Is CDH2 p.Gln229Pro (c.686A>C) pathogenic?

CDH2 p.Gln229Pro (c.686A>C) is classified Pathogenic in CDH2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-06-23). AlphaMissense: likely pathogenic (0.8384); Absent from gnomAD v4.1; Associated with arrhythmogenic right ventricular dysplasia, familial, 14.

What condition is associated with CDH2 p.Gln229Pro (c.686A>C)?

CDH2 p.Gln229Pro (c.686A>C) is associated with arrhythmogenic right ventricular dysplasia, familial, 14 (ClinVar).

How common is CDH2 p.Gln229Pro (c.686A>C) in the general population?

CDH2 p.Gln229Pro (c.686A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDH2 p.Gln229Pro (c.686A>C)?

AlphaMissense predicts likely pathogenic (score 0.8384) — an in-silico prediction, not a clinical call.

CDH2 p.Gln229Pro

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.686A>C · rs965753331 · VCV929497

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8384 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

arrhythmogenic right ventricular dysplasia, familial, 14

Computational evidence

Protein change
AlphaMissense	0.8384	likely pathogenic ✓ concordant with ClinVar
REVEL	0.142	moderately benign-leaning
SaProt	LLR -15.34	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP -2.7, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 27 kb · p 4e-09 · regional, not allelic
Overall
CADD	21.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDH2
Protein: p.Gln229Pro
Coding: c.686A>C
MANE Select: NM_001792
dbSNP: rs965753331
Type: single nucleotide variant
Location: chr18:28009733 (GRCh38)
Gene constraint: LOEUF 0.336 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.68
Residue 229: a UniProt-annotated variant site (in arvd14; uncertain significance); the cadherin 1 domain

Full CDH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

arrhythmogenic right ventricular dysplasia, familial, 14 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

CDH2 p.Gln229Ter Uncertain significance ★ same residue
CDH2 c.1344+1G>A Pathogenic/Likely pathogenic ★★ same condition
CDH2 p.Asn378Ser Uncertain significance ★★ ⚠ same condition
CDH2 p.Thr535Ser Uncertain significance ★★ ⚠ same condition
CDH2 c.702+6A>T Benign/Likely benign ★★ same condition
CDH2 p.Asp295= Benign/Likely benign ★★ same condition
CDH2 c.1159-1G>A Pathogenic ★ same condition
CDH2 p.Ala5Val Conflicting classifications of pathogenicity ★ ⚠ 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/cdh2-p-gln229pro (accessed [today's date]).

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