Is CDH23 p.Pro650fs (c.1949del) pathogenic?

CDH23 p.Pro650fs (c.1949del) is classified Pathogenic/Likely pathogenic in CDH23 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-14). Very rare (popmax 0.00501%, amr); Associated with CDH23-related disorder.

What condition is associated with CDH23 p.Pro650fs (c.1949del)?

CDH23 p.Pro650fs (c.1949del) is associated with CDH23-related disorder (ClinVar).

How common is CDH23 p.Pro650fs (c.1949del) in the general population?

CDH23 p.Pro650fs (c.1949del) is very rare (popmax 0.00501%, amr) (gnomAD).

CDH23 p.Pro650fs

c.1949del · VCV4696091

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00501%, amr)

Conditions

CDH23-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 18 of 70
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.1	GERP -1.8, phastCons 0.92
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00501% Admixed American · 3/59,930 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000372% 6/1,613,254 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00501%	19,977
European (non-Finnish)	0.000254%	393,244

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.Pro650fs
Coding: c.1949del
MANE Select: NM_022124
Type: Deletion
Location: chr10:71682530 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 650: the cadherin 6 domain

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

Disease context

CDH23-related disorder

Similar variants

CDH23 p.Asn1889fs Likely pathogenic ★★ same condition
CDH23 p.Ile2132fs Pathogenic ★★ same condition
CDH23 p.Ile3210fs Pathogenic/Likely pathogenic ★★ same condition
CDH23 p.Phe2577fs Pathogenic/Likely pathogenic ★★ same condition
CDH23 p.Phe995fs Pathogenic/Likely pathogenic ★★ same condition
CDH23 p.Pro2323fs Pathogenic/Likely pathogenic ★★ same condition
CDH23 p.Thr1587fs Pathogenic ★★ same condition
CDH23 p.Thr2052fs Pathogenic/Likely pathogenic ★★ 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-pro650fs (accessed [today's date]).

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