Is CLCN2 p.Met477Val (c.1429A>G) pathogenic?

CLCN2 p.Met477Val (c.1429A>G) is classified Uncertain significance in CLCN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-17). AlphaMissense: likely benign (0.308); Very rare (popmax 0.00599%, eas); Associated with Inborn genetic diseases.

What condition is associated with CLCN2 p.Met477Val (c.1429A>G)?

CLCN2 p.Met477Val (c.1429A>G) is associated with Inborn genetic diseases (ClinVar).

How common is CLCN2 p.Met477Val (c.1429A>G) in the general population?

CLCN2 p.Met477Val (c.1429A>G) is very rare (popmax 0.00599%, eas) (gnomAD).

What do computational predictors say about CLCN2 p.Met477Val (c.1429A>G)?

AlphaMissense predicts likely benign (score 0.308) — an in-silico prediction, not a clinical call.

CLCN2 p.Met477Val

c.1429A>G · VCV3833762

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.308 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00599%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.308	likely benign
REVEL	0.781	moderately pathogenic-leaning
SaProt	LLR -10.84	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 0.41, 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

Grpmax group 0.00599% East Asian · 2/33,382 alleles

Filtering AF 0.000992% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000371%

Overall 0.00036% 5/1,389,030 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00599%	16,691
Ashkenazi Jewishnot grpmax-eligible	0.0037%	26,992
European (non-Finnish)	0.000176%	568,844

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.Met477Val
Coding: c.1429A>G
MANE Select: NM_004366
Type: single nucleotide variant
Location: chr3:184354626 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 8 PDB
Residue 477: an α-helix

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.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
CLCN2 p.Arg598Gln 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-met477val (accessed [today's date]).

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