Is DSG2 p.Leu499Pro (c.1496T>C) pathogenic?

DSG2 p.Leu499Pro (c.1496T>C) is classified Uncertain significance in DSG2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-13). AlphaMissense: likely pathogenic (0.7821); Absent from gnomAD v4.1; Associated with arrhythmogenic right ventricular cardiomyopathy.

What condition is associated with DSG2 p.Leu499Pro (c.1496T>C)?

DSG2 p.Leu499Pro (c.1496T>C) is associated with arrhythmogenic right ventricular cardiomyopathy (ClinVar).

How common is DSG2 p.Leu499Pro (c.1496T>C) in the general population?

DSG2 p.Leu499Pro (c.1496T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DSG2 p.Leu499Pro (c.1496T>C)?

AlphaMissense predicts likely pathogenic (score 0.7821) — an in-silico prediction, not a clinical call.

DSG2 p.Leu499Pro

c.1496T>C · rs2510917845 · VCV2300621

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7821 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

arrhythmogenic right ventricular cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.7821	likely pathogenic
REVEL	0.607	indeterminate
SaProt	LLR -15.06	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 48 kb · p 0.014 · regional, not allelic
Overall
CADD	23.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DSG2
Protein: p.Leu499Pro
Coding: c.1496T>C
MANE Select: NM_001943
dbSNP: rs2510917845
Type: single nucleotide variant
Location: chr18:31536274 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB
Residue 499: 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 cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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.216+2T>C Uncertain significance ★★ same condition
DSG2 c.216+3A>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-leu499pro (accessed [today's date]).

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