Is CLCN2 p.Ser516Phe (c.1547C>T) pathogenic?

CLCN2 p.Ser516Phe (c.1547C>T) is classified Uncertain significance in CLCN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-01). AlphaMissense: likely pathogenic (0.9991); Absent from gnomAD v4.1; Associated with epilepsy, idiopathic generalized, susceptibility to, 11.

What condition is associated with CLCN2 p.Ser516Phe (c.1547C>T)?

CLCN2 p.Ser516Phe (c.1547C>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.Ser516Phe (c.1547C>T) in the general population?

CLCN2 p.Ser516Phe (c.1547C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLCN2 p.Ser516Phe (c.1547C>T)?

AlphaMissense predicts likely pathogenic (score 0.9991) — an in-silico prediction, not a clinical call.

CLCN2 p.Ser516Phe

c.1547C>T · VCV3589017

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9991 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

epilepsy, idiopathic generalized, susceptibility to, 11

Computational evidence

Protein change
AlphaMissense	0.9991	likely pathogenic · top 1% in CLCN2
REVEL	0.973	strongly pathogenic-leaning
SaProt	LLR -14.14	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.37	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 15 kb · p 6e-06 · regional, not allelic
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CLCN2
Protein: p.Ser516Phe
Coding: c.1547C>T
MANE Select: NM_004366
Type: single nucleotide variant
Location: chr3:184354275 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 8 PDB

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.Ser516= Likely benign ★★ 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-ser516phe (accessed [today's date]).

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