Is CLCN4 p.Arg604Trp (c.1810C>T) pathogenic?

CLCN4 p.Arg604Trp (c.1810C>T) is classified Likely benign in CLCN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-11). AlphaMissense: likely benign (0.2382); Very rare (popmax 0.00217%, amr).

How common is CLCN4 p.Arg604Trp (c.1810C>T) in the general population?

CLCN4 p.Arg604Trp (c.1810C>T) is very rare (popmax 0.00217%, amr) (gnomAD).

What do computational predictors say about CLCN4 p.Arg604Trp (c.1810C>T)?

AlphaMissense predicts likely benign (score 0.2382) — an in-silico prediction, not a clinical call.

CLCN4 p.Arg604Trp

c.1810C>T · rs760806121 · VCV2999396

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2382 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00217%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2382	likely benign
REVEL	0.794	moderately pathogenic-leaning
SaProt	LLR -11.09	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 0.7	GERP 1.2, phastCons 0.92
Regional constraint	o/e 0.68	unconstrained · MANE · 6,907 bp · p 0.001 · regional, not allelic
Overall
CADD	24.2	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 0.00217% Admixed American · 1/46,084 alleles

Filtering AF 0.000164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000119%

Overall 0.00073% 8/1,096,623 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00217%	46,084
Remaining individualsnot grpmax-eligible	0.0021%	47,513
South Asian	0.00176%	56,955
European (non-Finnish)	0.000559%	179,019

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: CLCN4
Protein: p.Arg604Trp
Coding: c.1810C>T
MANE Select: NM_001830
dbSNP: rs760806121
Type: single nucleotide variant
Location: chrX:10213914 (GRCh38)
Structure: AlphaFold pLDDT 84.66
Residue 604: the cbs 1 domain

Full CLCN4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLCN4 c.844-1G>A Pathogenic/Likely pathogenic ★★ same type
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CLCN4 p.Arg718Trp Pathogenic ★★ same type
CLCN4 p.Asp89Asn Pathogenic/Likely pathogenic ★★ same type
CLCN4 p.Gly467Ser Likely pathogenic ★★ same type
CLCN4 p.Gly544Arg Pathogenic ★★ same type
CLCN4 p.Gly731Arg Pathogenic ★★ same type
CLCN4 p.Val275Met Pathogenic ★★ same type

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/clcn4-p-arg604trp (accessed [today's date]).

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