Is CDH23 p.Ile515Val (c.1543A>G) pathogenic?

CDH23 p.Ile515Val (c.1543A>G) is classified Conflicting classifications of pathogenicity in CDH23 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-25). AlphaMissense: likely benign (0.0845); Very rare (popmax 0.00502%, amr); Associated with Inborn genetic diseases.

What condition is associated with CDH23 p.Ile515Val (c.1543A>G)?

CDH23 p.Ile515Val (c.1543A>G) is associated with Inborn genetic diseases (ClinVar).

How common is CDH23 p.Ile515Val (c.1543A>G) in the general population?

CDH23 p.Ile515Val (c.1543A>G) is very rare (popmax 0.00502%, amr) (gnomAD).

What do computational predictors say about CDH23 p.Ile515Val (c.1543A>G)?

AlphaMissense predicts likely benign (score 0.0845) — an in-silico prediction, not a clinical call.

CDH23 p.Ile515Val

c.1543A>G · rs727504914 · VCV179509

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0845 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00502%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0845	likely benign
REVEL	0.063	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 4.7	GERP -0.59, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	10.53	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 0.00502% Admixed American · 3/59,716 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00067%

Overall 0.000559% 9/1,611,158 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00502%	19,905
Remaining individualsnot grpmax-eligible	0.00481%	20,799
African / African-American	0.00401%	24,953

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.Ile515Val
Coding: c.1543A>G
MANE Select: NM_022124
dbSNP: rs727504914
Type: single nucleotide variant
Location: chr10:71677484 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 515: the cadherin 5 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.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
CDH23 p.Ala1974Thr Uncertain significance ★★ ⚠ same condition
CDH23 p.Ala1987Thr Uncertain significance ★★ same condition
CDH23 p.Ala2031Thr 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-ile515val (accessed [today's date]).

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