Is CLCN4 p.Pro690Ser (c.2068C>T) pathogenic?

CLCN4 p.Pro690Ser (c.2068C>T) is classified Uncertain significance in CLCN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-13). AlphaMissense: likely benign (0.1582); Very rare (popmax 0.00175%, sas); Associated with intellectual disability, X-linked 49.

What condition is associated with CLCN4 p.Pro690Ser (c.2068C>T)?

CLCN4 p.Pro690Ser (c.2068C>T) is associated with intellectual disability, X-linked 49 (ClinVar).

How common is CLCN4 p.Pro690Ser (c.2068C>T) in the general population?

CLCN4 p.Pro690Ser (c.2068C>T) is very rare (popmax 0.00175%, sas) (gnomAD).

What do computational predictors say about CLCN4 p.Pro690Ser (c.2068C>T)?

AlphaMissense predicts likely benign (score 0.1582) — an in-silico prediction, not a clinical call.

CLCN4 p.Pro690Ser

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.2068C>T · VCV4532137

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1582 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00175%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

intellectual disability, X-linked 49

Computational evidence

Protein change
AlphaMissense	0.1582	likely benign
REVEL	0.594	indeterminate
SaProt	LLR -10.42	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.2, phastCons 0.99
Regional constraint	o/e 0.68	unconstrained · MANE · 6,907 bp · p 0.001 · regional, not allelic
Overall
CADD	20.1	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 0.00175% South Asian · 1/56,993 alleles

Overall 9.11e-05% 1/1,097,794 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.Pro690Ser
Coding: c.2068C>T
MANE Select: NM_001830
Type: single nucleotide variant
Location: chrX:10220753 (GRCh38)
Structure: AlphaFold pLDDT 84.66
Residue 690: the 'required for localization in the endoplasmic reticulum' region

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.Pro690= 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.Ala4Ser Uncertain significance ★★ ⚠ same condition
CLCN4 p.Ala4Val 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-pro690ser (accessed [today's date]).

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