Is CLCN4 p.Ala4Ser (c.10G>T) pathogenic?

CLCN4 p.Ala4Ser (c.10G>T) is classified Uncertain significance in CLCN4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-13). AlphaMissense: likely benign (0.0785); Very rare (popmax 0.00218%, amr); Associated with intellectual disability, X-linked 49.

What condition is associated with CLCN4 p.Ala4Ser (c.10G>T)?

CLCN4 p.Ala4Ser (c.10G>T) is associated with intellectual disability, X-linked 49 (ClinVar).

How common is CLCN4 p.Ala4Ser (c.10G>T) in the general population?

CLCN4 p.Ala4Ser (c.10G>T) is very rare (popmax 0.00218%, amr) (gnomAD).

What do computational predictors say about CLCN4 p.Ala4Ser (c.10G>T)?

AlphaMissense predicts likely benign (score 0.0785) — an in-silico prediction, not a clinical call.

CLCN4 p.Ala4Ser

Q: How is CLCN4-related X-linked intellectual disability syndrome inherited?

Typically X-linked dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.10G>T · rs1015209935 · VCV625920

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0785 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00218%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, X-linked 49

Computational evidence

Protein change
AlphaMissense	0.0785	likely benign
REVEL	0.277	benign-leaning
SaProt	LLR -5.01	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.3, phastCons 0.99
Regional constraint	o/e 0.43	unconstrained · MANE · 22 kb · p 1.3e-16 · regional, not allelic
Overall
CADD	17.95	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00218% Admixed American · 1/45,784 alleles

Overall 0.000183% 2/1,094,508 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00218%	45,784
Remaining individualsnot grpmax-eligible	0.00211%	47,473

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.Ala4Ser
Coding: c.10G>T
MANE Select: NM_001830
dbSNP: rs1015209935
Type: single nucleotide variant
Location: chrX:10185042 (GRCh38)
Structure: AlphaFold pLDDT 84.66

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

Disease context

intellectual disability, X-linked 49 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For CLCN4-related X-linked intellectual disability syndrome (Orphanet):

Inheritance: X-linked dominant
Onset: Childhood, Infancy
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

CLCN4 p.Ala4Val Uncertain significance ★★ ⚠ same residue
CLCN4 p.Ala4= Likely benign ★ same residue
CLCN4 p.Ala555Val Pathogenic ★★ ⚠ same condition
CLCN4 p.Arg718Trp Pathogenic ★★ same condition
CLCN4 p.Gly467Ser Likely pathogenic ★★ same condition
CLCN4 p.Gly544Arg Pathogenic ★★ same condition
CLCN4 p.Val317Ile Pathogenic/Likely pathogenic ★★ same condition
CLCN4 p.Ala521Thr 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/clcn4-p-ala4ser (accessed [today's date]).

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