Is CLCN4 p.Arg652Thr (c.1955G>C) pathogenic?

CLCN4 p.Arg652Thr (c.1955G>C) is classified Uncertain significance in CLCN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-01-31). AlphaMissense: likely pathogenic (0.7542); Absent from gnomAD v4.1.

How common is CLCN4 p.Arg652Thr (c.1955G>C) in the general population?

CLCN4 p.Arg652Thr (c.1955G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLCN4 p.Arg652Thr (c.1955G>C)?

AlphaMissense predicts likely pathogenic (score 0.7542) — an in-silico prediction, not a clinical call.

CLCN4 p.Arg652Thr

c.1955G>C · rs1064794549 · VCV420547

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7542 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7542	likely pathogenic
REVEL	0.857	moderately pathogenic-leaning
SaProt	LLR -3.25	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 6,907 bp · p 0.001 · regional, not allelic
Overall
CADD	24.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CLCN4
Protein: p.Arg652Thr
Coding: c.1955G>C
MANE Select: NM_001830
dbSNP: rs1064794549
Type: single nucleotide variant
Location: chrX:10214059 (GRCh38)
Structure: AlphaFold pLDDT 84.66
Residue 652: 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
CLCN4 p.Ala555Val Pathogenic ★★ same type
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-arg652thr (accessed [today's date]).

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