Is DSG2 p.Pro453= (c.1359T>G) pathogenic?

DSG2 p.Pro453= (c.1359T>G) is classified Conflicting classifications of pathogenicity in DSG2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-08-15). Very rare (popmax 0.00161%, nfe); Associated with arrhythmogenic right ventricular dysplasia 10.

What condition is associated with DSG2 p.Pro453= (c.1359T>G)?

DSG2 p.Pro453= (c.1359T>G) is associated with arrhythmogenic right ventricular dysplasia 10, arrhythmogenic right ventricular cardiomyopathy (ClinVar).

How common is DSG2 p.Pro453= (c.1359T>G) in the general population?

DSG2 p.Pro453= (c.1359T>G) is very rare (popmax 0.00161%, nfe) (gnomAD).

DSG2 p.Pro453=

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.1359T>G · rs948681475 · VCV2165359

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Conditions

arrhythmogenic right ventricular dysplasia 10

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.34	acceptor loss · deltas
Constraint at this position
Conservation	phyloP -2.5	GERP -2.3
Overall
CADD	7.766	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00161% European (non-Finnish) · 19/1,177,528 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000832%

Overall 0.0013% 21/1,610,770 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00321%	31,196
European (non-Finnish)grpmax	0.00161%	61,975

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro453=
Coding: c.1359T>G
MANE Select: NM_001943
dbSNP: rs948681475
Type: single nucleotide variant
Location: chr18:31535348 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB
Residue 453: 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

Also linked: arrhythmogenic right ventricular cardiomyopathy

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

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
DSG2 c.690+1G>A Pathogenic ★★ same condition
DSG2 c.81+1G>T Likely pathogenic ★★ same condition
DSG2 c.829-2A>T Likely pathogenic ★★ same condition
DSG2 p.Arg46Gln Pathogenic/Likely pathogenic ★★ same condition
DSG2 p.Arg46Trp 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-pro453 (accessed [today's date]).

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