Is CDH23 p.Pro1591Leu (c.4772C>T) pathogenic?

CDH23 p.Pro1591Leu (c.4772C>T) is classified Uncertain significance in CDH23 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-28). AlphaMissense: likely benign (0.1166); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with CDH23 p.Pro1591Leu (c.4772C>T)?

CDH23 p.Pro1591Leu (c.4772C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CDH23 p.Pro1591Leu (c.4772C>T) in the general population?

CDH23 p.Pro1591Leu (c.4772C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CDH23 p.Pro1591Leu (c.4772C>T)?

AlphaMissense predicts likely benign (score 0.1166) — an in-silico prediction, not a clinical call.

CDH23 p.Pro1591Leu

c.4772C>T · VCV4609438

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1166 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1166	likely benign
REVEL	0.223	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.1, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 359 kb · p 0.017 · regional, not allelic
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,078 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00124% 20/1,610,856 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,078
East Asian	0.0134%	7,470
Admixed American	0.00167%	59,714
European (non-Finnish)	0.00102%	98,236

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.Pro1591Leu
Coding: c.4772C>T
MANE Select: NM_022124
Type: single nucleotide variant
Location: chr10:71741848 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1591: the cadherin 15 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.Pro1591= 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-pro1591leu (accessed [today's date]).

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