Is CDH23 p.Arg1140Leu (c.3419G>T) pathogenic?

CDH23 p.Arg1140Leu (c.3419G>T) is classified Uncertain significance in CDH23 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-04-20). AlphaMissense: ambiguous (0.4785); Very rare (popmax 0.0024%, eas); Associated with Usher syndrome type 1.

What condition is associated with CDH23 p.Arg1140Leu (c.3419G>T)?

CDH23 p.Arg1140Leu (c.3419G>T) is associated with Usher syndrome type 1 (ClinVar).

How common is CDH23 p.Arg1140Leu (c.3419G>T) in the general population?

CDH23 p.Arg1140Leu (c.3419G>T) is very rare (popmax 0.0024%, eas) (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.Arg1140Leu (c.3419G>T)?

AlphaMissense predicts ambiguous (score 0.4785) — an in-silico prediction, not a clinical call.

CDH23 p.Arg1140Leu

c.3419G>T · VCV4064043

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4785 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0024%, eas)

Conditions

Usher syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.4785	ambiguous
REVEL	0.68	pathogenic-leaning
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 9.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	25.6	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 0.0024% East Asian · 1/41,614 alleles

Filtering AF 0.000394% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000147%

Overall 0.000513% 8/1,558,358 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0024%	41,614
South Asian	0.00237%	42,184
European (non-Finnish)	0.000434%	230,155

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.Arg1140Leu
Coding: c.3419G>T
MANE Select: NM_001164375 · reported on NM_022124
Type: single nucleotide variant
Location: chr10:71724094 (GRCh38)

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)

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-arg1140leu (accessed [today's date]).

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