Is CLCN5 p.Pro765His (c.2294C>A) pathogenic?

CLCN5 p.Pro765His (c.2294C>A) is classified Uncertain significance in CLCN5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: likely pathogenic (0.8749); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CLCN5 p.Pro765His (c.2294C>A)?

CLCN5 p.Pro765His (c.2294C>A) is associated with Inborn genetic diseases (ClinVar).

How common is CLCN5 p.Pro765His (c.2294C>A) in the general population?

CLCN5 p.Pro765His (c.2294C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLCN5 p.Pro765His (c.2294C>A)?

AlphaMissense predicts likely pathogenic (score 0.8749) — an in-silico prediction, not a clinical call.

CLCN5 p.Pro765His

c.2294C>A · VCV4229485

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8749 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8749	likely pathogenic
REVEL	0.909	moderately pathogenic-leaning
SaProt	LLR -13.40	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 7.5	GERP 2.7, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 12 kb · p 1.3e-15 · regional, not allelic
Overall
CADD	27.1	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: CLCN5
Protein: p.Pro765His
Coding: c.2294C>A
MANE Select: NM_001127898
Type: single nucleotide variant
Location: chrX:50090820 (GRCh38)
Structure: AlphaFold pLDDT 80.48 · 2 PDB
Residue 765: the cbs 2 domain

Full CLCN5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CLCN5 p.Pro765Ser Uncertain significance ★★ ⚠ same residue
CLCN5 p.Ala319Val Uncertain significance ★★ ⚠ same condition
CLCN5 p.Ala806Val Uncertain significance ★★ ⚠ same condition
CLCN5 p.Arg372Cys Uncertain significance ★★ ⚠ same condition
CLCN5 p.Arg408Cys Uncertain significance ★★ ⚠ same condition
CLCN5 p.Arg696Trp Uncertain significance ★★ ⚠ same condition
CLCN5 p.Glu176Lys Uncertain significance ★★ ⚠ same condition
CLCN5 p.Glu474Asp 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/clcn5-p-pro765his (accessed [today's date]).

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