SNAP25

Chr 20AD

synaptosome associated protein 25

Also known as: CMS18, DEE117, RIC-4, RIC4, SEC9, SNAP, SNAP-25, SUP

NCBI Gene: 6616 ENSG00000132639 UniProt: P60880 OMIM: 600322

The protein contributes two of the four helices required for the t-SNARE complex that mediates synaptic vesicle docking and fusion, thereby regulating neurotransmitter release at presynaptic terminals. Mutations cause developmental and epileptic encephalopathy 117 through an autosomal dominant inheritance pattern. The high pLI score (0.99) and low LOEUF score (0.23) indicate the gene is highly intolerant to loss-of-function variants, suggesting haploinsufficiency as the likely pathogenic mechanism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Synaptic vesicle membrane docking and fusion is mediated by SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) located on the vesicle membrane (v-SNAREs) and the target membrane (t-SNAREs). The assembled v-SNARE/t-SNARE complex consists of a bundle of four helices, one of which is supplied by v-SNARE and the other three by t-SNARE. For t-SNAREs on the plasma membrane, the protein syntaxin supplies one helix and the protein encoded by this gene contributes the other two. Therefore, this gene product is a presynaptic plasma membrane protein involved in the regulation of neurotransmitter release. Two alternative transcript variants encoding different protein isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.231 OMIM phenotype

Clinical Summary— SNAP25

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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 0.99). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.23LOEUF

pLI 0.987

Z-score 3.35

OE 0.00 (0.00–0.23)

Highly constrained

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

Missense Constraint?

2.96Z-score

OE missense 0.27 (0.21–0.36)

36 obs / 131.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.23)

0≤0.351.4

Missense OE?0.27 (0.21–0.36)

0≤0.61.4

Synonymous OE?0.62

0≤1.21.6

LoF obs/exp: 0 / 13.0Missense obs/exp: 36 / 131.3Syn Z: 1.93

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSNAP25-related epilepsy and intellectual disabilityLOFAD

This gene — mechanism propensity

0.4983th %ile

GOF

0.72top 25%

LOF

0.56top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.23

GOFprediction above median

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNIn vitro liposome fusion experiments showed that the I67N mutant interfered with calcium-induced fusion, and transfection of the mutation into chromaffin cells showed that it inhibited exocytosis of catecholamine-containing vesicles. The mutation exerted a dominant-negative effect, and Shen et al. (1

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

References