Is CLCN2 p.Glu18Asp (c.54G>C) pathogenic?

CLCN2 p.Glu18Asp (c.54G>C) is classified Uncertain significance in CLCN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-27). AlphaMissense: likely pathogenic (0.9187); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CLCN2 p.Glu18Asp (c.54G>C)?

CLCN2 p.Glu18Asp (c.54G>C) is associated with Inborn genetic diseases (ClinVar).

How common is CLCN2 p.Glu18Asp (c.54G>C) in the general population?

CLCN2 p.Glu18Asp (c.54G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLCN2 p.Glu18Asp (c.54G>C)?

AlphaMissense predicts likely pathogenic (score 0.9187) — an in-silico prediction, not a clinical call.

CLCN2 p.Glu18Asp

c.54G>C · VCV4615894

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9187 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9187	likely pathogenic
REVEL	0.185	benign-leaning
SaProt	LLR -7.12	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP 0.26, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 15 kb · p 6e-06 · regional, not allelic
Overall
CADD	23.3	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

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.Glu18Asp
Coding: c.54G>C
MANE Select: NM_004366
Type: single nucleotide variant
Location: chr3:184361426 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 8 PDB
Residue 18: the 'essential for channel gating by both voltage and cell volume' region; a β-strand

Full CLCN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CLCN2 p.Glu18Gln Uncertain significance ★ ⚠ same residue
CLCN2 p.Ala243Pro Uncertain significance ★★ ⚠ same condition
CLCN2 p.Ala253Val Uncertain significance ★★ ⚠ same condition
CLCN2 p.Ala638Thr Uncertain significance ★★ ⚠ same condition
CLCN2 p.Ala70Thr Uncertain significance ★★ ⚠ same condition
CLCN2 p.Ala717Thr Uncertain significance ★★ ⚠ same condition
CLCN2 p.Arg297Gln Uncertain significance ★★ ⚠ same condition
CLCN2 p.Arg558Gln 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-glu18asp (accessed [today's date]).

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