Is CDH23 p.Val2181Glu (c.6542T>A) pathogenic?

CDH23 p.Val2181Glu (c.6542T>A) is classified Uncertain significance in CDH23 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-20). AlphaMissense: ambiguous (0.453); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CDH23 p.Val2181Glu (c.6542T>A)?

CDH23 p.Val2181Glu (c.6542T>A) is associated with Inborn genetic diseases (ClinVar).

How common is CDH23 p.Val2181Glu (c.6542T>A) in the general population?

CDH23 p.Val2181Glu (c.6542T>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CDH23 p.Val2181Glu (c.6542T>A)?

AlphaMissense predicts ambiguous (score 0.453) — an in-silico prediction, not a clinical call.

CDH23 p.Val2181Glu

c.6542T>A · rs1452832791 · VCV3141216

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.453 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.453	ambiguous
REVEL	0.743	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	26.9	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 8.48e-05% European (non-Finnish) · 1/1,179,880 alleles

Overall 6.84e-05% 1/1,461,710 alleles · very 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.Val2181Glu
Coding: c.6542T>A
MANE Select: NM_022124
dbSNP: rs1452832791
Type: single nucleotide variant
Location: chr10:71793470 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2181: the cadherin 21 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDH23 p.Val2181= Likely benign ★ same residue
CDH23 p.Ala129Thr Uncertain significance ★★ ⚠ same condition
CDH23 p.Ala1464Glu Uncertain significance ★★ ⚠ same condition
CDH23 p.Ala1482Val Uncertain significance ★★ ⚠ same condition
CDH23 p.Ala1673Val Uncertain significance ★★ same condition
CDH23 p.Ala1878Thr Uncertain significance ★★ same condition
CDH23 p.Ala1974Thr Uncertain significance ★★ ⚠ same condition
CDH23 p.Ala1987Thr 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-val2181glu (accessed [today's date]).

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