Is DSG2 p.Pro189= (c.567C>T) pathogenic?

DSG2 p.Pro189= (c.567C>T) is classified Likely benign in DSG2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-09). Very rare (popmax 0.00133%, afr); Associated with arrhythmogenic right ventricular cardiomyopathy.

What condition is associated with DSG2 p.Pro189= (c.567C>T)?

DSG2 p.Pro189= (c.567C>T) is associated with arrhythmogenic right ventricular cardiomyopathy, cardiomyopathy (ClinVar).

How common is DSG2 p.Pro189= (c.567C>T) in the general population?

DSG2 p.Pro189= (c.567C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

DSG2 p.Pro189=

c.567C>T · rs745574525 · VCV1332507

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

arrhythmogenic right ventricular cardiomyopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.49	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 0.85	GERP 0.044, phastCons 1
Overall
CADD	19.45	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,022 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000342% 5/1,461,558 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,022
European (non-Finnish)	0.000339%	294,950

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.Pro189=
Coding: c.567C>T
MANE Select: NM_001943
dbSNP: rs745574525
Type: single nucleotide variant
Location: chr18:31522126 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB
Residue 189: the cadherin 2 domain; a β-strand

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

Disease context

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

Also linked: cardiomyopathy

Similar variants

DSG2 p.Arg46Gln Pathogenic/Likely pathogenic ★★ same condition
DSG2 p.Arg46Trp Pathogenic/Likely pathogenic ★★ same condition
DSG2 p.Arg49His Pathogenic/Likely pathogenic ★★ same condition
DSG2 p.Ser314Ter Pathogenic/Likely pathogenic ★★ same condition
DSG2 p.Tyr130Ter Likely pathogenic ★★ same condition
DSG2 p.Tyr783Ter Pathogenic/Likely pathogenic ★★ same condition
DSG2 c.1014+5G>T Uncertain significance ★★ same condition
DSG2 c.216+2T>C 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/dsg2-p-pro189 (accessed [today's date]).

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