SCN7A

Chr 2

sodium voltage-gated channel alpha subunit 7

Also known as: NaG, Nav2.1, Nav2.2, SCN6A

NCBI Gene: 6332 ENSG00000136546 UniProt: Q01118 OMIM: 182392

This protein functions as a sodium leak channel that acts as an osmosensor, regulating sodium ion levels across tissues including glial cells in the central nervous system and keratinocytes in skin barrier homeostasis. The gene is extremely intolerant to loss-of-function variants, but no human diseases have been definitively associated with SCN7A mutations to date. The inheritance pattern for any potential SCN7A-related disorders remains to be established.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes one of the many voltage-gated sodium channel proteins. For proper functioning of neurons and muscles during action potentials, voltage-gated sodium channels direct sodium ion diffusion for membrane depolarization. This sodium channel protein has some atypical characteristics; the similarity between the human and mouse proteins is lower compared to other orthologous sodium channel pairs. Also, the S4 segments, which sense voltage changes, have fewer positive charged residues that in other sodium channels; domain 4 has fewer arginine and lysine residues compared to other sodium channel proteins. Several alternatively spliced transcript variants exist, but the full-length natures of all of them remain unknown. [provided by RefSeq, Dec 2011]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.78

Clinical Summary— SCN7A

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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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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 199 VUS of 278 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.78LOEUF

pLI 0.000

Z-score 2.95

OE 0.60 (0.46–0.78)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.41Z-score

OE missense 0.96 (0.90–1.02)

761 obs / 793.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.60 (0.46–0.78)

0≤0.351.4

Missense OE?0.96 (0.90–1.02)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 37 / 62.1Missense obs/exp: 761 / 793.3Syn Z: -0.59

This gene — mechanism propensity

0.78top 25%

GOF

0.77top 25%

LOF

0.1796th %ile

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

DNprediction above median

GOFprediction 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

278 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS199

Likely Benign42

Benign28

Conflicting1

Likely Pathogenic

199

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	1	0	0	0	1
VUS	4	195	0	0	199
Likely Benign	1	24	0	17	42
Benign	2	15	3	8	28
Conflicting	—				1
Total	8	234	3	25	271

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

View in ClinVar →

35 pathogenic / likely-pathogenic (of 45) ClinVar copy-number / structural variants overlap SCN7A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →