Is DSC2 p.Ser359Pro (c.1075T>C) pathogenic?

DSC2 p.Ser359Pro (c.1075T>C) is classified Uncertain significance in DSC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-26). AlphaMissense: ambiguous (0.4787); Absent from gnomAD v4.1; Associated with cardiomyopathy.

What condition is associated with DSC2 p.Ser359Pro (c.1075T>C)?

DSC2 p.Ser359Pro (c.1075T>C) is associated with cardiomyopathy (ClinVar).

How common is DSC2 p.Ser359Pro (c.1075T>C) in the general population?

DSC2 p.Ser359Pro (c.1075T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DSC2 p.Ser359Pro (c.1075T>C)?

AlphaMissense predicts ambiguous (score 0.4787) — an in-silico prediction, not a clinical call.

DSC2 p.Ser359Pro

c.1075T>C · VCV3894336

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4787 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.4787	ambiguous
REVEL	0.027	moderately benign-leaning
SaProt	LLR -15.95	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP 1.8, phastCons 0.99
Regional constraint	o/e 0.98	unconstrained · MANE · 34 kb · p 0.48 · regional, not allelic
Overall
CADD	20.3	PHRED · no single calibrated threshold — expert panels disagree

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: DSC2
Protein: p.Ser359Pro
Coding: c.1075T>C
MANE Select: NM_024422
Type: single nucleotide variant
Location: chr18:31082928 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 359: a β-strand; the cadherin 3 domain

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

Disease context

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

Similar variants

DSC2 p.Ser359Tyr Uncertain significance ★★ ⚠ same residue
DSC3 p.Ala359Ser Uncertain significance ★ ⚠ same residue
DSC2 c.1077+2T>G Uncertain significance ★★ same condition
DSC2 c.1520+4C>T Uncertain significance ★★ same condition
DSC2 c.942+3A>G Uncertain significance ★★ same condition
DSC2 c.942+6A>G Uncertain significance ★★ same condition
DSC2 p.Ala138Ser Uncertain significance ★★ ⚠ same condition
DSC2 p.Ala213Val 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-ser359pro (accessed [today's date]).

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