
Middle Eastern	~2,884	≈ 1 in 2,900	none seen

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): All 5 coding exons well covered in gnomAD exomes and genomes.? see exons ↓