Is CDH23 p.Arg1594Cys (c.4780C>T) pathogenic?

CDH23 p.Arg1594Cys (c.4780C>T) is classified Uncertain significance in CDH23 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2024-10-01). AlphaMissense: likely pathogenic (0.6658); Ultra-rare (popmax 0.0123%, nfe); Associated with autosomal recessive nonsyndromic hearing loss 12.

What condition is associated with CDH23 p.Arg1594Cys (c.4780C>T)?

CDH23 p.Arg1594Cys (c.4780C>T) is associated with autosomal recessive nonsyndromic hearing loss 12, Usher syndrome type 1, Usher syndrome type 1D (ClinVar).

How common is CDH23 p.Arg1594Cys (c.4780C>T) in the general population?

CDH23 p.Arg1594Cys (c.4780C>T) is ultra-rare (popmax 0.0123%, nfe) (gnomAD).

What do computational predictors say about CDH23 p.Arg1594Cys (c.4780C>T)?

AlphaMissense predicts likely pathogenic (score 0.6658) — an in-silico prediction, not a clinical call.

CDH23 p.Arg1594Cys

c.4780C>T · rs200664666 · VCV300435

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.6658 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0123%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

autosomal recessive nonsyndromic hearing loss 12

Computational evidence

Protein change
AlphaMissense	0.6658	likely pathogenic
REVEL	0.803	moderately pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.1, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	29.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0123% European (non-Finnish) · 145/1,178,918 alleles

Filtering AF 0.0106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00998%

Overall 0.011% 177/1,610,918 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0363%	2,754
European (non-Finnish)grpmax	0.0123%	8,130
Remaining individualsnot grpmax-eligible	0.00802%	12,466
African / African-American	0.00401%	24,961
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,492

Finnish 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.Arg1594Cys
Coding: c.4780C>T
MANE Select: NM_022124
dbSNP: rs200664666
Type: single nucleotide variant
Location: chr10:71741856 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1594: the cadherin 15 domain

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

Disease context

autosomal recessive nonsyndromic hearing loss 12 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Usher syndrome type 1 Usher syndrome type 1D

Similar variants

CDH23 p.Arg1594His Uncertain significance ★★ same residue
CDH23 p.Arg1594Leu Uncertain significance ★★ ⚠ same residue
CDH23 p.Arg1594= Conflicting classifications of pathogenicity ★ 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-arg1594cys (accessed [today's date]).

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