Is CDH23 p.Ala129Val (c.386C>T) pathogenic?

CDH23 p.Ala129Val (c.386C>T) is classified Uncertain significance in CDH23 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-02-12). AlphaMissense: likely benign (0.0982); Ultra-rare (popmax 0.0446%, eas); Associated with autosomal recessive nonsyndromic hearing loss 12.

What condition is associated with CDH23 p.Ala129Val (c.386C>T)?

CDH23 p.Ala129Val (c.386C>T) is associated with autosomal recessive nonsyndromic hearing loss 12, Usher syndrome type 1, Usher syndrome type 1D (ClinVar).

How common is CDH23 p.Ala129Val (c.386C>T) in the general population?

CDH23 p.Ala129Val (c.386C>T) is ultra-rare (popmax 0.0446%, eas) (gnomAD).

What do computational predictors say about CDH23 p.Ala129Val (c.386C>T)?

AlphaMissense predicts likely benign (score 0.0982) — an in-silico prediction, not a clinical call.

CDH23 p.Ala129Val

c.386C>T · rs183046743 · VCV300400

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0982 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0446%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

autosomal recessive nonsyndromic hearing loss 12

Computational evidence

Protein change
AlphaMissense	0.0982	likely benign
REVEL	0.141	moderately 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 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0446% East Asian · 20/44,858 alleles

Filtering AF 0.031% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0271%

Overall 0.00607% 98/1,613,652 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0446%	2,243
African / African-American	0.0427%	2,344
Remaining individualsnot grpmax-eligible	0.0304%	3,288
South Asian	0.0022%	45,534
European (non-Finnish)	0.00203%	49,152
Admixed American	0.00167%	60,004

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.Ala129Val
Coding: c.386C>T
MANE Select: NM_022124
dbSNP: rs183046743
Type: single nucleotide variant
Location: chr10:71511169 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 129: the cadherin 1 domain

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

Disease context

autosomal recessive nonsyndromic hearing loss 12 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Usher syndrome type 1 Usher syndrome type 1D

Similar variants

CDH23 p.Ala129Thr Uncertain significance ★★ ⚠ same residue
CDH23 p.Ala129= 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-ala129val (accessed [today's date]).

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