Is CDH23 p.Arg457Trp (c.1369C>T) pathogenic?

CDH23 p.Arg457Trp (c.1369C>T) is classified Conflicting classifications of pathogenicity in CDH23 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2023-12-01). AlphaMissense: likely benign (0.315); Very rare (popmax 0.0011%, sas); Associated with Rare genetic deafness.

What condition is associated with CDH23 p.Arg457Trp (c.1369C>T)?

CDH23 p.Arg457Trp (c.1369C>T) is associated with Rare genetic deafness, autosomal recessive nonsyndromic hearing loss 12, inherited retinal dystrophy (ClinVar).

How common is CDH23 p.Arg457Trp (c.1369C>T) in the general population?

CDH23 p.Arg457Trp (c.1369C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CDH23 p.Arg457Trp (c.1369C>T)?

AlphaMissense predicts likely benign (score 0.315) — an in-silico prediction, not a clinical call.

CDH23 p.Arg457Trp

c.1369C>T · rs727504455 · VCV178675

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.315 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Rare genetic deafness

Computational evidence

Protein change
AlphaMissense	0.315	likely benign
REVEL	0.416	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 1.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	28.4	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

Grpmax group 0.0011% South Asian · 1/91,080 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.00062% 10/1,613,854 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,464
South Asiangrpmax	0.0011%	91,080
European (non-Finnish)	0.000678%	147,488

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: CDH23
Protein: p.Arg457Trp
Coding: c.1369C>T
MANE Select: NM_022124
dbSNP: rs727504455
Type: single nucleotide variant
Location: chr10:71646537 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 457: the cadherin 4 domain

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

Disease context

Rare genetic deafness — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive nonsyndromic hearing loss 12 inherited retinal dystrophy

Similar variants

CDH23 p.Arg457Gln Uncertain significance ★ 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 p.Ala3190Val Uncertain significance ★★★ ⚠ same condition
CDH23 p.Arg301Gln Uncertain significance ★★★ same condition
CDH23 p.Arg3189Trp 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-arg457trp (accessed [today's date]).

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