Is CLCN2 p.Arg577Gln (c.1730G>A) pathogenic?

CLCN2 p.Arg577Gln (c.1730G>A) is classified Conflicting classifications of pathogenicity in CLCN2 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-01-14). AlphaMissense: likely benign (0.0756); Rare (popmax 0.102%, amr); Associated with epilepsy, idiopathic generalized, susceptibility to, 11.

What condition is associated with CLCN2 p.Arg577Gln (c.1730G>A)?

CLCN2 p.Arg577Gln (c.1730G>A) is associated with epilepsy, idiopathic generalized, susceptibility to, 11, cerebral palsy, leukoencephalopathy with mild cerebellar ataxia and white matter edema (ClinVar).

How common is CLCN2 p.Arg577Gln (c.1730G>A) in the general population?

CLCN2 p.Arg577Gln (c.1730G>A) is rare (popmax 0.102%, amr) (gnomAD).

What do computational predictors say about CLCN2 p.Arg577Gln (c.1730G>A)?

AlphaMissense predicts likely benign (score 0.0756) — an in-silico prediction, not a clinical call.

CLCN2 p.Arg577Gln

c.1730G>A · rs137852682 · VCV9039

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0756 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.102%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

epilepsy, idiopathic generalized, susceptibility to, 11

Computational evidence

Protein change
AlphaMissense	0.0756	likely benign
REVEL	0.518	indeterminate
SaProt	LLR -6.29	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 15 kb · p 6e-06 · regional, not allelic
Overall
CADD	24.9	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 0.102% Admixed American · 60/58,598 alleles

Filtering AF 0.0816% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0741%

Overall 0.0253% 407/1,605,954 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.102%	977
East Asian	0.0448%	2,230
European (non-Finnish)	0.0259%	3,859
Remaining individualsnot grpmax-eligible	0.0193%	5,181
Finnishnot grpmax-eligible	0.00954%	10,477
African / African-American	0.00401%	24,947
South Asian	0.00112%	89,590

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.Arg577Gln
Coding: c.1730G>A
MANE Select: NM_004366
dbSNP: rs137852682
Type: single nucleotide variant
Location: chr3:184353787 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 8 PDB
Residue 577: an α-helix; a UniProt-annotated variant site (in eig11; associated with disease susceptibility; the mutant channel has accelerated deactivation rates compared to wild-type, but normal activation and peak current; has accelerated atp-dependent common gating)

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: cerebral palsy leukoencephalopathy with mild cerebellar ataxia and white matter edema

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.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
CLCN2 c.2415+6G>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-arg577gln (accessed [today's date]).

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