SV2A

Chr 1AR

synaptic vesicle glycoprotein 2A

Also known as: DEE113, SLC22B1, SV2

NCBI Gene: 9900 ENSG00000159164 UniProt: Q7L0J3 OMIM: 185860

SV2A encodes a synaptic vesicle protein that enhances low-frequency neurotransmission by maintaining the readily releasable pool of secretory vesicles and positively regulating vesicle fusion. Autosomal recessive mutations cause developmental and epileptic encephalopathy 113, typically presenting in early childhood. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.414), suggesting some tolerance to heterozygous loss.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is one of three related synaptic vesicle proteins. The encoded protein may interact with synaptotagmin to enhance low frequency neurotransmission in quiescent neurons. [provided by RefSeq, Jun 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.411 OMIM phenotype

Clinical Summary— SV2A

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 79 VUS of 115 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SV2A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.41LOEUF

pLI 0.228

Z-score 4.36

OE 0.24 (0.14–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.12Z-score

OE missense 0.72 (0.66–0.79)

328 obs / 455.0 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.24 (0.14–0.41)

0≤0.351.4

Missense OE?0.72 (0.66–0.79)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 9 / 38.0Missense obs/exp: 328 / 455.0Syn Z: 0.20

This gene — mechanism propensity

0.6646th %ile

GOF

0.73top 25%

LOF

0.2969th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

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.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

115 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic2

VUS79

Likely Benign16

Benign5

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Synonymous	Total
Pathogenic	1	0	0	1
Likely Pathogenic	2	0	0	2
VUS	1	77	1	79
Likely Benign	0	3	13	16
Benign	0	0	5	5
Total	4	80	19	103

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap SV2A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →