Is DSG2 p.Pro497Arg (c.1490C>G) pathogenic?

DSG2 p.Pro497Arg (c.1490C>G) is classified Uncertain significance in DSG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-15). AlphaMissense: likely pathogenic (0.9704); Very rare (popmax 0.0022%, sas); Associated with arrhythmogenic right ventricular cardiomyopathy.

What condition is associated with DSG2 p.Pro497Arg (c.1490C>G)?

DSG2 p.Pro497Arg (c.1490C>G) is associated with arrhythmogenic right ventricular cardiomyopathy (ClinVar).

How common is DSG2 p.Pro497Arg (c.1490C>G) in the general population?

DSG2 p.Pro497Arg (c.1490C>G) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about DSG2 p.Pro497Arg (c.1490C>G)?

AlphaMissense predicts likely pathogenic (score 0.9704) — an in-silico prediction, not a clinical call.

DSG2 p.Pro497Arg

c.1490C>G · rs2510917832 · VCV3070959

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9704 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

arrhythmogenic right ventricular cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.9704	likely pathogenic · top 3% in DSG2
REVEL	0.791	moderately pathogenic-leaning
SaProt	LLR -19.09	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 48 kb · p 0.014 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,084 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000137% 2/1,461,874 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.Pro497Arg
Coding: c.1490C>G
MANE Select: NM_001943
dbSNP: rs2510917832
Type: single nucleotide variant
Location: chr18:31536268 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB
Residue 497: the cadherin 4 domain

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

Similar variants

DSG2 p.Pro497= Benign/Likely benign ★★ same residue
DSG2 p.Pro497Ala Uncertain significance ★★ ⚠ same residue
DSG2 p.Pro497Thr Uncertain significance ★★ ⚠ same residue
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

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-pro497arg (accessed [today's date]).

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