Is CDH23 p.Pro346= (c.1038G>A) pathogenic?

CDH23 p.Pro346= (c.1038G>A) is classified Benign in CDH23 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-06-26). Common (popmax 7.97%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Usher syndrome type 1D.

What condition is associated with CDH23 p.Pro346= (c.1038G>A)?

CDH23 p.Pro346= (c.1038G>A) is associated with Usher syndrome type 1D, Usher syndrome type 1, autosomal recessive nonsyndromic hearing loss 12 (ClinVar).

CDH23 p.Pro346=

Q: How common is CDH23 p.Pro346= (c.1038G>A) in the general population?

CDH23 p.Pro346= (c.1038G>A) is common (popmax 7.97%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1038G>A · rs74608315 · VCV44112

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 7.97%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

Usher syndrome type 1D

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -12	GERP -3.5
Overall
CADD	0.16	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.97% East Asian · 3,577/44,880 alleles

Filtering AF 7.75% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.66%

Overall 1.18% 19,056/1,613,950 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	7.97%	13
Middle Eastern	6.85%	15
Ashkenazi Jewishnot grpmax-eligible	4.81%	21
South Asian	2.36%	42
Remaining individualsnot grpmax-eligible	1.63%	61
Admixed American	1.62%	62
Amishnot grpmax-eligible	1.32%	76
European (non-Finnish)	0.788%	127
African / African-American	0.193%	517
Finnishnot grpmax-eligible	0.0797%	1,255

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.Pro346=
Coding: c.1038G>A
MANE Select: NM_022124
dbSNP: rs74608315
Type: single nucleotide variant
Location: chr10:71617297 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 346: the cadherin 3 domain

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

Disease context

Usher syndrome type 1D — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Usher syndrome type 1 autosomal recessive nonsyndromic hearing loss 12

Similar variants

CDH23 p.Pro346Leu Pathogenic/Likely pathogenic ★★ same residue
CDH23 p.Pro346Ser Pathogenic/Likely pathogenic ★★ 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

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-pro346 (accessed [today's date]).

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