Is CDH23 p.Arg1684Pro (c.5051G>C) pathogenic?

CDH23 p.Arg1684Pro (c.5051G>C) is classified Conflicting classifications of pathogenicity in CDH23 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-08-11). AlphaMissense: likely pathogenic (0.6931); Ultra-rare (popmax 0.05%, amr); Associated with Inborn genetic diseases.

What condition is associated with CDH23 p.Arg1684Pro (c.5051G>C)?

CDH23 p.Arg1684Pro (c.5051G>C) is associated with Inborn genetic diseases (ClinVar).

How common is CDH23 p.Arg1684Pro (c.5051G>C) in the general population?

CDH23 p.Arg1684Pro (c.5051G>C) is ultra-rare (popmax 0.05%, amr) (gnomAD).

What do computational predictors say about CDH23 p.Arg1684Pro (c.5051G>C)?

AlphaMissense predicts likely pathogenic (score 0.6931) — an in-silico prediction, not a clinical call.

CDH23 p.Arg1684Pro

c.5051G>C · rs111033475 · VCV45963

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.6931 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.05%, amr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6931	likely pathogenic
REVEL	0.261	benign-leaning
⇒ AlphaMissense calls this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.2	GERP -3.8
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	7.842	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 0.05% Admixed American · 30/60,026 alleles

Filtering AF 0.0359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0312%

Overall 0.00223% 36/1,613,890 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.05%	2,001
Remaining individualsnot grpmax-eligible	0.008%	12,498
European (non-Finnish)	8.48e-05%	1,179,878

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.Arg1684Pro
Coding: c.5051G>C
MANE Select: NM_022124
dbSNP: rs111033475
Type: single nucleotide variant
Location: chr10:71777885 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1684: the cadherin 16 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.Arg1684Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
CDH23 p.Arg1684His Likely benign ★★ same residue
CDH23 p.Arg1684= 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-arg1684pro (accessed [today's date]).

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