Is SCNN1A p.Pro33= (c.99C>T) pathogenic?

SCNN1A p.Pro33= (c.99C>T) is classified Benign/Likely benign in SCNN1A (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-18). Common (popmax 8.86%, eas) — too common for a highly-penetrant pathogenic allele; Associated with bronchiectasis with or without elevated sweat chloride 2.

What condition is associated with SCNN1A p.Pro33= (c.99C>T)?

SCNN1A p.Pro33= (c.99C>T) is associated with bronchiectasis with or without elevated sweat chloride 2, pseudohypoaldosteronism, type IB1, autosomal recessive, Liddle syndrome 3 (ClinVar).

How is Idiopathic bronchiectasis inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

SCNN1A p.Pro33=

Q: How common is SCNN1A p.Pro33= (c.99C>T) in the general population?

SCNN1A p.Pro33= (c.99C>T) is common (popmax 8.86%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.99C>T · rs13306619 · VCV310153

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 8.86%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

bronchiectasis with or without elevated sweat chloride 2

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 -2.8	GERP -4.3
Overall
CADD	4.989	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.86% East Asian · 3,976/44,872 alleles

Filtering AF 8.63% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.54%

Overall 0.795% 12,838/1,613,896 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	8.86%	11
South Asian	4.9%	20
African / African-American	2.1%	48
Remaining individualsnot grpmax-eligible	1.1%	91
Finnishnot grpmax-eligible	1.02%	98
Middle Eastern	0.512%	195
Ashkenazi Jewishnot grpmax-eligible	0.476%	210
Admixed American	0.283%	353
European (non-Finnish)	0.0972%	1,029

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.Pro33=
Coding: c.99C>T
MANE Select: NM_001038
dbSNP: rs13306619
Type: single nucleotide variant
Location: chr12:6374685 (GRCh38)
Gene constraint: LOEUF 1.105 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.66 · 3 PDB
Residue 33: the 'disordered' region

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

Disease context

bronchiectasis with or without elevated sweat chloride 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: pseudohypoaldosteronism, type IB1, autosomal recessive Liddle syndrome 3

For Idiopathic bronchiectasis (Orphanet):

Inheritance: Not applicable
Onset: All ages
Prevalence: 1-9 / 100 000 (Finland)

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-pro33 (accessed [today's date]).

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