Is CDH23 p.Ala1990= (c.5970A>G) pathogenic?

CDH23 p.Ala1990= (c.5970A>G) is classified Conflicting classifications of pathogenicity in CDH23 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-02). Ultra-rare (popmax 0.0468%, eas); Associated with Usher syndrome type 1D.

What condition is associated with CDH23 p.Ala1990= (c.5970A>G)?

CDH23 p.Ala1990= (c.5970A>G) is associated with Usher syndrome type 1D, autosomal recessive nonsyndromic hearing loss 12 (ClinVar).

How common is CDH23 p.Ala1990= (c.5970A>G) in the general population?

CDH23 p.Ala1990= (c.5970A>G) is ultra-rare (popmax 0.0468%, eas) (gnomAD).

CDH23 p.Ala1990=

c.5970A>G · rs542473653 · VCV878134

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0468%, eas)

Conditions

Usher syndrome type 1D

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.32	acceptor loss, 2 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -5.7	GERP -3.1
Overall
CADD	0.147	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0468% East Asian · 21/44,886 alleles

Filtering AF 0.0313% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0263%

Overall 0.0013% 21/1,613,900 alleles · ultra-rare

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.Ala1990=
Coding: c.5970A>G
MANE Select: NM_022124
dbSNP: rs542473653
Type: single nucleotide variant
Location: chr10:71790334 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1990: the cadherin 19 domain

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

Similar variants

CDH23 p.Ala1990Ser Uncertain significance ★ ⚠ same residue
CDH23 p.Ala1990Thr Uncertain significance ★ ⚠ 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-ala1990 (accessed [today's date]).

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