Is CLCN5 p.Ala232= (c.696G>A) pathogenic?

CLCN5 p.Ala232= (c.696G>A) is classified Conflicting classifications of pathogenicity in CLCN5 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-06-13). Very rare (popmax 0.00707%, afr); Associated with Dent disease type 1.

What condition is associated with CLCN5 p.Ala232= (c.696G>A)?

CLCN5 p.Ala232= (c.696G>A) is associated with Dent disease type 1 (ClinVar).

How common is CLCN5 p.Ala232= (c.696G>A) in the general population?

CLCN5 p.Ala232= (c.696G>A) is very rare (popmax 0.00707%, afr) (gnomAD).

How is Dent disease inherited?

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

CLCN5 p.Ala232=

c.696G>A · rs140312372 · VCV368475

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00707%, afr)

Conditions

Dent disease type 1

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 -1.4	GERP -5
Overall
CADD	2.714	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00707% African / African-American · 4/56,583 alleles

Filtering AF 0.00443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00401%

Overall 0.00482% 58/1,202,167 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00707%	14,146
European (non-Finnish)	0.00574%	17,435
East Asian	0.00297%	33,687
Finnishnot grpmax-eligible	0.00216%	46,244
Remaining individualsnot grpmax-eligible	0.00211%	47,363

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: CLCN5
Protein: p.Ala232=
Coding: c.696G>A
MANE Select: NM_001127898
dbSNP: rs140312372
Type: single nucleotide variant
Location: chrX:50080686 (GRCh38)
Structure: AlphaFold pLDDT 80.48 · 2 PDB

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

Disease context

Dent disease type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Dent disease (Orphanet):

Inheritance: X-linked recessive
Onset: Childhood

Similar variants

CLCN5 c.1014+1G>A Pathogenic/Likely pathogenic ★★ same condition
CLCN5 c.604-1G>C Likely pathogenic ★★ same condition
CLCN5 c.933+1G>A Pathogenic/Likely pathogenic ★★ same condition
CLCN5 p.Arg104Ter Pathogenic/Likely pathogenic ★★ same condition
CLCN5 p.Arg417Ter Pathogenic ★★ same condition
CLCN5 p.Arg537Ter Pathogenic ★★ same condition
CLCN5 p.Arg586Trp Pathogenic/Likely pathogenic ★★ same condition
CLCN5 p.Arg707Ter Pathogenic ★★ 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-ala232 (accessed [today's date]).

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