Is CLCN2 p.Cys744Arg (c.2230T>C) pathogenic?

CLCN2 p.Cys744Arg (c.2230T>C) is classified Uncertain significance in CLCN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-04). AlphaMissense: likely benign (0.0749); Very rare (popmax 0.00424%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CLCN2 p.Cys744Arg (c.2230T>C)?

CLCN2 p.Cys744Arg (c.2230T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CLCN2 p.Cys744Arg (c.2230T>C) in the general population?

CLCN2 p.Cys744Arg (c.2230T>C) is very rare (popmax 0.00424%, nfe) (gnomAD).

What do computational predictors say about CLCN2 p.Cys744Arg (c.2230T>C)?

AlphaMissense predicts likely benign (score 0.0749) — an in-silico prediction, not a clinical call.

CLCN2 p.Cys744Arg

c.2230T>C · rs747458694 · VCV3145407

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0749 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00424%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0749	likely benign
REVEL	0.179	moderately benign-leaning
SaProt	LLR -4.04	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 1.9	GERP -0.57, phastCons 0.51
Regional constraint	o/e 0.87	unconstrained · MANE · 15 kb · p 6e-06 · regional, not allelic
Overall
CADD	13.29	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 0.00424% European (non-Finnish) · 50/1,179,946 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00294%

Overall 0.00329% 53/1,613,122 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00424%	23,599
East Asian	0.00223%	44,878
Admixed American	0.00167%	59,942
South Asian	0.0011%	90,984

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.Cys744Arg
Coding: c.2230T>C
MANE Select: NM_004366
dbSNP: rs747458694
Type: single nucleotide variant
Location: chr3:184352484 (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

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

Similar variants

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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-cys744arg (accessed [today's date]).

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