Is CDH23 p.Asp987Asn (c.2959G>A) pathogenic?

CDH23 p.Asp987Asn (c.2959G>A) is classified Uncertain significance in CDH23 (ClinVar, Expert panel, 6 submitters; last evaluated 2025-10-08). AlphaMissense: likely pathogenic (0.791); Very rare (popmax 0.00517%, amr); Associated with nonsyndromic genetic hearing loss.

What condition is associated with CDH23 p.Asp987Asn (c.2959G>A)?

CDH23 p.Asp987Asn (c.2959G>A) is associated with nonsyndromic genetic hearing loss, autosomal recessive nonsyndromic hearing loss 12, pituitary adenoma 5, multiple types (ClinVar).

How common is CDH23 p.Asp987Asn (c.2959G>A) in the general population?

CDH23 p.Asp987Asn (c.2959G>A) is very rare (popmax 0.00517%, amr) (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.Asp987Asn (c.2959G>A)?

AlphaMissense predicts likely pathogenic (score 0.791) — an in-silico prediction, not a clinical call.

CDH23 p.Asp987Asn

c.2959G>A · rs770665588 · VCV1036903

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.791 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00517%, amr)

Conditions

nonsyndromic genetic hearing loss

ClinGen expert panel — Hearing Loss VCEP

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

PM2_Supporting PM3

Curation rationale (ClinGen, verbatim)

The NM_022124.6(CDH23):c.2959G>A variant in the CDH23 gene is a missense variant predicted to cause the substitution of aspartic acid vy asparagine at amino acid 987. This variant has been reported in 1 proband with apparently isolated hearing loss. This individual is compound heterozygous for the variant and a pathogenic variant confirmed in trans by family testing (PMID : 26226137)(PM3). An additional patient with isolated HL at the age of 28 y.o have been reported, in association with another missense of unknown significance (phase unknown, PMID : 38855775). The allele frequency of this variant is 0.001% (3/58080) of Admixed American chromosomes by gnomAD v.4, which is lower than the thresholds defined by the ClinGen Hearing Loss Expert Panel for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.48, which is neither above nor below the thresholds predicting a damaging or benign impact on CDH23 function. In summary, this variant has been classified as a variant of uncertain significance for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_P, PM3 (ClinGen Hearing Loss VCEP specifications version 2; 10/8/2025).

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

Computational evidence

Protein change
AlphaMissense	0.791	likely pathogenic
REVEL	0.48	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	27.7	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 0.00517% Admixed American · 3/58,080 alleles

Filtering AF 0.00137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00068%

Overall 0.000207% 3/1,447,258 alleles · very 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.Asp987Asn
Coding: c.2959G>A
MANE Select: NM_022124
dbSNP: rs770665588
Type: single nucleotide variant
Location: chr10:71706902 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 987: the cadherin 9 domain

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: 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

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-asp987asn (accessed [today's date]).

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