Is CDH23 p.Pro240Leu (c.719C>T) pathogenic?

CDH23 p.Pro240Leu (c.719C>T) is classified Pathogenic in CDH23 (ClinVar, Expert panel, 11 submitters; last evaluated 2019-07-22). AlphaMissense: likely pathogenic (0.7771); Rare (popmax 0.12%, eas); Associated with nonsyndromic genetic hearing loss.

What condition is associated with CDH23 p.Pro240Leu (c.719C>T)?

CDH23 p.Pro240Leu (c.719C>T) is associated with nonsyndromic genetic hearing loss, Usher syndrome type 1, Usher syndrome type 1D (ClinVar).

How common is CDH23 p.Pro240Leu (c.719C>T) in the general population?

CDH23 p.Pro240Leu (c.719C>T) is rare (popmax 0.12%, eas) (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.Pro240Leu (c.719C>T)?

AlphaMissense predicts likely pathogenic (score 0.7771) — an in-silico prediction, not a clinical call.

CDH23 p.Pro240Leu

c.719C>T · rs121908354 · VCV4928

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 11 submitters

AlphaMissense

likely pathogenic

0.7771 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.12%, eas)

Conditions

nonsyndromic genetic hearing loss

ClinGen expert panel — Hearing Loss VCEP

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

PP1_Strong PM2_Supporting PS4 PM3_Strong

Curation rationale (ClinGen, verbatim)

The allele frequency of the c.719C>T (p.Pro240Leu) variant in the CDH23 gene is 0.05% (10/17246) of East Asian chromosomes by gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). This variant has been reported in > 10 probands with hearing loss without evidence of retinal disease, including >5 homozygotes, at least 1 compound heterozygote with c.6712+1G>A variant, and >5 compound heterozygotes with rare variants of uncertain significance (PM3_Strong; PMID:24164807, 24618850, 25963016, 26264712, 17850630, 22899989). This variant has also segregated in 3 siblings with hearing loss (PP1_Strong, PMID: 17850630, 22899989). The variant was identified in the heterozygous state in a patient with Usher syndrome who also harbored a homozygous missense variant in MYO7A (PMID: 24618850). A case-control meta analysis found that the p.Pro240Leu variant was associated with a 12-fold higher risk of hearing loss compared to the wild-type allele (OR = 11.68; 95% CI = 3.16–43.24; PS4), though it should be noted that it appears that some probands were included in more than one study included in the meta-analysis (PMID 30367262). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PP1_Strong, PM3_Strong, PM2_Supporting, PS4.

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

Computational evidence

Protein change
AlphaMissense	0.7771	likely pathogenic ✓ concordant with ClinVar
REVEL	0.516	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	24.9	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 0.12% East Asian · 54/44,886 alleles

Filtering AF 0.0946% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0855%

Overall 0.00335% 54/1,614,020 alleles · rare

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.Pro240Leu
Coding: c.719C>T
MANE Select: NM_022124
dbSNP: rs121908354
Type: single nucleotide variant
Location: chr10:71570884 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 240: the cadherin 3 domain; a UniProt-annotated variant site (in dfnb12)

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 Usher syndrome type 1D autosomal recessive nonsyndromic hearing loss 12 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

VSIR p.Ile240Thr Benign ★ same residue
CDH23 p.Arg2029Trp Pathogenic ★★★ ⚠ same condition
CDH23 p.Asp127Gly Likely pathogenic ★★★ same condition
CDH23 p.Glu956Lys 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-pro240leu (accessed [today's date]).

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