Is CDH23 p.Pro2380Leu (c.7139C>T) pathogenic?

CDH23 p.Pro2380Leu (c.7139C>T) is classified Benign/Likely benign in CDH23 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.3133); Common (popmax 57%, eas) — too common for a highly-penetrant pathogenic allele; Associated with retinitis pigmentosa-deafness syndrome.

What condition is associated with CDH23 p.Pro2380Leu (c.7139C>T)?

CDH23 p.Pro2380Leu (c.7139C>T) is associated with retinitis pigmentosa-deafness syndrome, Usher syndrome type 1, Usher syndrome type 1D (ClinVar).

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.Pro2380Leu (c.7139C>T)?

AlphaMissense predicts likely benign (score 0.3133) — an in-silico prediction, not a clinical call.

CDH23 p.Pro2380Leu

Q: How common is CDH23 p.Pro2380Leu (c.7139C>T) in the general population?

CDH23 p.Pro2380Leu (c.7139C>T) is common (popmax 57%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.7139C>T · rs4747195 · VCV46028

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.3133 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 57%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

retinitis pigmentosa-deafness syndrome

Computational evidence

Protein change
AlphaMissense	0.3133	likely benign
REVEL	0.262	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 4.9	GERP 2, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 4,473 bp · p 9.3e-05 · regional, not allelic
Overall
CADD	26.7	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 57% East Asian · 25,580/44,850 alleles

Filtering AF 56.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 56.2%

Overall 28.7% 463,730/1,613,748 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	57%	2
Admixed American	39.5%	3
Amishnot grpmax-eligible	38.2%	3
Finnishnot grpmax-eligible	34.5%	3
Remaining individualsnot grpmax-eligible	28.5%	4
European (non-Finnish)	27.8%	4
African / African-American	24.8%	4
South Asian	22.8%	4
Ashkenazi Jewishnot grpmax-eligible	21.2%	5
Middle Eastern	15.7%	6

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.Pro2380Leu
Coding: c.7139C>T
MANE Select: NM_022124
dbSNP: rs4747195
Type: single nucleotide variant
Location: chr10:71799195 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2380: a UniProt-annotated variant site (in); the cadherin 22 domain

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

Disease context

retinitis pigmentosa-deafness syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Usher syndrome type 1 Usher syndrome type 1D 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.Pro2380= 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-pro2380leu (accessed [today's date]).

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