Is CLCN5 p.Arg774Ter (c.2320C>T) pathogenic?

CLCN5 p.Arg774Ter (c.2320C>T) is classified Conflicting classifications of pathogenicity in CLCN5 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2024-02-16). Very rare (popmax 0.000223%, nfe); Associated with Dent disease type 1.

How common is CLCN5 p.Arg774Ter (c.2320C>T) in the general population?

CLCN5 p.Arg774Ter (c.2320C>T) is very rare (popmax 0.000223%, nfe) (gnomAD).

How is Dent disease inherited?

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

CLCN5 p.Arg774Ter

Q: What condition is associated with CLCN5 p.Arg774Ter (c.2320C>T)?

CLCN5 p.Arg774Ter (c.2320C>T) is associated with Dent disease type 1, proteinuria, low molecular weight, with hypercalciuria and nephrocalcinosis, nephrolithiasis, X-linked recessive, with renal failure (ClinVar).

c.2320C>T · rs151340624 · VCV11800

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000223%, nfe)

Conditions

Dent disease type 1

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.5	GERP 2.7, phastCons 1
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000223% European (non-Finnish) · 2/895,152 alleles

Filtering AF 3.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000248% 3/1,211,068 alleles · very rare exomes 3/1,097,831 · genomes 0/113,237 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0021%	47,631
European (non-Finnish)grpmax	0.000223%	447,575

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg774Ter
Coding: c.2320C>T
MANE Select: NM_001127898
dbSNP: rs151340624
Type: single nucleotide variant
Location: chrX:50090846 (GRCh38)

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

Also linked: proteinuria, low molecular weight, with hypercalciuria and nephrocalcinosis nephrolithiasis, X-linked recessive, with renal failure

For Dent disease (Orphanet):

Inheritance: X-linked recessive
Onset: Childhood

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-arg774ter (accessed [today's date]).

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