Is CLCN4 p.Val586= (c.1758G>A) pathogenic?

CLCN4 p.Val586= (c.1758G>A) is classified Benign/Likely benign in CLCN4 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-02). Rare (popmax 0.551%, mid); Associated with intellectual disability, X-linked 49.

What condition is associated with CLCN4 p.Val586= (c.1758G>A)?

CLCN4 p.Val586= (c.1758G>A) is associated with intellectual disability, X-linked 49 (ClinVar).

How common is CLCN4 p.Val586= (c.1758G>A) in the general population?

CLCN4 p.Val586= (c.1758G>A) is rare (popmax 0.551%, mid) (gnomAD).

CLCN4 p.Val586=

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.1758G>A · rs143437511 · VCV210732

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.551%, mid)

Conditions

intellectual disability, X-linked 49

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.44	GERP -0.054, phastCons 0.99
Overall
CADD	1.647	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.551% Middle Eastern · 24/4,355 alleles

Filtering AF 0.497% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.492%

Overall 0.422% 5,104/1,210,610 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.551%	181
Ashkenazi Jewishnot grpmax-eligible	0.545%	184
European (non-Finnish)	0.51%	196
Remaining individualsnot grpmax-eligible	0.37%	271
Finnishnot grpmax-eligible	0.268%	374
Admixed American	0.0849%	1,177
African / African-American	0.0609%	1,641
South Asian	0.0387%	2,584

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.Val586=
Coding: c.1758G>A
MANE Select: NM_001830
dbSNP: rs143437511
Type: single nucleotide variant
Location: chrX:10213862 (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.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
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-val586 (accessed [today's date]).

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