Is CLCN2 p.Pro381Thr (c.1141C>A) pathogenic?

CLCN2 p.Pro381Thr (c.1141C>A) is classified Uncertain significance in CLCN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-10). AlphaMissense: likely benign (0.1586); Very rare (popmax 8.47e-05%, nfe); Associated with familial hyperaldosteronism type II.

What condition is associated with CLCN2 p.Pro381Thr (c.1141C>A)?

CLCN2 p.Pro381Thr (c.1141C>A) is associated with familial hyperaldosteronism type II (ClinVar).

How common is CLCN2 p.Pro381Thr (c.1141C>A) in the general population?

CLCN2 p.Pro381Thr (c.1141C>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Familial hyperaldosteronism type II inherited?

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

What do computational predictors say about CLCN2 p.Pro381Thr (c.1141C>A)?

AlphaMissense predicts likely benign (score 0.1586) — an in-silico prediction, not a clinical call.

CLCN2 p.Pro381Thr

c.1141C>A · rs141605519 · VCV2719668

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1586 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial hyperaldosteronism type II

Computational evidence

Protein change
AlphaMissense	0.1586	likely benign
REVEL	0.791	moderately pathogenic-leaning
SaProt	LLR -12.08	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 15 kb · p 6e-06 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,044 alleles

Overall 6.84e-05% 1/1,461,886 alleles · very rare

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: CLCN2
Protein: p.Pro381Thr
Coding: c.1141C>A
MANE Select: NM_004366
dbSNP: rs141605519
Type: single nucleotide variant
Location: chr3:184355723 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 8 PDB
Residue 381: a turn

Full CLCN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial hyperaldosteronism type II — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial hyperaldosteronism type II (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

CLCN2 p.Pro381Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
CLCN2 p.Pro381Arg Uncertain significance ★ ⚠ same residue
CLCN2 p.Pro381Ser Uncertain significance ★ ⚠ same residue
CLCN2 c.898+1G>A Likely pathogenic ★★ same condition
CLCN2 p.Arg172Gln Pathogenic ★★ same condition
CLCN2 p.Arg610Ter Pathogenic/Likely pathogenic ★★ same condition
CLCN2 p.Gly24Asp Pathogenic/Likely pathogenic ★★ ⚠ same condition
CLCN2 p.Trp570Ter Pathogenic/Likely pathogenic ★★ 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/clcn2-p-pro381thr (accessed [today's date]).

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