Is CDH23 p.Leu2002Val (c.6004C>G) pathogenic?

CDH23 p.Leu2002Val (c.6004C>G) is classified Uncertain significance in CDH23 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.1497); Ultra-rare (popmax 0.015%, amr); Associated with autosomal recessive nonsyndromic hearing loss 12.

What condition is associated with CDH23 p.Leu2002Val (c.6004C>G)?

CDH23 p.Leu2002Val (c.6004C>G) is associated with autosomal recessive nonsyndromic hearing loss 12, Usher syndrome type 1, Usher syndrome type 1D (ClinVar).

How common is CDH23 p.Leu2002Val (c.6004C>G) in the general population?

CDH23 p.Leu2002Val (c.6004C>G) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about CDH23 p.Leu2002Val (c.6004C>G)?

AlphaMissense predicts likely benign (score 0.1497) — an in-silico prediction, not a clinical call.

CDH23 p.Leu2002Val

c.6004C>G · rs756459547 · VCV300449

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1497 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Conditions

autosomal recessive nonsyndromic hearing loss 12

Computational evidence

Protein change
AlphaMissense	0.1497	likely benign
REVEL	0.401	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.39, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	25.4	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 0.015% Admixed American · 9/59,994 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.00112% 18/1,613,638 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,666
Remaining individualsnot grpmax-eligible	0.0032%	31,227
East Asian	0.00223%	44,898
European (non-Finnish)	0.000509%	196,645

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.Leu2002Val
Coding: c.6004C>G
MANE Select: NM_022124
dbSNP: rs756459547
Type: single nucleotide variant
Location: chr10:71790368 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2002: the cadherin 19 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 pituitary adenoma 5, multiple types

Similar variants

CDH23 p.Leu2002Pro Uncertain significance ★★ ⚠ same residue
CDH23 p.Leu2002Met Uncertain significance ★ same residue
CDH23 p.Leu2002= 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

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-leu2002val (accessed [today's date]).

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