Is CDH23 p.Ala1464Val (c.4391C>T) pathogenic?

CDH23 p.Ala1464Val (c.4391C>T) is classified Conflicting classifications of pathogenicity in CDH23 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.108); Ultra-rare (popmax 0.066%, mid); Associated with Usher syndrome type 1D.

What condition is associated with CDH23 p.Ala1464Val (c.4391C>T)?

CDH23 p.Ala1464Val (c.4391C>T) is associated with Usher syndrome type 1D, Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 12 (ClinVar).

How common is CDH23 p.Ala1464Val (c.4391C>T) in the general population?

CDH23 p.Ala1464Val (c.4391C>T) is ultra-rare (popmax 0.066%, mid) (gnomAD).

What do computational predictors say about CDH23 p.Ala1464Val (c.4391C>T)?

AlphaMissense predicts likely benign (score 0.108) — an in-silico prediction, not a clinical call.

CDH23 p.Ala1464Val

c.4391C>T · rs374362883 · VCV45947

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.108 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.066%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Usher syndrome type 1D

Computational evidence

Protein change
AlphaMissense	0.108	likely benign
REVEL	0.042	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 1.9	GERP -2.2, phastCons 0.96
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	18.31	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 0.066% Middle Eastern · 4/6,060 alleles

Filtering AF 0.0359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0347%

Overall 0.0319% 514/1,613,206 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.768%	130
Middle Easterngrpmax	0.066%	1,515
European (non-Finnish)	0.0388%	2,575
Remaining individualsnot grpmax-eligible	0.0256%	3,904
Admixed American	0.015%	6,660
South Asian	0.0121%	8,264
African / African-American	0.00933%	10,715
East Asian	0.00223%	44,858
Finnishnot grpmax-eligible	0.00156%	63,936

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala1464Val
Coding: c.4391C>T
MANE Select: NM_022124
dbSNP: rs374362883
Type: single nucleotide variant
Location: chr10:71739675 (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 1D — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

CDH23 p.Ala1464Glu Uncertain significance ★★ ⚠ same residue
CDH23 p.Ala1464Thr Uncertain significance ★★ ⚠ same residue
CDH23 p.Ala1464Ser Conflicting classifications of pathogenicity ★ ⚠ 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-ala1464val (accessed [today's date]).

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