Is CLCN5 p.Val321Ile (c.961G>A) pathogenic?

CLCN5 p.Val321Ile (c.961G>A) is classified Uncertain significance in CLCN5 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-01-01). AlphaMissense: likely benign (0.2846); Very rare (popmax 9.12e-05%); Associated with Dent disease type 1.

What condition is associated with CLCN5 p.Val321Ile (c.961G>A)?

CLCN5 p.Val321Ile (c.961G>A) is associated with Dent disease type 1 (ClinVar).

How common is CLCN5 p.Val321Ile (c.961G>A) in the general population?

CLCN5 p.Val321Ile (c.961G>A) is very rare (popmax 9.12e-05%) (gnomAD).

How is Dent disease inherited?

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

What do computational predictors say about CLCN5 p.Val321Ile (c.961G>A)?

AlphaMissense predicts likely benign (score 0.2846) — an in-silico prediction, not a clinical call.

CLCN5 p.Val321Ile

c.961G>A · rs1557193807 · VCV982703

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2846 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9.12e-05%)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Dent disease type 1

Computational evidence

Protein change
AlphaMissense	0.2846	likely benign
REVEL	0.564	indeterminate
SaProt	LLR -12.22	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 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 12 kb · p 1.3e-15 · regional, not allelic
Overall
CADD	27.8	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 9.12e-05%

Overall 9.12e-05% 1/1,096,549 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: CLCN5
Protein: p.Val321Ile
Coding: c.961G>A
MANE Select: NM_001127898
dbSNP: rs1557193807
Type: single nucleotide variant
Location: chrX:50086007 (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

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CLCN5 c.604-1G>C Likely pathogenic ★★ same condition
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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-val321ile (accessed [today's date]).

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