Is CLCN2 p.Arg753Pro (c.2258G>C) pathogenic?

CLCN2 p.Arg753Pro (c.2258G>C) is classified Uncertain significance in CLCN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-05). AlphaMissense: likely pathogenic (0.6767); Very rare (popmax 0.0055%, sas); Associated with Inborn genetic diseases.

What condition is associated with CLCN2 p.Arg753Pro (c.2258G>C)?

CLCN2 p.Arg753Pro (c.2258G>C) is associated with Inborn genetic diseases (ClinVar).

How common is CLCN2 p.Arg753Pro (c.2258G>C) in the general population?

CLCN2 p.Arg753Pro (c.2258G>C) is very rare (popmax 0.0055%, sas) (gnomAD).

What do computational predictors say about CLCN2 p.Arg753Pro (c.2258G>C)?

AlphaMissense predicts likely pathogenic (score 0.6767) — an in-silico prediction, not a clinical call.

CLCN2 p.Arg753Pro

c.2258G>C · rs151278282 · VCV2332431

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6767 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0055%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6767	likely pathogenic
REVEL	0.628	indeterminate
SaProt	LLR -9.93	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 15 kb · p 6e-06 · regional, not allelic
Overall
CADD	25.4	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 0.0055% South Asian · 5/90,978 alleles

Filtering AF 0.00318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00286%

Overall 0.00353% 57/1,613,162 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0055%	18,196
European (non-Finnish)	0.00415%	24,080
Remaining individualsnot grpmax-eligible	0.0032%	31,238
African / African-American	0.00133%	74,910

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.Arg753Pro
Coding: c.2258G>C
MANE Select: NM_004366
dbSNP: rs151278282
Type: single nucleotide variant
Location: chr3:184352456 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 8 PDB
Residue 753: a UniProt-annotated variant site (in lkpat; decreased voltage-gated chloride channel activity; does not affect protein expression; does not affect localization at the cell membrane)

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.Arg753Ter Pathogenic ★ same residue
CLCN2 p.Arg753Gln 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

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-arg753pro (accessed [today's date]).

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