Is CLCN4 p.Ala259Ser (c.775G>T) pathogenic?

CLCN4 p.Ala259Ser (c.775G>T) is classified Uncertain significance in CLCN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-30). AlphaMissense: likely benign (0.1524); Absent from gnomAD v4.1; Associated with CLCN4-related disorder.

What condition is associated with CLCN4 p.Ala259Ser (c.775G>T)?

CLCN4 p.Ala259Ser (c.775G>T) is associated with CLCN4-related disorder (ClinVar).

How common is CLCN4 p.Ala259Ser (c.775G>T) in the general population?

CLCN4 p.Ala259Ser (c.775G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLCN4 p.Ala259Ser (c.775G>T)?

AlphaMissense predicts likely benign (score 0.1524) — an in-silico prediction, not a clinical call.

CLCN4 p.Ala259Ser

c.775G>T · rs2518884463 · VCV2629204

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1524 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CLCN4-related disorder

Computational evidence

Protein change
AlphaMissense	0.1524	likely benign
REVEL	0.645	pathogenic-leaning
SaProt	LLR -7.91	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 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.43	unconstrained · MANE · 22 kb · p 1.3e-16 · regional, not allelic
Overall
CADD	24.0	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.Ala259Ser
Coding: c.775G>T
MANE Select: NM_001830
dbSNP: rs2518884463
Type: single nucleotide variant
Location: chrX:10206708 (GRCh38)
Structure: AlphaFold pLDDT 84.66

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

Disease context

CLCN4-related disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CLCN4 p.Ala555Val Pathogenic ★★ same condition
CLCN4 p.Arg718Trp Pathogenic ★★ same condition
CLCN4 p.Val275Met Pathogenic ★★ same condition
CLCN4 p.Ile498Val Uncertain significance ★★ ⚠ same condition
CLCN4 c.1389+1G>C Likely pathogenic ★ same condition
CLCN4 p.Leu221Pro Pathogenic ★ same condition
CLCN4 p.Ser534Leu Pathogenic ★ same condition
CLCN4 p.Val212Gly Pathogenic ★ 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/clcn4-p-ala259ser (accessed [today's date]).

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