Is CLCN5 p.Phe166Ser (c.497T>C) pathogenic?

CLCN5 p.Phe166Ser (c.497T>C) is classified Uncertain significance in CLCN5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-04). AlphaMissense: likely pathogenic (0.798); Absent from gnomAD v4.1; Associated with Dent disease type 1.

What condition is associated with CLCN5 p.Phe166Ser (c.497T>C)?

CLCN5 p.Phe166Ser (c.497T>C) is associated with Dent disease type 1 (ClinVar).

How common is CLCN5 p.Phe166Ser (c.497T>C) in the general population?

CLCN5 p.Phe166Ser (c.497T>C) is absent from gnomAD v4.1 (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.Phe166Ser (c.497T>C)?

AlphaMissense predicts likely pathogenic (score 0.798) — an in-silico prediction, not a clinical call.

CLCN5 p.Phe166Ser

c.497T>C · VCV3773724

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.798 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Dent disease type 1

Computational evidence

Protein change
AlphaMissense	0.798	likely pathogenic
REVEL	0.708	pathogenic-leaning
SaProt	LLR -9.42	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP -1.6, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 5,948 bp · p 0.00033 · regional, not allelic
Overall
CADD	24.4	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

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.Phe166Ser
Coding: c.497T>C
MANE Select: NM_001127898
Type: single nucleotide variant
Location: chrX:50075876 (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-phe166ser (accessed [today's date]).

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