SCN9A

Chr 2

sodium voltage-gated channel alpha subunit 9

Also known as: ETHA, FEB3B, GEFSP7, HSAN2D, NE-NA, NENA, Nav1.7, PN1

NCBI Gene: 6335ENSG00000169432UniProt: Q15858

This gene encodes a voltage-gated sodium channel which plays a significant role in nociception signaling. Mutations in this gene have been associated with primary erythermalgia, channelopathy-associated insensitivity to pain, and paroxysmal extreme pain disorder. [provided by RefSeq, Aug 2009]

Primary Disease Associations & Inheritance

UniProtPrimary erythermalgia
UniProtIndifference to pain, congenital, autosomal recessive
UniProtParoxysmal extreme pain disorder
3111
ClinVar variants
15
Pathogenic / LP
0.00
pLI score
3
Active trials
Clinical Summary— SCN9A
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
15 Pathogenic / Likely Pathogenic· 97 VUS of 3111 total submissions
💊
Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (2)

omim: Error: OMIM fetch failed: 429

pubmed: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.71LOEUF
pLI 0.000
Z-score 3.70
OE 0.55 (0.43–0.71)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.06Z-score
OE missense 0.91 (0.86–0.96)
913 obs / 1007.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.55 (0.43–0.71)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.91 (0.86–0.96)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.07
0≤1.21.6
LoF obs/exp: 43 / 78.3Missense obs/exp: 913 / 1007.5Syn Z: -1.08

ClinVar Variant Classifications

3111 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9
Likely Pathogenic6
VUS97
Likely Benign87
Benign1
9
Pathogenic
6
Likely Pathogenic
97
VUS
87
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
0
4
0
9
Likely Pathogenic
6
0
0
0
6
VUS
0
85
9
3
97
Likely Benign
0
0
27
60
87
Benign
0
0
1
0
1
Total11854163200

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.

Gene2Phenotype Curations

SCN9A-related erythromelalgia, primary

definitive
ADGain Of FunctionAltered Gene Product Structure
Skin
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Pain That Challenges Survival: A Novel SCN9A Variant (p.Leu1623Gln) Causing Carbamazepine-Refractory Paroxysmal Extreme Pain Disorder in a Chinese Family - Case Report.
Yip MK et al.·Reports (MDPI)
2026🔓 Open AccessCase report
Diffusion Tensor Imaging Reveals Altered Centrality of Pain-Related Regions in SCN9A-Associated Small Fiber Neuropathy.
Drenthen GS et al.·J Neuroimaging
2025🔓 Open Access
Association of compression pressure and SCN8A and SCN9A gene polymorphisms with the recurrence of balloon compression-treated trigeminal neuralgia.
Wang X et al.·Neurosurg Rev
2025
SCN9A should not be considered an epilepsy gene; Refuting a gene-disease association.
Ghanty I et al.·Epilepsia
2025🔓 Open Access
Effect of pain-related sodium channels SCN9A and SCN10A polymorphisms in migraine chronification.
Kilic E et al.·Neurol Res
2025
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Breast CancerChronic PainAcute Pain

Evaluation And Risk Assessment For Persistent Postsurgical Pain After Breast Surgery

ACTIVE NOT RECRUITING
NCT03408717KK Women's and Children's HospitalStarted 2018-01-03
QuestionnairesMechanical Temporal Summation assessmentPain threshold assessment
Pulpitis - Irreversible

Single Gene Polymorphism and the Success Rate of Inferior Alveolar Nerve Block

RECRUITING
NCT07012382Phase NAJamia Millia IslamiaStarted 2025-05-10
Inferior Alveolar Nerve BlockInferior-Alveolar-Nerve-Block
Familial Erythromelalgia

A Phase 1b Study of BHV-7000 in Participants With Inherited Erythromelalgia

ENROLLING BY INVITATION
NCT07262268Phase PHASE1Biohaven Therapeutics Ltd.Started 2026-01-15
BHV-7000Placebo

External Resources

Links to major genomics databases and tools