Is CDH23 p.Arg3Leu (c.8G>T) pathogenic?

CDH23 p.Arg3Leu (c.8G>T) is classified Uncertain significance in CDH23 (ClinVar, Single submitter, 2 submitters; last evaluated 2020-01-10). AlphaMissense: likely benign (0.093); Very rare (popmax 0.00377%, amr); Associated with Usher syndrome type 1.

What condition is associated with CDH23 p.Arg3Leu (c.8G>T)?

CDH23 p.Arg3Leu (c.8G>T) is associated with Usher syndrome type 1 (ClinVar).

How common is CDH23 p.Arg3Leu (c.8G>T) in the general population?

CDH23 p.Arg3Leu (c.8G>T) is very rare (popmax 0.00377%, amr) (gnomAD).

How is Usher syndrome inherited?

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

What do computational predictors say about CDH23 p.Arg3Leu (c.8G>T)?

AlphaMissense predicts likely benign (score 0.093) — an in-silico prediction, not a clinical call.

CDH23 p.Arg3Leu

c.8G>T · rs397517363 · VCV1036299

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.093 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00377%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Usher syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.093	likely benign
REVEL	0.068	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -1.3, phastCons 0.014
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	17.41	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00377% Admixed American · 2/53,048 alleles

Filtering AF 0.000625% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000234%

Overall 0.000424% 6/1,413,888 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00377%	26,524
European (non-Finnish)	0.000346%	288,608

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: CDH23
Protein: p.Arg3Leu
Coding: c.8G>T
MANE Select: NM_022124
dbSNP: rs397517363
Type: single nucleotide variant
Location: chr10:71439839 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 3: a UniProt-annotated variant site (in)

Full CDH23 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For Usher syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

CDH23 p.Arg3His Uncertain significance ★★ ⚠ same residue
CDH23 p.Arg3Cys Benign/Likely benign ★★ same residue
CDH23 p.Arg3= Likely benign ★ same residue
CDH23 p.Arg2029Trp Pathogenic ★★★ ⚠ same condition
CDH23 p.Asp127Gly Likely pathogenic ★★★ same condition
CDH23 p.Glu956Lys Pathogenic ★★★ same condition
CDH23 p.Pro240Leu Pathogenic ★★★ same condition
CDH23 c.1515-12G>A Uncertain significance ★★★ 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/cdh23-p-arg3leu (accessed [today's date]).

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