Is CDH23 p.Arg2506Gln (c.7517G>A) pathogenic?

CDH23 p.Arg2506Gln (c.7517G>A) is classified Uncertain significance in CDH23 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-07-05). AlphaMissense: likely benign (0.1073); Very rare (popmax 0.00314%, nfe); Associated with Usher syndrome type 1.

What condition is associated with CDH23 p.Arg2506Gln (c.7517G>A)?

CDH23 p.Arg2506Gln (c.7517G>A) is associated with Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 12 (ClinVar).

How common is CDH23 p.Arg2506Gln (c.7517G>A) in the general population?

CDH23 p.Arg2506Gln (c.7517G>A) is very rare (popmax 0.00314%, nfe) (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.Arg2506Gln (c.7517G>A)?

AlphaMissense predicts likely benign (score 0.1073) — an in-silico prediction, not a clinical call.

CDH23 p.Arg2506Gln

c.7517G>A · rs727502932 · VCV162942

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1073 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00314%, nfe)

Conditions

Usher syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.1073	likely benign
REVEL	0.462	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP -1.8, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 4,473 bp · p 9.3e-05 · regional, not allelic
Overall
CADD	26.4	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 0.00314% European (non-Finnish) · 37/1,179,894 alleles

Filtering AF 0.00231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00202%

Overall 0.00273% 44/1,613,868 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,821
European (non-Finnish)grpmax	0.00314%	31,889
African / African-American	0.00267%	37,447
Admixed American	0.00167%	60,002
Finnishnot grpmax-eligible	0.00156%	64,024

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg2506Gln
Coding: c.7517G>A
MANE Select: NM_022124
dbSNP: rs727502932
Type: single nucleotide variant
Location: chr10:71802932 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2506: the cadherin 23 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

Also linked: autosomal recessive nonsyndromic hearing loss 12

For Usher syndrome (Orphanet):

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

Similar variants

CDH23 p.Arg2506Trp Uncertain significance ★★ ⚠ same residue
CDH23 p.Arg2506= 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
CDH23 p.Ala3190Val 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-arg2506gln (accessed [today's date]).

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