SCN2A
Chr 2ADsodium voltage-gated channel alpha subunit 2
Also known as: BFIC3, BFIS3, BFNIS, DEE11, EA9, EIEE11, HBA, HBSCI
The protein encoded by this gene forms voltage-gated sodium channels that generate and propagate action potentials in neurons. Mutations cause developmental and epileptic encephalopathy 11, benign familial infantile seizures type 3, and episodic ataxia type 9 through an autosomal dominant inheritance pattern. Disease mechanisms are variant-dependent, with early infantile seizures typically caused by gain-of-function mutations and later-onset seizures often resulting from loss-of-function mutations.
Definitive — sufficient evidence for diagnostic panels
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Among the most LoF-intolerant genes (~top 3%)
Extremely missense-constrained (top ~0.01%)
Nav1.2 is monomeric. Early-onset DEE variants (<3 months) are GOF with increased persistent current. Later-onset epilepsy and ASD/ID variants are LOF. Mechanism is age-of-onset and variant-dependent.
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.
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
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
581 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 30 | 21 | 18 | 0 | 69 |
Likely Pathogenic | 15 | 44 | 4 | 0 | 63 |
VUS | 4 | 259 | 12 | 5 | 280 |
Likely Benign | 0 | 2 | 44 | 83 | 129 |
Benign | 0 | 2 | 7 | 8 | 17 |
Conflicting | — | 17 | |||
| Total | 49 | 328 | 85 | 96 | 575 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
SCN2A · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
A Cohort Study of Disease Prediction Model for High-risk Population With Bipolar Disorder
RECRUITINGOnline Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight
RECRUITINGExploring the Physiological Mechanisms of Austism Through Organoids
NOT YET RECRUITINGExternal Resources
Links to major genomics databases and tools