Is DSG2 p.Ile323Arg (c.968T>G) pathogenic?

DSG2 p.Ile323Arg (c.968T>G) is classified Uncertain significance in DSG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely pathogenic (0.9259); Absent from gnomAD v4.1; Associated with arrhythmogenic right ventricular dysplasia 10.

What condition is associated with DSG2 p.Ile323Arg (c.968T>G)?

DSG2 p.Ile323Arg (c.968T>G) is associated with arrhythmogenic right ventricular dysplasia 10 (ClinVar).

How common is DSG2 p.Ile323Arg (c.968T>G) in the general population?

DSG2 p.Ile323Arg (c.968T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DSG2 p.Ile323Arg (c.968T>G)?

AlphaMissense predicts likely pathogenic (score 0.9259) — an in-silico prediction, not a clinical call.

DSG2 p.Ile323Arg

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.968T>G · rs370140174 · VCV890153

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9259 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

arrhythmogenic right ventricular dysplasia 10

Computational evidence

Protein change
AlphaMissense	0.9259	likely pathogenic · top 6% in DSG2
REVEL	0.682	pathogenic-leaning
SaProt	LLR -18.89	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 6.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 48 kb · p 0.014 · regional, not allelic
Overall
CADD	25.5	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.Ile323Arg
Coding: c.968T>G
MANE Select: NM_001943
dbSNP: rs370140174
Type: single nucleotide variant
Location: chr18:31524842 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB
Residue 323: a β-strand; the 'interacts with human adenovirus b3 fiber protein' region; the cadherin 3 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.Ile323Thr Uncertain significance ★★ ⚠ same residue
DSG2 p.Ile323Val Uncertain significance ★★ ⚠ same residue
DSG2 p.Ile323Leu Uncertain significance ★ ⚠ same residue
DSG2 p.Ile323Met 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
DSG2 c.690+1G>A 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-ile323arg (accessed [today's date]).

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