Is CLCN2 p.Arg124Trp (c.370C>T) pathogenic?

CLCN2 p.Arg124Trp (c.370C>T) is classified Conflicting classifications of pathogenicity in CLCN2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-18). AlphaMissense: likely benign (0.1117); Rare (popmax 0.259%, afr); Associated with Inborn genetic diseases.

What condition is associated with CLCN2 p.Arg124Trp (c.370C>T)?

CLCN2 p.Arg124Trp (c.370C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CLCN2 p.Arg124Trp (c.370C>T) in the general population?

CLCN2 p.Arg124Trp (c.370C>T) is rare (popmax 0.259%, afr) (gnomAD).

What do computational predictors say about CLCN2 p.Arg124Trp (c.370C>T)?

AlphaMissense predicts likely benign (score 0.1117) — an in-silico prediction, not a clinical call.

CLCN2 p.Arg124Trp

c.370C>T · rs139188499 · VCV1315589

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1117 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.259%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1117	likely benign
REVEL	0.666	pathogenic-leaning
SaProt	LLR -9.59	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.4, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 15 kb · p 6e-06 · regional, not allelic
Overall
CADD	25.6	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 0.259% African / African-American · 194/75,032 alleles

Filtering AF 0.229% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.217%

Overall 0.0136% 220/1,614,050 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.259%	387
Middle Eastern	0.0166%	6,026
Remaining individualsnot grpmax-eligible	0.0144%	6,945
Admixed American	0.005%	20,006
South Asian	0.00329%	30,363
European (non-Finnish)	0.000847%	118,003

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.Arg124Trp
Coding: c.370C>T
MANE Select: NM_004366
dbSNP: rs139188499
Type: single nucleotide variant
Location: chr3:184358293 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.82 · 8 PDB
Residue 124: 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.Arg124Gln 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-arg124trp (accessed [today's date]).

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