Is CLCN2 p.Ala242= (c.726C>T) pathogenic?

CLCN2 p.Ala242= (c.726C>T) is classified Benign/Likely benign in CLCN2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-04-10). Very rare (popmax 0.00619%, nfe); Associated with epilepsy, idiopathic generalized, susceptibility to, 11.

What condition is associated with CLCN2 p.Ala242= (c.726C>T)?

CLCN2 p.Ala242= (c.726C>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.Ala242= (c.726C>T) in the general population?

CLCN2 p.Ala242= (c.726C>T) is very rare (popmax 0.00619%, nfe) (gnomAD).

CLCN2 p.Ala242=

c.726C>T · rs768569603 · VCV1532487

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00619%, nfe)

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 -20	GERP -3
Overall
CADD	0.615	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00619% European (non-Finnish) · 73/1,180,036 alleles

Filtering AF 0.00503% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00462%

Overall 0.0112% 180/1,614,014 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.294%	340
Remaining individualsnot grpmax-eligible	0.0208%	4,808
European (non-Finnish)grpmax	0.00619%	16,165
Admixed American	0.005%	20,010
East Asian	0.00446%	22,444
Finnishnot grpmax-eligible	0.00157%	63,816
South Asian	0.0011%	91,088

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala242=
Coding: c.726C>T
MANE Select: NM_004366
dbSNP: rs768569603
Type: single nucleotide variant
Location: chr3:184357666 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 8 PDB
Residue 242: 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.Ala242Val 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
CLCN2 c.1721+4C>T 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-ala242 (accessed [today's date]).

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