Is CDH23 p.Arg1136His (c.3407G>A) pathogenic?

CDH23 p.Arg1136His (c.3407G>A) is classified Uncertain significance in CDH23 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-05-30). AlphaMissense: likely benign (0.0861); Ultra-rare (popmax 0.0336%, eas); Associated with Usher syndrome type 1D.

What condition is associated with CDH23 p.Arg1136His (c.3407G>A)?

CDH23 p.Arg1136His (c.3407G>A) is associated with Usher syndrome type 1D, autosomal recessive nonsyndromic hearing loss 12 (ClinVar).

How common is CDH23 p.Arg1136His (c.3407G>A) in the general population?

CDH23 p.Arg1136His (c.3407G>A) is ultra-rare (popmax 0.0336%, eas) (gnomAD).

What do computational predictors say about CDH23 p.Arg1136His (c.3407G>A)?

AlphaMissense predicts likely benign (score 0.0861) — an in-silico prediction, not a clinical call.

CDH23 p.Arg1136His

c.3407G>A · rs753822806 · VCV878719

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0861 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0336%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Usher syndrome type 1D

Computational evidence

Protein change
AlphaMissense	0.0861	likely benign
REVEL	0.167	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 3.4	GERP 1.1, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0336% East Asian · 14/41,706 alleles

Filtering AF 0.0203% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0181%

Overall 0.0187% 292/1,559,904 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0336%	2,979
Remaining individualsnot grpmax-eligible	0.0331%	3,025
European (non-Finnish)	0.0212%	4,720
South Asian	0.013%	7,675
Admixed American	0.00385%	25,981
African / African-American	0.00136%	73,658

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.Arg1136His
Coding: c.3407G>A
MANE Select: NM_001164375 · reported on NM_022124
dbSNP: rs753822806
Type: single nucleotide variant
Location: chr10:71724082 (GRCh38)

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

Disease context

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

Also linked: autosomal recessive nonsyndromic hearing loss 12

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-arg1136his (accessed [today's date]).

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