Is CLCN4 p.Leu305Pro (c.914T>C) pathogenic?

CLCN4 p.Leu305Pro (c.914T>C) is classified Uncertain significance in CLCN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-16). AlphaMissense: likely pathogenic (0.999); Absent from gnomAD v4.1; Associated with intellectual disability, X-linked 49.

What condition is associated with CLCN4 p.Leu305Pro (c.914T>C)?

CLCN4 p.Leu305Pro (c.914T>C) is associated with intellectual disability, X-linked 49 (ClinVar).

How common is CLCN4 p.Leu305Pro (c.914T>C) in the general population?

CLCN4 p.Leu305Pro (c.914T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLCN4 p.Leu305Pro (c.914T>C)?

AlphaMissense predicts likely pathogenic (score 0.999) — an in-silico prediction, not a clinical call.

CLCN4 p.Leu305Pro

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.914T>C · rs2518885314 · VCV1805903

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, X-linked 49

Computational evidence

Protein change
AlphaMissense	0.999	likely pathogenic · top 4% in CLCN4
REVEL	0.972	strongly pathogenic-leaning
SaProt	LLR -17.92	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.3, phastCons 1
Regional constraint	o/e 0.16	constrained · MANE · 1,460 bp · p 1.7e-09 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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.Leu305Pro
Coding: c.914T>C
MANE Select: NM_001830
dbSNP: rs2518885314
Type: single nucleotide variant
Location: chrX:10208115 (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-leu305pro (accessed [today's date]).

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