Is CLCN2 p.Ser658Phe (c.1973C>T) pathogenic?

CLCN2 p.Ser658Phe (c.1973C>T) is classified Uncertain significance in CLCN2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-16). AlphaMissense: likely benign (0.1098); Very rare (popmax 0.01%, amr); Associated with epilepsy, idiopathic generalized, susceptibility to, 11.

What condition is associated with CLCN2 p.Ser658Phe (c.1973C>T)?

CLCN2 p.Ser658Phe (c.1973C>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.Ser658Phe (c.1973C>T) in the general population?

CLCN2 p.Ser658Phe (c.1973C>T) is very rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about CLCN2 p.Ser658Phe (c.1973C>T)?

AlphaMissense predicts likely benign (score 0.1098) — an in-silico prediction, not a clinical call.

CLCN2 p.Ser658Phe

c.1973C>T · rs778697594 · VCV2050778

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1098 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

epilepsy, idiopathic generalized, susceptibility to, 11

Computational evidence

Protein change
AlphaMissense	0.1098	likely benign
REVEL	0.25	benign-leaning
SaProt	LLR -9.16	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP 0.41, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 15 kb · p 6e-06 · regional, not allelic
Overall
CADD	16.06	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/60,008 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000372% 6/1,613,626 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.Ser658Phe
Coding: c.1973C>T
MANE Select: NM_004366
dbSNP: rs778697594
Type: single nucleotide variant
Location: chr3:184353305 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 8 PDB
Residue 658: the 'disordered' region

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 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-ser658phe (accessed [today's date]).

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