Is CDH2 p.Asn378Ser (c.1133A>G) pathogenic?

CDH2 p.Asn378Ser (c.1133A>G) is classified Uncertain significance in CDH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-05). AlphaMissense: ambiguous (0.4344); Very rare (popmax 0.00534%, afr); Associated with arrhythmogenic right ventricular dysplasia, familial, 14.

What condition is associated with CDH2 p.Asn378Ser (c.1133A>G)?

CDH2 p.Asn378Ser (c.1133A>G) is associated with arrhythmogenic right ventricular dysplasia, familial, 14 (ClinVar).

How common is CDH2 p.Asn378Ser (c.1133A>G) in the general population?

CDH2 p.Asn378Ser (c.1133A>G) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about CDH2 p.Asn378Ser (c.1133A>G)?

AlphaMissense predicts ambiguous (score 0.4344) — an in-silico prediction, not a clinical call.

CDH2 p.Asn378Ser

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.1133A>G · rs199977445 · VCV1927969

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4344 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Conditions

arrhythmogenic right ventricular dysplasia, familial, 14

Computational evidence

Protein change
AlphaMissense	0.4344	ambiguous
REVEL	0.509	indeterminate
SaProt	LLR -11.77	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 2.9, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 27 kb · p 4e-09 · regional, not allelic
Overall
CADD	26.0	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 0.00534% African / African-American · 4/74,924 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00211% 34/1,614,000 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,731
European (non-Finnish)	0.00229%	43,704
South Asian	0.0022%	45,534
Admixed American	0.00167%	59,996

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: CDH2
Protein: p.Asn378Ser
Coding: c.1133A>G
MANE Select: NM_001792
dbSNP: rs199977445
Type: single nucleotide variant
Location: chr18:27993525 (GRCh38)
Gene constraint: LOEUF 0.336 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.68
Residue 378: the cadherin 2 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 c.1344+1G>A Pathogenic/Likely pathogenic ★★ 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
CDH2 p.Asp407Asn Conflicting classifications of pathogenicity ★ ⚠ same condition
CDH2 p.Asp436Asn 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-asn378ser (accessed [today's date]).

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