CDH23 p.Ala3190Val
c.9569C>T · rs111033536 · VCV46076
ClinGen expert panel — Hearing Loss VCEP
Uncertain Significance for Usher syndrome. Applied ACMG criteria (verbatim):
PP3 BS2
Curation rationale (ClinGen, verbatim)
The c.9569C>T variant (NM_022124.6(CDH23):c.9569C>T (p.Ala3190Val)) in CDH23 is a missense variant predicted to cause substitution of alanine by valine at amino acid 3190 (p.Ala3190Val). The highest minor allele frequency in gnomAD v4.0.0 is 694/1179698 alleles (0.0005517), in the European (non-Finnish) population (no population codes met). This variant has been observed in a homozygous state in one parent reported to have no features of Usher syndrome (BS2; Invitae internal data; ClinVar SCV001110059.2). The computational predictor REVEL gives a score of 0.836, which is above the Hearing Loss VCEP threshold of 0.7, evidence that correlates with impact to CDH23 function (PP3). The variant was found in a compound heterozygous state with a deletion of exon 29, a variant which was not able to be confirmed by aCGH (PMID: 25404053). The variant was also found in an unknown phase with p.Arg3206Cys (c.9616C>T), a variant of uncertain significance, in an affected patient with nonsyndromic hearing loss (PMID: 27068579; PM3 not met). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Expert Panel: BS2, PP3 (Version 2; 11/15/2023).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.4483 | ambiguous |
|---|---|---|
| REVEL | 0.836 | moderately pathogenic-leaning |
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 7.6 | GERP 1.9, phastCons 1 |
| Regional constraint | o/e 1.01 | unconstrained · MANE · 12 kb · p 0.86 · regional, not allelic |
| Overall | ||
| CADD | 28.7 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Ashkenazi Jewishnot grpmax-eligible | 0.0845% | 1,184 |
| Remaining individualsnot grpmax-eligible | 0.0609% | 1,643 |
| European (non-Finnish)grpmax | 0.0588% | 1,700 |
| Admixed American | 0.0367% | 2,724 |
| African / African-American | 0.00667% | 14,987 |
| Finnishnot grpmax-eligible | 0.00312% | 32,001 |
Ashkenazi Jewish 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.Ala3190Val
- Coding
- c.9569C>T
- MANE Select
- NM_022124
- dbSNP
- rs111033536
- Type
- single nucleotide variant
- Location
- chr10:71812826 (GRCh38)
- Gene constraint
- LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Residue 3190
- an α-helix
Disease context
Usher syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: hearing loss disorderUsher syndrome type 1Dautosomal recessive nonsyndromic hearing loss 12pituitary adenoma 5, multiple types
For Usher syndrome (Orphanet):
- Inheritance
- Autosomal recessive
- Onset
- Childhood, Infancy, Neonatal
- Prevalence
- 1-9 / 100 000 (Worldwide)
Similar variants
- CDH23 p.Ala3190Asp 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.Arg301Gln Uncertain significance ★★★ same condition
- CDH23 p.Arg3189Gln 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-ala3190val (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown