Is CLCN2 p.Glu628= (c.1884G>A) pathogenic?

CLCN2 p.Glu628= (c.1884G>A) is classified Uncertain significance in CLCN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-23). Very rare (popmax 0.000424%, nfe); Associated with epilepsy, idiopathic generalized, susceptibility to, 11.

What condition is associated with CLCN2 p.Glu628= (c.1884G>A)?

CLCN2 p.Glu628= (c.1884G>A) 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.Glu628= (c.1884G>A) in the general population?

CLCN2 p.Glu628= (c.1884G>A) is very rare (popmax 0.000424%, nfe) (gnomAD).

CLCN2 p.Glu628=

c.1884G>A · VCV3589005

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Conditions

epilepsy, idiopathic generalized, susceptibility to, 11

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.75	acceptor gain · deltas
Pangolin	Δ0.22	gain · loss 0.03 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 1.7	GERP 0.79, phastCons 1
Overall
CADD	21.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,492 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,459,902 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.Glu628=
Coding: c.1884G>A
MANE Select: NM_004366
Type: single nucleotide variant
Location: chr3:184353394 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 8 PDB
Residue 628: a β-strand; the cbs 1 domain

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.Glu628Lys 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-glu628 (accessed [today's date]).

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