Is CLCN4 p.Ala649Ser (c.1945G>T) pathogenic?

CLCN4 p.Ala649Ser (c.1945G>T) is classified Uncertain significance in CLCN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-06). AlphaMissense: likely benign (0.2468); Very rare (popmax 0.00298%, eas).

How common is CLCN4 p.Ala649Ser (c.1945G>T) in the general population?

CLCN4 p.Ala649Ser (c.1945G>T) is very rare (popmax 0.00298%, eas) (gnomAD).

What do computational predictors say about CLCN4 p.Ala649Ser (c.1945G>T)?

AlphaMissense predicts likely benign (score 0.2468) — an in-silico prediction, not a clinical call.

CLCN4 p.Ala649Ser

c.1945G>T · VCV4082973

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2468 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00298%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2468	likely benign
REVEL	0.671	pathogenic-leaning
SaProt	LLR -10.71	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 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	24.2	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 0.00298% East Asian · 1/33,547 alleles

Overall 9.35e-05% 1/1,069,336 alleles · very rare

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.Ala649Ser
Coding: c.1945G>T
MANE Select: NM_001830
Type: single nucleotide variant
Location: chrX:10214049 (GRCh38)
Structure: AlphaFold pLDDT 84.66
Residue 649: 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-ala649ser (accessed [today's date]).

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