Is DSG2 p.Arg427Ter (c.1279A>T) pathogenic?

DSG2 p.Arg427Ter (c.1279A>T) is classified Pathogenic in DSG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-17). Very rare (popmax 0.00167%, amr); Associated with arrhythmogenic right ventricular dysplasia 10.

What condition is associated with DSG2 p.Arg427Ter (c.1279A>T)?

DSG2 p.Arg427Ter (c.1279A>T) is associated with arrhythmogenic right ventricular dysplasia 10 (ClinVar).

How common is DSG2 p.Arg427Ter (c.1279A>T) in the general population?

DSG2 p.Arg427Ter (c.1279A>T) is very rare (popmax 0.00167%, amr) (gnomAD).

DSG2 p.Arg427Ter

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.1279A>T · VCV3702235

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

arrhythmogenic right ventricular dysplasia 10

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 15
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 1.6, phastCons 0.98
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,014 alleles

Overall 6.84e-05% 1/1,461,736 alleles · very rare

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: DSG2
Protein: p.Arg427Ter
Coding: c.1279A>T
MANE Select: NM_001943
Type: single nucleotide variant
Location: chr18:31531251 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB
Residue 427: a β-strand; the cadherin 4 domain

Full DSG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

arrhythmogenic right ventricular dysplasia 10 — 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

DSG2 p.Arg427Ser Uncertain significance ★★ ⚠ same residue
DSG2 p.Arg427= Likely benign ★ same residue
DSG2 p.Arg427Gly Uncertain significance ★ ⚠ same residue
DSG2 p.Arg427Lys Uncertain significance ★ ⚠ same residue
DSG2 p.Arg427Thr Uncertain significance ★ ⚠ same residue
DSG2 c.1423+1G>T Likely pathogenic ★★ same condition
DSG2 c.1424-1G>A Likely pathogenic ★★ same condition
DSG2 c.523+1G>T Pathogenic/Likely pathogenic ★★ 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/dsg2-p-arg427ter (accessed [today's date]).

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