Is CDH23 p.Asp990Asn (c.2968G>A) pathogenic?

CDH23 p.Asp990Asn (c.2968G>A) is classified Pathogenic/Likely pathogenic in CDH23 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-11-18). AlphaMissense: likely pathogenic (0.6); Ultra-rare (popmax 0.0113%, sas); Associated with CDH23-related disorder.

What condition is associated with CDH23 p.Asp990Asn (c.2968G>A)?

CDH23 p.Asp990Asn (c.2968G>A) is associated with CDH23-related disorder, Usher syndrome type 1, Usher syndrome type 1D (ClinVar).

How common is CDH23 p.Asp990Asn (c.2968G>A) in the general population?

CDH23 p.Asp990Asn (c.2968G>A) is ultra-rare (popmax 0.0113%, sas) (gnomAD).

What do computational predictors say about CDH23 p.Asp990Asn (c.2968G>A)?

AlphaMissense predicts likely pathogenic (score 0.6) — an in-silico prediction, not a clinical call.

CDH23 p.Asp990Asn

c.2968G>A · rs771766431 · VCV861900

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.6 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0113%, sas)

Conditions

CDH23-related disorder

Computational evidence

Protein change
AlphaMissense	0.6	likely pathogenic ✓ concordant with ClinVar
REVEL	0.494	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	28.9	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 0.0113% South Asian · 10/88,700 alleles

Filtering AF 0.00609% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00464%

Overall 0.00106% 17/1,602,166 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0113%	8,870
Admixed American	0.00342%	29,241
European (non-Finnish)	0.000426%	234,978

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.Asp990Asn
Coding: c.2968G>A
MANE Select: NM_022124
dbSNP: rs771766431
Type: single nucleotide variant
Location: chr10:71706911 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 990: a UniProt-annotated variant site (in dfnb12); the cadherin 9 domain

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

Disease context

CDH23-related disorder

Also linked: Usher syndrome type 1 Usher syndrome type 1D autosomal recessive nonsyndromic hearing loss 12 Usher syndrome hearing loss, autosomal recessive pituitary adenoma 5, multiple types

Similar variants

CDH23 p.Asp990= Conflicting classifications of pathogenicity ★ 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
CDH23 p.Arg301Gln 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-asp990asn (accessed [today's date]).

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