Is CLCN2 p.Arg273= (c.819G>T) pathogenic?

CLCN2 p.Arg273= (c.819G>T) is classified Conflicting classifications of pathogenicity in CLCN2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-02). Very rare (popmax 0.00133%, afr); Associated with epilepsy, idiopathic generalized, susceptibility to, 11.

What condition is associated with CLCN2 p.Arg273= (c.819G>T)?

CLCN2 p.Arg273= (c.819G>T) is associated with epilepsy, idiopathic generalized, susceptibility to, 11, familial hyperaldosteronism type II, leukoencephalopathy with mild cerebellar ataxia and white matter edema (ClinVar).

How common is CLCN2 p.Arg273= (c.819G>T) in the general population?

CLCN2 p.Arg273= (c.819G>T) is very rare (popmax 0.00133%, afr) (gnomAD).

CLCN2 p.Arg273=

c.819G>T · VCV3589035

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

epilepsy, idiopathic generalized, susceptibility to, 11

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 -3.1	GERP -3.1
Overall
CADD	1.874	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,930 alleles

Overall 0.000657% 1/152,216 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.Arg273=
Coding: c.819G>T
MANE Select: NM_004366
Type: single nucleotide variant
Location: chr3:184357441 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 8 PDB
Residue 273: an α-helix

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

Disease context

epilepsy, idiopathic generalized, susceptibility to, 11 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hyperaldosteronism type II leukoencephalopathy with mild cerebellar ataxia and white matter edema

Similar variants

CLCN2 p.Arg273Gln Uncertain significance ★ ⚠ same residue
CLCN2 p.Arg273Trp 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
CLCN2 c.1171-3T>C 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-arg273 (accessed [today's date]).

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