Is CDH23 p.Arg301Gln (c.902G>A) pathogenic?

CDH23 p.Arg301Gln (c.902G>A) is classified Uncertain significance in CDH23 (ClinVar, Expert panel, 10 submitters; last evaluated 2020-11-02). AlphaMissense: ambiguous (0.4724); Very rare (popmax 0.00134%, afr); Associated with nonsyndromic genetic hearing loss.

What condition is associated with CDH23 p.Arg301Gln (c.902G>A)?

CDH23 p.Arg301Gln (c.902G>A) is associated with nonsyndromic genetic hearing loss, Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 12 (ClinVar).

How common is CDH23 p.Arg301Gln (c.902G>A) in the general population?

CDH23 p.Arg301Gln (c.902G>A) is very rare (popmax 0.00134%, afr) (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.Arg301Gln (c.902G>A)?

AlphaMissense predicts ambiguous (score 0.4724) — an in-silico prediction, not a clinical call.

CDH23 p.Arg301Gln

c.902G>A · rs121908355 · VCV4929

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 10 submitters

AlphaMissense

ambiguous

0.4724 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

nonsyndromic genetic hearing loss

ClinGen expert panel — Hearing Loss VCEP

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

PM2 PM3

Curation rationale (ClinGen, verbatim)

The allele frequency of the c.902G>A (p.Arg301Gln) variant in the CDH23 gene is 0.0046% (3/64572) of European (non-Finnish) chromosomes by gnomAD v3, which is a low enough frequency to apply PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss. This variant was detected in 4 individuals with sensorineural hearing loss with the P240L variant in CDH23. For 2 of these probands the pathogenic P240L variant in CDH23 was present in trans; however, because all the families were of East Asian descent and this variant was always observed with the P240L variant, PM3 was kept at the moderate level (PM3, PMIDs: 17850630, 22443853, 22899989). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein (PP3 not met). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2, PM3.

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

Computational evidence

Protein change
AlphaMissense	0.4724	ambiguous
REVEL	0.563	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	27.9	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 0.00134% African / African-American · 1/74,898 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000868% 14/1,613,794 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,898
European (non-Finnish)	0.0011%	90,759

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.Arg301Gln
Coding: c.902G>A
MANE Select: NM_022124
dbSNP: rs121908355
Type: single nucleotide variant
Location: chr10:71615573 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 301: the cadherin 3 domain; a UniProt-annotated variant site (in dfnb12; uncertain significance)

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 autosomal recessive nonsyndromic hearing loss 12 Usher syndrome 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.Arg301Trp Conflicting classifications of pathogenicity ★ same residue
CDH23 p.Arg301= 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
CDH23 p.Ala3190Val 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-arg301gln (accessed [today's date]).

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