Is CDH23 p.Arg1684His (c.5051G>A) pathogenic?

CDH23 p.Arg1684His (c.5051G>A) is classified Likely benign in CDH23 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-22). AlphaMissense: likely benign (0.0575); Ultra-rare (popmax 0.0493%, mid); Associated with Usher syndrome type 1.

What condition is associated with CDH23 p.Arg1684His (c.5051G>A)?

CDH23 p.Arg1684His (c.5051G>A) is associated with Usher syndrome type 1 (ClinVar).

How common is CDH23 p.Arg1684His (c.5051G>A) in the general population?

CDH23 p.Arg1684His (c.5051G>A) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

How is Usher syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CDH23 p.Arg1684His (c.5051G>A)?

AlphaMissense predicts likely benign (score 0.0575) — an in-silico prediction, not a clinical call.

CDH23 p.Arg1684His

c.5051G>A · rs111033475 · VCV725069

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0575 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Usher syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.0575	likely benign
REVEL	0.144	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 -3.2	GERP -3.8
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	0.167	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 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0237% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0205%

Overall 0.00434% 70/1,613,772 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,028
South Asian	0.0329%	3,036
African / African-American	0.0107%	9,361
Admixed American	0.005%	20,002
East Asian	0.00446%	22,433
Remaining individualsnot grpmax-eligible	0.0032%	31,233
European (non-Finnish)	0.00186%	53,631

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.Arg1684His
Coding: c.5051G>A
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

Usher syndrome type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Usher syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

CDH23 p.Arg1684Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
CDH23 p.Arg1684Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
CDH23 p.Arg1684= 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
CDH23 c.1515-12G>A 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-arg1684his (accessed [today's date]).

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