SCN9A

Chr 2ADAR

sodium voltage-gated channel alpha subunit 9

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

NCBI Gene: 6335 ENSG00000169432 UniProt: Q15858 OMIM: 603415

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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

GOFmechanismAD/ARLOEUF 0.715 OMIM phenotypes

Clinical Summary— SCN9A

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Gene-Disease Validity (ClinGen)

epilepsy · ADRefuted

Refuted — evidence has disproved this relationship

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Clinical Trials

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

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GeneReview available — SCN9A

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.71LOEUF

pLI 0.000

Z-score 3.70

OE 0.55 (0.43–0.71)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.06Z-score

OE missense 0.91 (0.86–0.96)

913 obs / 1007.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.55 (0.43–0.71)

0≤0.351.4

Missense OE?0.91 (0.86–0.96)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 43 / 78.3Missense obs/exp: 913 / 1007.5Syn Z: -1.08

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSCN9A-related erythromelalgia, primaryGOFAD

This gene — mechanism propensity

0.83top 10%

GOF

0.87top 5%

LOF

0.1994th %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 · 1 literature citation

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.

Literature Evidence

GOFThese data do not correlate with the clinical picture of our case and her father, but intra- and interfamily phenotypic diversity in symptoms associated with a gain-of-function variant of Na(V)1.7 are also described and may explain our case.1

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

References