Is DSC2 p.Arg136Ser (c.408A>T) pathogenic?

DSC2 p.Arg136Ser (c.408A>T) is classified Uncertain significance in DSC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-24). AlphaMissense: likely pathogenic (0.8808); Very rare (popmax 0.00153%, nfe); Associated with arrhythmogenic right ventricular dysplasia 11.

What condition is associated with DSC2 p.Arg136Ser (c.408A>T)?

DSC2 p.Arg136Ser (c.408A>T) is associated with arrhythmogenic right ventricular dysplasia 11 (ClinVar).

How common is DSC2 p.Arg136Ser (c.408A>T) in the general population?

DSC2 p.Arg136Ser (c.408A>T) is very rare (popmax 0.00153%, nfe) (gnomAD).

What do computational predictors say about DSC2 p.Arg136Ser (c.408A>T)?

AlphaMissense predicts likely pathogenic (score 0.8808) — an in-silico prediction, not a clinical call.

DSC2 p.Arg136Ser

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.408A>T · VCV4752403

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8808 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

arrhythmogenic right ventricular dysplasia 11

Computational evidence

Protein change
AlphaMissense	0.8808	likely pathogenic
REVEL	0.393	indeterminate
SaProt	LLR -5.69	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.4	GERP 2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 34 kb · p 0.48 · regional, not allelic
Overall
CADD	25.3	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

Grpmax group 0.00153% European (non-Finnish) · 18/1,179,960 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00118% 19/1,613,948 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00153%	65,553
African / African-American	0.00133%	74,926

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.Arg136Ser
Coding: c.408A>T
MANE Select: NM_024422
Type: single nucleotide variant
Location: chr18:31091094 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 136: the cadherin 1 domain

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

Disease context

arrhythmogenic right ventricular dysplasia 11 — 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.Arg136= Conflicting classifications of pathogenicity ★ same residue
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
DSC2 p.Glu593Ter 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-arg136ser (accessed [today's date]).

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