Is DSC2 p.Ile345Thr (c.1034T>C) pathogenic?

DSC2 p.Ile345Thr (c.1034T>C) is classified Uncertain significance in DSC2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-07-11). AlphaMissense: likely pathogenic (0.5781); Very rare (popmax 0.0022%, sas); Associated with Cardiovascular phenotype.

What condition is associated with DSC2 p.Ile345Thr (c.1034T>C)?

DSC2 p.Ile345Thr (c.1034T>C) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic right ventricular dysplasia 11 (ClinVar).

How common is DSC2 p.Ile345Thr (c.1034T>C) in the general population?

DSC2 p.Ile345Thr (c.1034T>C) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about DSC2 p.Ile345Thr (c.1034T>C)?

AlphaMissense predicts likely pathogenic (score 0.5781) — an in-silico prediction, not a clinical call.

DSC2 p.Ile345Thr

c.1034T>C · rs777688726 · VCV241471

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.5781 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.5781	likely pathogenic
REVEL	0.51	indeterminate
SaProt	LLR -11.40	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 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 34 kb · p 0.48 · regional, not allelic
Overall
CADD	24.5	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

Grpmax group 0.0022% South Asian · 2/91,056 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000992% 16/1,613,540 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,528
Admixed American	0.00167%	60,002
Remaining individualsnot grpmax-eligible	0.0016%	62,438
European (non-Finnish)	0.00102%	98,328

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.Ile345Thr
Coding: c.1034T>C
MANE Select: NM_024422
dbSNP: rs777688726
Type: single nucleotide variant
Location: chr18:31082969 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 345: a UniProt-annotated variant site (in arvd11; uncertain significance; abolishes localization at desmosomes and mis-localizes to the cytoplasm); a β-strand; the cadherin 2 domain

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiomyopathy arrhythmogenic right ventricular dysplasia 11 familial isolated arrhythmogenic right ventricular dysplasia arrhythmogenic right ventricular cardiomyopathy

Similar variants

DSC2 p.Ile345Val Uncertain significance ★★ ⚠ same residue
DSC2 p.Ile345Met Uncertain significance ★ ⚠ same residue
DSC2 c.1521-1G>A Likely pathogenic ★★ same condition
DSC2 c.1664-1G>A Likely pathogenic ★★ same condition
DSC2 c.354+2T>A Likely pathogenic ★★ same condition
DSC2 c.355-1G>A Likely pathogenic ★★ same condition
DSC2 p.Gln554Ter Pathogenic ★★ same condition
DSC2 p.Gln620Ter 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/dsc2-p-ile345thr (accessed [today's date]).

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