Is CDH23 p.Ala1464Ser (c.4390G>T) pathogenic?

CDH23 p.Ala1464Ser (c.4390G>T) is classified Conflicting classifications of pathogenicity in CDH23 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-27). AlphaMissense: likely benign (0.0725); Ultra-rare (popmax 0.0768%, amr); Associated with Usher syndrome type 1.

What condition is associated with CDH23 p.Ala1464Ser (c.4390G>T)?

CDH23 p.Ala1464Ser (c.4390G>T) is associated with Usher syndrome type 1 (ClinVar).

How common is CDH23 p.Ala1464Ser (c.4390G>T) in the general population?

CDH23 p.Ala1464Ser (c.4390G>T) is ultra-rare (popmax 0.0768%, amr) (gnomAD).

How is Usher syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CDH23 p.Ala1464Ser (c.4390G>T)?

AlphaMissense predicts likely benign (score 0.0725) — an in-silico prediction, not a clinical call.

CDH23 p.Ala1464Ser

c.4390G>T · rs756674688 · VCV845440

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0725 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0768%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Usher syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.0725	likely benign
REVEL	0.057	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	18.62	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 0.0768% Admixed American · 46/59,906 alleles

Filtering AF 0.0591% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0529%

Overall 0.00372% 60/1,613,008 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0768%	1,302
European (non-Finnish)	0.00119%	84,253

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.Ala1464Ser
Coding: c.4390G>T
MANE Select: NM_022124
dbSNP: rs756674688
Type: single nucleotide variant
Location: chr10:71739674 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1464: the cadherin 14 domain; an α-helix

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

Disease context

Usher syndrome type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Usher syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

CDH23 p.Ala1464Glu Uncertain significance ★★ ⚠ same residue
CDH23 p.Ala1464Val Conflicting classifications of pathogenicity ★ ⚠ same residue
CDH23 p.Ala1464Thr Uncertain significance ★★ ⚠ same residue
CDH23 p.Ala1464= 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

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-ala1464ser (accessed [today's date]).

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