Is CLCN2 p.Ser865Arg (c.2593A>C) pathogenic?

CLCN2 p.Ser865Arg (c.2593A>C) is classified Pathogenic in CLCN2 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2018-08-10). AlphaMissense: ambiguous (0.5529); Absent from gnomAD v4.1; Associated with familial hyperaldosteronism type II.

What condition is associated with CLCN2 p.Ser865Arg (c.2593A>C)?

CLCN2 p.Ser865Arg (c.2593A>C) is associated with familial hyperaldosteronism type II (ClinVar).

How common is CLCN2 p.Ser865Arg (c.2593A>C) in the general population?

CLCN2 p.Ser865Arg (c.2593A>C) is absent from gnomAD v4.1 (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.Ser865Arg (c.2593A>C)?

AlphaMissense predicts ambiguous (score 0.5529) — an in-silico prediction, not a clinical call.

CLCN2 p.Ser865Arg

c.2593A>C · rs1553853557 · VCV441168

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5529 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

familial hyperaldosteronism type II

Computational evidence

Protein change
AlphaMissense	0.5529	ambiguous
REVEL	0.416	indeterminate
SaProt	LLR -10.51	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.4, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 15 kb · p 6e-06 · regional, not allelic
Overall
CADD	26.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CLCN2
Protein: p.Ser865Arg
Coding: c.2593A>C
MANE Select: NM_004366
dbSNP: rs1553853557
Type: single nucleotide variant
Location: chr3:184346710 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 8 PDB
Residue 865: the 'disordered' region; a UniProt-annotated variant site (in lkpat; decreased voltage-gated chloride channel activity; does not affect protein expression; does not affect localization at the cell membrane); a UniProt-annotated variant site (in hald2; increased voltage-gated chloride currents due to higher channel open probabilities at physiological cell membrane potentials)

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 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
CLCN2 c.1171-3T>C Uncertain significance ★★ same condition
CLCN2 c.1721+4C>T Uncertain significance ★★ same condition
CLCN2 c.1721+5G>A 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/clcn2-p-ser865arg (accessed [today's date]).

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