SCNN1G

Chr 16

sodium channel epithelial 1 subunit gamma

NCBI Gene: 6340 ENSG00000166828 UniProt: P51170

This is one of the three pore-forming subunits of the heterotrimeric epithelial sodium channel (ENaC), a critical regulator of sodium balance and fluid homeostasis (PubMed:30251954, PubMed:32729833, PubMed:7550319, PubMed:7762608, PubMed:9792722). ENaC operates in epithelial tissues, where it mediates the electrodiffusion of sodium ions from extracellular fluid through the apical membrane of cells, with water following osmotically (PubMed:24124190). It plays a key role in maintaining sodium homeostasis through electrogenic sodium reabsorption in the kidneys (PubMed:12107247, PubMed:7550319, PubMed:8640238). Additionally, ENaC is essential for airway surface liquid homeostasis, which is crucial for proper mucus clearance (PubMed:18507830, PubMed:19017867, PubMed:24124190)

Primary Disease Associations & Inheritance

UniProtLiddle syndrome 2

UniProtBronchiectasis with or without elevated sweat chloride 3

UniProtPseudohypoaldosteronism 1B3, autosomal recessive

ClinVar variants

Pathogenic / LP

0.48

pLI score

Active trials

Clinical Summary— SCNN1G

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Gene-Disease Validity (ClinGen)

Liddle syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.22) despite low pLI — interpret in context.

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ClinVar Variants

3 Pathogenic / Likely Pathogenic· 69 VUS of 96 total submissions

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

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.

0.41LOEUF

pLI 0.482

Z-score 4.12

OE 0.22 (0.12–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

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.

0.56Z-score

OE missense 0.92 (0.84–1.00)

328 obs / 357.9 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.0.22 (0.12–0.41)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.92 (0.84–1.00)

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.1.05

0≤1.21.6

LoF obs/exp: 7 / 32.2Missense obs/exp: 328 / 357.9Syn Z: -0.49