Is CDH23 p.Phe1888Ser (c.5663T>C) pathogenic?

CDH23 p.Phe1888Ser (c.5663T>C) is classified Pathogenic in CDH23 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-05). AlphaMissense: likely pathogenic (0.9819); Very rare (popmax 8.48e-05%, nfe); Associated with Usher syndrome.

What condition is associated with CDH23 p.Phe1888Ser (c.5663T>C)?

CDH23 p.Phe1888Ser (c.5663T>C) is associated with Usher syndrome, autosomal recessive nonsyndromic hearing loss 12 (ClinVar).

How common is CDH23 p.Phe1888Ser (c.5663T>C) in the general population?

CDH23 p.Phe1888Ser (c.5663T>C) is very rare (popmax 8.48e-05%, nfe) (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.Phe1888Ser (c.5663T>C)?

AlphaMissense predicts likely pathogenic (score 0.9819) — an in-silico prediction, not a clinical call.

CDH23 p.Phe1888Ser

c.5663T>C · rs121908352 · VCV4924

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9819 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

Usher syndrome

Computational evidence

Protein change
AlphaMissense	0.9819	likely pathogenic ✓ concordant with ClinVar · top 6% in CDH23
REVEL	0.653	pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 0.69, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	27.3	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) · 1/1,179,908 alleles

Overall 6.84e-05% 1/1,461,702 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.Phe1888Ser
Coding: c.5663T>C
MANE Select: NM_022124
dbSNP: rs121908352
Type: single nucleotide variant
Location: chr10:71785051 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1888: a UniProt-annotated variant site (in dfnb12); the cadherin 18 domain

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

Disease context

Usher syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive nonsyndromic hearing loss 12

For Usher syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

CDH23 p.Phe1888= Likely benign ★ 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
CDH23 p.Arg301Gln 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-phe1888ser (accessed [today's date]).

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