SCN9A
Chr 2ADARsodium voltage-gated channel alpha subunit 9
Also known as: ETHA, FEB3B, GEFSP7, HSAN2D, NE-NA, NENA, Nav1.7, PN1
This gene encodes a voltage-gated sodium channel that mediates nociception signaling in peripheral sensory neurons. Mutations cause a spectrum of pain disorders including primary erythermalgia, paroxysmal extreme pain disorder, congenital insensitivity to pain, and small fiber neuropathy, typically through gain-of-function mechanisms that alter channel activity. Inheritance is autosomal dominant for most pain disorders, though some forms show autosomal recessive inheritance.
Refuted — evidence has disproved this relationship
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Mild missense constraint
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.
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.
ClinVar Variant Classifications
500 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 | 17 | 2 | 1 | 0 | 20 |
Likely Pathogenic | 8 | 2 | 0 | 0 | 10 |
VUS | 4 | 288 | 12 | 4 | 308 |
Likely Benign | 0 | 1 | 52 | 94 | 147 |
Benign | 0 | 0 | 1 | 0 | 1 |
| Total | 29 | 293 | 66 | 98 | 486 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
SCN9A · 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 Phase 1b Study of BHV-7000 in Participants With Inherited Erythromelalgia
ENROLLING BY INVITATIONEvaluation And Risk Assessment For Persistent Postsurgical Pain After Breast Surgery
ACTIVE NOT RECRUITINGProspective Study to Determine the Prevalence of Signs of Central Sensitization in Adults With ASD Without Intellectual Developmental Disorders
RECRUITINGSCN9A Gene Expression and Inflammatory Cytokines
NOT YET RECRUITINGExternal Resources
Links to major genomics databases and tools