Is DSC2 p.Ile109Val (c.325A>G) pathogenic?

DSC2 p.Ile109Val (c.325A>G) is classified Uncertain significance in DSC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-24). AlphaMissense: likely benign (0.1136); Ultra-rare (popmax 0.0168%, mid); Associated with familial isolated arrhythmogenic right ventricular dysplasia.

What condition is associated with DSC2 p.Ile109Val (c.325A>G)?

DSC2 p.Ile109Val (c.325A>G) is associated with familial isolated arrhythmogenic right ventricular dysplasia (ClinVar).

How common is DSC2 p.Ile109Val (c.325A>G) in the general population?

DSC2 p.Ile109Val (c.325A>G) is ultra-rare (popmax 0.0168%, mid) (gnomAD).

What do computational predictors say about DSC2 p.Ile109Val (c.325A>G)?

AlphaMissense predicts likely benign (score 0.1136) — an in-silico prediction, not a clinical call.

DSC2 p.Ile109Val

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.325A>G · VCV3386553

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1136 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial isolated arrhythmogenic right ventricular dysplasia

Computational evidence

Protein change
AlphaMissense	0.1136	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -7.00	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.83	GERP 2, phastCons 0.65
Regional constraint	o/e 0.98	unconstrained · MANE · 34 kb · p 0.48 · regional, not allelic
Overall
CADD	14.85	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0168% Middle Eastern · 1/5,954 alleles

Overall 0.000248% 4/1,613,130 alleles · ultra-rare exomes 4/1,460,788 · genomes 0/152,342 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0168%	5,954
Remaining individualsnot grpmax-eligible	0.0032%	31,220
South Asian	0.0011%	91,012

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: DSC2
Protein: p.Ile109Val
Coding: c.325A>G
MANE Select: NM_024422
Type: single nucleotide variant
Location: chr18:31092130 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB

Full DSC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial isolated arrhythmogenic right ventricular dysplasia — 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

DSC2 p.Ile109Leu Uncertain significance ★★ ⚠ same residue
DSC2 p.Ile109Met Conflicting classifications of pathogenicity ★ ⚠ same residue
DSC3 p.Val109Gly Uncertain significance ★ ⚠ same residue
DSC2 c.1077+2T>G Uncertain significance ★★ same condition
DSC2 c.1520+6T>C Uncertain significance ★★ same condition
DSC2 c.942+3A>G Uncertain significance ★★ same condition
DSC2 p.Ala138Ser Uncertain significance ★★ ⚠ same condition
DSC2 p.Ala13Val 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/dsc2-p-ile109val (accessed [today's date]).

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