Is CDH23 p.Arg2465Trp (c.7393C>T) pathogenic?

CDH23 p.Arg2465Trp (c.7393C>T) is classified Uncertain significance in CDH23 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-07-14). AlphaMissense: likely pathogenic (0.7032); Very rare (popmax 0.00549%, sas); Associated with autosomal recessive nonsyndromic hearing loss 12.

What condition is associated with CDH23 p.Arg2465Trp (c.7393C>T)?

CDH23 p.Arg2465Trp (c.7393C>T) is associated with autosomal recessive nonsyndromic hearing loss 12, Usher syndrome type 1D (ClinVar).

How common is CDH23 p.Arg2465Trp (c.7393C>T) in the general population?

CDH23 p.Arg2465Trp (c.7393C>T) is very rare (popmax 0.00549%, sas) (gnomAD).

What do computational predictors say about CDH23 p.Arg2465Trp (c.7393C>T)?

AlphaMissense predicts likely pathogenic (score 0.7032) — an in-silico prediction, not a clinical call.

CDH23 p.Arg2465Trp

c.7393C>T · rs760879110 · VCV1064756

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7032 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

Conditions

autosomal recessive nonsyndromic hearing loss 12

Computational evidence

Protein change
AlphaMissense	0.7032	likely pathogenic
REVEL	0.555	indeterminate
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ1.00 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 4,473 bp · p 9.3e-05 · regional, not allelic
Overall
CADD	33.0	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 0.00549% South Asian · 5/91,070 alleles

Filtering AF 0.0021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000821% 12/1,461,690 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00549%	18,214
Finnishnot grpmax-eligible	0.00156%	64,000
African / African-American	0.00133%	75,000
European (non-Finnish)	0.000424%	235,976

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.Arg2465Trp
Coding: c.7393C>T
MANE Select: NM_022124
dbSNP: rs760879110
Type: single nucleotide variant
Location: chr10:71800666 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2465: a UniProt-annotated variant site (in dfnb12); the cadherin 23 domain

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

Disease context

autosomal recessive nonsyndromic hearing loss 12 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Usher syndrome type 1D

Similar variants

CDH23 p.Arg2465Gln Conflicting classifications of pathogenicity ★ 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
CDH23 p.Ala3190Val Uncertain significance ★★★ ⚠ same condition
CDH23 p.Arg301Gln 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-arg2465trp (accessed [today's date]).

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