Is CDH23 p.Val1045Ala (c.3134T>C) pathogenic?

CDH23 p.Val1045Ala (c.3134T>C) is classified Uncertain significance in CDH23 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-07). AlphaMissense: ambiguous (0.4922); Ultra-rare (popmax 0.0133%, amr); Associated with Inborn genetic diseases.

What condition is associated with CDH23 p.Val1045Ala (c.3134T>C)?

CDH23 p.Val1045Ala (c.3134T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CDH23 p.Val1045Ala (c.3134T>C) in the general population?

CDH23 p.Val1045Ala (c.3134T>C) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about CDH23 p.Val1045Ala (c.3134T>C)?

AlphaMissense predicts ambiguous (score 0.4922) — an in-silico prediction, not a clinical call.

CDH23 p.Val1045Ala

c.3134T>C · rs1045482647 · VCV2154516

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4922 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4922	ambiguous
REVEL	0.745	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	26.7	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 0.0133% Admixed American · 8/60,006 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.000744% 12/1,613,778 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,501
Remaining individualsnot grpmax-eligible	0.0048%	20,820
European (non-Finnish)	8.48e-05%	1,179,898

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.Val1045Ala
Coding: c.3134T>C
MANE Select: NM_022124
dbSNP: rs1045482647
Type: single nucleotide variant
Location: chr10:71709125 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1045: the cadherin 10 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDH23 p.Val1045Met Uncertain significance ★★ same residue
CDH23 p.Val1045Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CDH23 p.Val1045= Likely benign ★ same residue
CDH23 p.Ala129Thr Uncertain significance ★★ ⚠ same condition
CDH23 p.Ala1464Glu Uncertain significance ★★ ⚠ same condition
CDH23 p.Ala1482Val Uncertain significance ★★ ⚠ same condition
CDH23 p.Ala1673Val Uncertain significance ★★ same condition
CDH23 p.Ala1878Thr 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-val1045ala (accessed [today's date]).

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