Is SCNN1A p.Phe280= (c.840C>T) pathogenic?

SCNN1A p.Phe280= (c.840C>T) is classified Conflicting classifications of pathogenicity in SCNN1A (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-21). Rare (popmax 0.119%, afr); Associated with pseudohypoaldosteronism, type IB1, autosomal recessive.

What condition is associated with SCNN1A p.Phe280= (c.840C>T)?

SCNN1A p.Phe280= (c.840C>T) is associated with pseudohypoaldosteronism, type IB1, autosomal recessive, bronchiectasis with or without elevated sweat chloride 2 (ClinVar).

How common is SCNN1A p.Phe280= (c.840C>T) in the general population?

SCNN1A p.Phe280= (c.840C>T) is rare (popmax 0.119%, afr) (gnomAD).

How is Pseudohypoaldosteronism type 1 inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

SCNN1A p.Phe280=

c.840C>T · rs139335335 · VCV310147

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.119%, afr)

Conditions

pseudohypoaldosteronism, type IB1, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.26	GERP -4.6
Overall
CADD	9.787	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.119% African / African-American · 89/75,078 alleles

Filtering AF 0.0986% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0912%

Overall 0.00923% 149/1,614,238 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.119%	844
Middle Eastern	0.0661%	1,514
Remaining individualsnot grpmax-eligible	0.0336%	2,977
Admixed American	0.00833%	12,007
South Asian	0.00329%	30,363
East Asian	0.00223%	44,892
European (non-Finnish)	0.0022%	45,386

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SCNN1A
Protein: p.Phe280=
Coding: c.840C>T
MANE Select: NM_001038
dbSNP: rs139335335
Type: single nucleotide variant
Location: chr12:6362086 (GRCh38)
Gene constraint: LOEUF 1.105 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.66 · 3 PDB
Residue 280: a β-strand

Full SCNN1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pseudohypoaldosteronism, type IB1, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: bronchiectasis with or without elevated sweat chloride 2

For Pseudohypoaldosteronism type 1 (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (United Kingdom)

Similar variants

SCNN1A c.1360+2T>G Pathogenic ★★ same condition
SCNN1A c.1439+1G>A Pathogenic/Likely pathogenic ★★ same condition
SCNN1A c.685-1G>A Likely pathogenic ★★ same condition
SCNN1A c.875+1G>A Pathogenic/Likely pathogenic ★★ same condition
SCNN1A p.Arg492Ter Pathogenic ★★ same condition
SCNN1A p.Arg508Ter Pathogenic/Likely pathogenic ★★ same condition
SCNN1A p.Arg56Ter Pathogenic ★★ same condition
SCNN1A c.-23C>G Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/scnn1a-p-phe280 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown