Is CDH23 p.Ile2178Asn (c.6533T>A) pathogenic?

CDH23 p.Ile2178Asn (c.6533T>A) is classified Conflicting classifications of pathogenicity in CDH23 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-02-28). AlphaMissense: ambiguous (0.3693); Very rare (popmax 0.00667%, amr); Associated with autosomal recessive nonsyndromic hearing loss 12.

What condition is associated with CDH23 p.Ile2178Asn (c.6533T>A)?

CDH23 p.Ile2178Asn (c.6533T>A) is associated with autosomal recessive nonsyndromic hearing loss 12 (ClinVar).

How common is CDH23 p.Ile2178Asn (c.6533T>A) in the general population?

CDH23 p.Ile2178Asn (c.6533T>A) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about CDH23 p.Ile2178Asn (c.6533T>A)?

AlphaMissense predicts ambiguous (score 0.3693) — an in-silico prediction, not a clinical call.

CDH23 p.Ile2178Asn

c.6533T>A · rs772953914 · VCV1477521

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3693 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Conditions

autosomal recessive nonsyndromic hearing loss 12

Computational evidence

Protein change
AlphaMissense	0.3693	ambiguous
REVEL	0.13	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	24.1	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 0.00667% Admixed American · 4/59,992 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00031% 5/1,613,762 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,998
Remaining individualsnot grpmax-eligible	0.0016%	62,454

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.Ile2178Asn
Coding: c.6533T>A
MANE Select: NM_022124
dbSNP: rs772953914
Type: single nucleotide variant
Location: chr10:71793461 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2178: the cadherin 21 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

Similar variants

CDH23 p.Ile2178Phe Uncertain significance ★★ ⚠ same residue
CDH23 p.Ile2178= 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 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-ile2178asn (accessed [today's date]).

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