Is CDH23 p.Val475Met (c.1423G>A) pathogenic?

CDH23 p.Val475Met (c.1423G>A) is classified Benign/Likely benign in CDH23 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.1028); Low-frequency (popmax 4.01%, afr); Associated with Usher syndrome type 1D.

What condition is associated with CDH23 p.Val475Met (c.1423G>A)?

CDH23 p.Val475Met (c.1423G>A) is associated with Usher syndrome type 1D, Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 12 (ClinVar).

How common is CDH23 p.Val475Met (c.1423G>A) in the general population?

CDH23 p.Val475Met (c.1423G>A) is low-frequency (popmax 4.01%, afr) (gnomAD).

What do computational predictors say about CDH23 p.Val475Met (c.1423G>A)?

AlphaMissense predicts likely benign (score 0.1028) — an in-silico prediction, not a clinical call.

CDH23 p.Val475Met

c.1423G>A · rs62622410 · VCV45867

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.1028 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.01%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Usher syndrome type 1D

Computational evidence

Protein change
AlphaMissense	0.1028	likely benign
REVEL	0.284	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 1.6, phastCons 0.99
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	22.8	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 4.01% African / African-American · 3,011/75,008 alleles

Filtering AF 3.89% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.85%

Overall 0.223% 3,605/1,613,968 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.01%	25
Remaining individualsnot grpmax-eligible	0.35%	285
Admixed American	0.318%	314
Middle Eastern	0.247%	404
South Asian	0.0198%	5,060
European (non-Finnish)	0.0124%	8,081
East Asian	0.0111%	8,977

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.Val475Met
Coding: c.1423G>A
MANE Select: NM_022124
dbSNP: rs62622410
Type: single nucleotide variant
Location: chr10:71646591 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 475: the cadherin 5 domain

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

Disease context

Usher syndrome type 1D — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Usher syndrome type 1 autosomal recessive nonsyndromic hearing loss 12

Similar variants

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
CDH23 p.Arg3189Gln 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-val475met (accessed [today's date]).

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