Is CDH23 p.Arg2029Trp (c.6085C>T) pathogenic?

CDH23 p.Arg2029Trp (c.6085C>T) is classified Pathogenic in CDH23 (ClinVar, Expert panel, 10 submitters; last evaluated 2023-06-26). AlphaMissense: likely benign (0.2496); Rare (popmax 0.105%, eas); Associated with nonsyndromic genetic hearing loss.

What condition is associated with CDH23 p.Arg2029Trp (c.6085C>T)?

CDH23 p.Arg2029Trp (c.6085C>T) is associated with nonsyndromic genetic hearing loss, Usher syndrome type 1, Usher syndrome type 1D (ClinVar).

How common is CDH23 p.Arg2029Trp (c.6085C>T) in the general population?

CDH23 p.Arg2029Trp (c.6085C>T) is rare (popmax 0.105%, eas) (gnomAD).

How is Rare non-syndromic genetic deafness inherited?

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

What do computational predictors say about CDH23 p.Arg2029Trp (c.6085C>T)?

AlphaMissense predicts likely benign (score 0.2496) — an in-silico prediction, not a clinical call.

CDH23 p.Arg2029Trp

c.6085C>T · rs750880909 · VCV446446

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.2496 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.105%, eas)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

nonsyndromic genetic hearing loss

ClinGen expert panel — Hearing Loss VCEP

Pathogenic for nonsyndromic genetic deafness. Applied ACMG criteria (verbatim):

PM3_VeryStrong PP1_Supporting PP3

Curation rationale (ClinGen, verbatim)

The c.6085C>T variant in CDH23 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 2029 (p.Arg2029Trp). The highest population minor allele frequency in gnomAD v2.1.1 is 0.02% (3/17816 alleles) in the East Asian population. (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.7, evidence that correlates with impact to CDH23 function (PP3). This variant has been detected in many individuals with hearing loss or deafness, without any reported vision loss or evidence of retinopathy. Of those individuals, over 10 were homozygous or compound heterozygous for the variant and a pathogenic or likely pathogenic and many of those were confirmed in trans (6.75 PM3_Very Strong points, PMID: 35020051, 25963016, 22899989, 17850630). The variant has been reported to segregate with hearing loss in 1 affected family member from 1 family (PP1_Supporting; PMID: 22899989, 17850630). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3_VeryStrong, PP3, PP1. (VCEP specifications version 2; 06.26.2023).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.2496	likely benign ⚠ discordant with ClinVar
REVEL	0.701	pathogenic-leaning
⇒ REVEL calls this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.92 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.8	GERP 0.71, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	27.4	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 0.105% East Asian · 47/44,838 alleles

Filtering AF 0.0809% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0725%

Overall 0.00378% 61/1,612,088 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.105%	954
South Asian	0.00221%	45,263
Remaining individualsnot grpmax-eligible	0.0016%	62,396
African / African-American	0.00134%	74,886
European (non-Finnish)	0.000848%	117,931

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.Arg2029Trp
Coding: c.6085C>T
MANE Select: NM_022124
dbSNP: rs750880909
Type: single nucleotide variant
Location: chr10:71791167 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2029: a UniProt-annotated variant site (in dfnb12); the cadherin 19 domain

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

Disease context

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

Also linked: Usher syndrome type 1 Usher syndrome type 1D autosomal recessive nonsyndromic hearing loss 12 pituitary adenoma 5, multiple types

For Rare non-syndromic genetic deafness (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

Similar variants

CDH23 p.Arg2029Gln Uncertain significance ★★ ⚠ same residue
CDH23 p.Arg2029= Uncertain significance ★ same residue
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-arg2029trp (accessed [today's date]).

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