Is CDH23 p.Ile400Phe (c.1198A>T) pathogenic?

CDH23 p.Ile400Phe (c.1198A>T) is classified Uncertain significance in CDH23 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-11). AlphaMissense: likely pathogenic (0.6262); Very rare (popmax 0.0028%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CDH23 p.Ile400Phe (c.1198A>T)?

CDH23 p.Ile400Phe (c.1198A>T) is associated with Inborn genetic diseases (ClinVar).

How common is CDH23 p.Ile400Phe (c.1198A>T) in the general population?

CDH23 p.Ile400Phe (c.1198A>T) is very rare (popmax 0.0028%, nfe) (gnomAD).

What do computational predictors say about CDH23 p.Ile400Phe (c.1198A>T)?

AlphaMissense predicts likely pathogenic (score 0.6262) — an in-silico prediction, not a clinical call.

CDH23 p.Ile400Phe

c.1198A>T · rs370014467 · VCV1414766

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6262 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0028%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6262	likely pathogenic
REVEL	0.581	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 1.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0028% European (non-Finnish) · 33/1,179,580 alleles

Filtering AF 0.002% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00176%

Overall 0.00211% 34/1,613,416 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0028%	35,745
Remaining individualsnot grpmax-eligible	0.0016%	62,446

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.Ile400Phe
Coding: c.1198A>T
MANE Select: NM_022124
dbSNP: rs370014467
Type: single nucleotide variant
Location: chr10:71645888 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 400: the cadherin 4 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.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
CDH23 p.Ala2031Thr 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-ile400phe (accessed [today's date]).

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