Is CDH23 p.Arg184His (c.551G>A) pathogenic?

CDH23 p.Arg184His (c.551G>A) is classified Conflicting classifications of pathogenicity in CDH23 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-08-01). AlphaMissense: likely benign (0.2461); Ultra-rare (popmax 0.0185%, nfe).

How common is CDH23 p.Arg184His (c.551G>A) in the general population?

CDH23 p.Arg184His (c.551G>A) is ultra-rare (popmax 0.0185%, nfe) (gnomAD).

What do computational predictors say about CDH23 p.Arg184His (c.551G>A)?

AlphaMissense predicts likely benign (score 0.2461) — an in-silico prediction, not a clinical call.

CDH23 p.Arg184His

c.551G>A · rs201132251 · VCV178294

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2461 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0185%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.2461	likely benign
REVEL	0.15	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 7.5	GERP -0.51, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	21.2	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 0.0185% European (non-Finnish) · 218/1,179,878 alleles

Filtering AF 0.0165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0157%

Overall 0.0148% 239/1,613,926 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0185%	5,412
South Asian	0.00988%	10,119
Remaining individualsnot grpmax-eligible	0.008%	12,497
African / African-American	0.00533%	18,759
Admixed American	0.00333%	30,011
Finnishnot grpmax-eligible	0.00156%	63,980

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.Arg184His
Coding: c.551G>A
MANE Select: NM_022124
dbSNP: rs201132251
Type: single nucleotide variant
Location: chr10:71566863 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 184: the cadherin 2 domain

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

Similar variants

CDH23 p.Arg184Cys Uncertain significance ★★ ⚠ same residue
CDH23 p.Arg184= Likely benign ★★ same residue
CDH23 p.Arg2029Trp Pathogenic ★★★ ⚠ same type
CDH23 p.Asp127Gly Likely pathogenic ★★★ same type
CDH23 p.Glu956Lys Pathogenic ★★★ same type
CDH23 p.Pro240Leu Pathogenic ★★★ same type
CDH23 c.1515-12G>A Uncertain significance ★★★ same type
CDH23 p.Ala3190Val Uncertain significance ★★★ ⚠ same type

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-arg184his (accessed [today's date]).

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