Is CLCN2 p.Arg751Cys (c.2251C>T) pathogenic?

CLCN2 p.Arg751Cys (c.2251C>T) is classified Uncertain significance in CLCN2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-01). AlphaMissense: ambiguous (0.3745); Very rare (popmax 0.004%, afr); Associated with Inborn genetic diseases.

What condition is associated with CLCN2 p.Arg751Cys (c.2251C>T)?

CLCN2 p.Arg751Cys (c.2251C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CLCN2 p.Arg751Cys (c.2251C>T) in the general population?

CLCN2 p.Arg751Cys (c.2251C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about CLCN2 p.Arg751Cys (c.2251C>T)?

AlphaMissense predicts ambiguous (score 0.3745) — an in-silico prediction, not a clinical call.

CLCN2 p.Arg751Cys

c.2251C>T · VCV3622300

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3745 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3745	ambiguous
REVEL	0.618	indeterminate
SaProt	LLR -9.44	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.3	GERP 1.5, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 15 kb · p 6e-06 · regional, not allelic
Overall
CADD	25.9	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 0.004% African / African-American · 3/74,930 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00118% 19/1,613,168 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,977
East Asian	0.00223%	44,878
European (non-Finnish)	0.00119%	84,281
South Asian	0.0011%	90,982

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.Arg751Cys
Coding: c.2251C>T
MANE Select: NM_004366
Type: single nucleotide variant
Location: chr3:184352463 (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

CLCN2 p.Arg751His 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-arg751cys (accessed [today's date]).

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