Is CDH23 p.Arg528Ser (c.1582C>A) pathogenic?

CDH23 p.Arg528Ser (c.1582C>A) is classified Uncertain significance in CDH23 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-05). AlphaMissense: likely pathogenic (0.7908); Very rare (popmax 0.00335%, amr).

How common is CDH23 p.Arg528Ser (c.1582C>A) in the general population?

CDH23 p.Arg528Ser (c.1582C>A) is very rare (popmax 0.00335%, amr) (gnomAD).

What do computational predictors say about CDH23 p.Arg528Ser (c.1582C>A)?

AlphaMissense predicts likely pathogenic (score 0.7908) — an in-silico prediction, not a clinical call.

CDH23 p.Arg528Ser

c.1582C>A · VCV4907816

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7908 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00335%, amr)

Computational evidence

Protein change
AlphaMissense	0.7908	likely pathogenic
REVEL	0.465	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.4, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	22.3	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 0.00335% Admixed American · 2/59,784 alleles

Filtering AF 0.000555% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000208%

Overall 0.000342% 5/1,459,886 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00335%	29,892
Finnishnot grpmax-eligible	0.00157%	63,804
European (non-Finnish)	0.00017%	589,717

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.Arg528Ser
Coding: c.1582C>A
MANE Select: NM_022124
Type: single nucleotide variant
Location: chr10:71677523 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 528: the cadherin 5 domain

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

Similar variants

CDH23 p.Arg528His Uncertain significance ★★ same residue
CDH23 p.Arg528= Conflicting classifications of pathogenicity ★ same residue
CDH23 p.Arg528Cys Uncertain significance ★ ⚠ same residue
CDH23 p.Arg2029Trp Pathogenic ★★★ ⚠ same type
CDH23 p.Asp127Gly Likely pathogenic ★★★ same type
CDH23 p.Glu956Lys Pathogenic ★★★ same type
CDH23 p.Pro240Leu Pathogenic ★★★ same type
CDH23 c.1515-12G>A Uncertain significance ★★★ same type

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-arg528ser (accessed [today's date]).

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