Is DSC2 p.Arg132His (c.395G>A) pathogenic?

DSC2 p.Arg132His (c.395G>A) is classified Conflicting classifications of pathogenicity in DSC2 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-12-11). AlphaMissense: likely pathogenic (0.5937); Ultra-rare (popmax 0.011%, sas); Associated with familial isolated arrhythmogenic right ventricular dysplasia.

What condition is associated with DSC2 p.Arg132His (c.395G>A)?

DSC2 p.Arg132His (c.395G>A) is associated with familial isolated arrhythmogenic right ventricular dysplasia, cardiomyopathy, arrhythmogenic right ventricular dysplasia 11 (ClinVar).

How common is DSC2 p.Arg132His (c.395G>A) in the general population?

DSC2 p.Arg132His (c.395G>A) is ultra-rare (popmax 0.011%, sas) (gnomAD).

What do computational predictors say about DSC2 p.Arg132His (c.395G>A)?

AlphaMissense predicts likely pathogenic (score 0.5937) — an in-silico prediction, not a clinical call.

DSC2 p.Arg132His

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.395G>A · rs375410133 · VCV468383

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.5937 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial isolated arrhythmogenic right ventricular dysplasia

Computational evidence

Protein change
AlphaMissense	0.5937	likely pathogenic
REVEL	0.536	indeterminate
SaProt	LLR -11.43	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 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 34 kb · p 0.48 · regional, not allelic
Overall
CADD	25.8	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 0.011% South Asian · 10/91,068 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.00242% 39/1,613,818 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,107
African / African-American	0.00401%	24,963
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600
East Asian	0.00223%	44,876
European (non-Finnish)	0.00195%	51,301
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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.Arg132His
Coding: c.395G>A
MANE Select: NM_024422
dbSNP: rs375410133
Type: single nucleotide variant
Location: chr18:31091107 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 132: a UniProt-annotated variant site (in arvd11; uncertain significance)

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

Also linked: cardiomyopathy arrhythmogenic right ventricular dysplasia 11

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

DSC2 p.Arg132Cys Uncertain significance ★★ ⚠ same residue
DSC2 p.Arg132= Likely benign ★★ 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

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-arg132his (accessed [today's date]).

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