Is DSC2 p.Cys142Ser (c.425G>C) pathogenic?

DSC2 p.Cys142Ser (c.425G>C) is classified Uncertain significance in DSC2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-04-09). AlphaMissense: ambiguous (0.42); Very rare (popmax 0.000593%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with DSC2 p.Cys142Ser (c.425G>C)?

DSC2 p.Cys142Ser (c.425G>C) is associated with Cardiovascular phenotype, arrhythmogenic right ventricular dysplasia 11 (ClinVar).

How common is DSC2 p.Cys142Ser (c.425G>C) in the general population?

DSC2 p.Cys142Ser (c.425G>C) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about DSC2 p.Cys142Ser (c.425G>C)?

AlphaMissense predicts ambiguous (score 0.42) — an in-silico prediction, not a clinical call.

DSC2 p.Cys142Ser

c.425G>C · rs1478081073 · VCV1409163

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.42 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.42	ambiguous
REVEL	0.209	benign-leaning
SaProt	LLR -4.13	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 34 kb · p 0.48 · regional, not allelic
Overall
CADD	18.8	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

Grpmax group 0.000593% European (non-Finnish) · 7/1,179,960 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,613,904 alleles · very rare exomes 6/1,461,782 · genomes 1/152,122 · joint denominator

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.Cys142Ser
Coding: c.425G>C
MANE Select: NM_024422
dbSNP: rs1478081073
Type: single nucleotide variant
Location: chr18:31091077 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 142: a β-strand; the cadherin 1 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: arrhythmogenic right ventricular dysplasia 11

Similar variants

DSC2 p.Cys142Tyr 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
DSC2 p.Glu127Ter Pathogenic/Likely 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-cys142ser (accessed [today's date]).

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