SCNN1A

Chr 12ADAR

sodium channel epithelial 1 subunit alpha

Also known as: BESC2, ENaCa, ENaCalpha, LIDLS3, PHA1B1, SCNEA, SCNN1

NCBI Gene: 6337 ENSG00000111319 UniProt: P37088

The SCNN1A protein forms the alpha subunit of the epithelial sodium channel (ENaC), which regulates sodium balance and fluid homeostasis by mediating sodium reabsorption in the kidneys and maintaining airway surface liquid homeostasis for proper mucus clearance. Mutations cause pseudohypoaldosteronism type IB1 (a salt-wasting disorder), bronchiectasis with or without elevated sweat chloride, and Liddle syndrome, with inheritance patterns that can be either autosomal recessive or autosomal dominant depending on the specific condition. This gene shows very low constraint to loss-of-function variation, reflecting the multiple inheritance patterns and mechanisms associated with different disease phenotypes.

Summary from RefSeq, OMIM, UniProt

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Primary Disease Associations & Inheritance

?Liddle syndrome 3MIM #618126

Bronchiectasis with or without elevated sweat chloride 2MIM #613021

Pseudohypoaldosteronism, type IB1, autosomal recessiveMIM #264350

Active trials

Pubs (1 yr)

P/LP submissions

P/LP missense

0.91

LOEUF

Multiple*

Mechanism· predicted

Clinical Summary— SCNN1A

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Gene-Disease Validity (ClinGen)

pseudohypoaldosteronism, type IB1, autosomal recessive · ARStrong

Strong evidence — appropriate for clinical testing

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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

80 unique Pathogenic / Likely Pathogenic· 248 VUS of 500 total submissions

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GeneReview available — SCNN1A

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

0.91LOEUF

pLI 0.000

Z-score 1.97

OE 0.64 (0.46–0.91)

Tolerant

Typical tolerance to LoF variation

Missense Constraint

-0.49Z-score

OE missense 1.07 (0.99–1.16)

443 obs / 414.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios

LoF OE0.64 (0.46–0.91)

0≤0.351.4

Missense OE1.07 (0.99–1.16)

0≤0.61.4

Synonymous OE1.04

0≤1.21.6

LoF obs/exp: 23 / 35.7Missense obs/exp: 443 / 414.9Syn Z: -0.41

0.6744th %ile

GOF

0.6737th %ile

LOF

0.2580th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports gain-of-function. 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

GOFFunctional analysis demonstrated that the C479R change represents a gain-of-function mutation resulting in increased intrinsic channel activity, which the authors noted is a mechanism different from previously reported Liddle syndrome-associated mutations in the beta and gamma subunits.PMID:28710092

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