Is CLCN5 p.Ser314= (c.942G>A) pathogenic?

CLCN5 p.Ser314= (c.942G>A) is classified Benign in CLCN5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-20). Ultra-rare (popmax 0.0711%, eas); Associated with Dent disease type 1.

What condition is associated with CLCN5 p.Ser314= (c.942G>A)?

CLCN5 p.Ser314= (c.942G>A) is associated with Dent disease type 1 (ClinVar).

How common is CLCN5 p.Ser314= (c.942G>A) in the general population?

CLCN5 p.Ser314= (c.942G>A) is ultra-rare (popmax 0.0711%, eas) (gnomAD).

How is Dent disease inherited?

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

CLCN5 p.Ser314=

c.942G>A · rs782320623 · VCV912974

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0711%, eas)

Conditions

Dent disease type 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -6.7	GERP -5.9
Overall
CADD	0.65	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0711% East Asian · 24/33,754 alleles

Filtering AF 0.0489% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0417%

Overall 0.00365% 44/1,206,234 alleles · ultra-rare exomes 40/1,094,131 · genomes 4/112,103 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0711%	1,406
Admixed American	0.00436%	22,920
Finnishnot grpmax-eligible	0.00215%	46,545
European (non-Finnish)	0.00191%	52,453

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.Ser314=
Coding: c.942G>A
MANE Select: NM_001127898
dbSNP: rs782320623
Type: single nucleotide variant
Location: chrX:50085988 (GRCh38)
Structure: AlphaFold pLDDT 80.48 · 2 PDB
Residue 314: a UniProt-annotated variant site (in xlhrr; trafficks normally to the cell surface and to early endosomes; displays complex glycosylation at the cell surface like wild-type protein; exhibits reduced current)

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 p.Ser314Leu Pathogenic ★★ same residue
CLCN5 p.Ser314Ter Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-ser314 (accessed [today's date]).

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