Is DSC2 p.Ala897fs (c.2686_2687dup) pathogenic?

DSC2 p.Ala897fs (c.26862687dup) is classified Benign/Likely benign in DSC2 (ClinVar, Multiple submitters, 23 submitters; last evaluated 2026-06-01). Low-frequency (popmax 1.27%, nfe); Associated with familial isolated arrhythmogenic right ventricular dysplasia.

What condition is associated with DSC2 p.Ala897fs (c.2686_2687dup)?

DSC2 p.Ala897fs (c.2686_2687dup) is associated with familial isolated arrhythmogenic right ventricular dysplasia, cardiomyopathy, arrhythmogenic right ventricular dysplasia 11 (ClinVar).

How common is DSC2 p.Ala897fs (c.2686_2687dup) in the general population?

DSC2 p.Ala897fs (c.2686_2687dup) is low-frequency (popmax 1.27%, nfe) (gnomAD).

DSC2 p.Ala897fs

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.2686_2687dup · rs200056085 · VCV46186

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 23 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

low-frequency (popmax 1.27%, nfe)

Conditions

familial isolated arrhythmogenic right ventricular dysplasia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (16 of 16) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.2	GERP 2, phastCons 0.92
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.27% European (non-Finnish) · 14,959/1,179,934 alleles

Filtering AF 1.25% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.24%

Overall 1.06% 17,069/1,613,982 alleles · low-frequency

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	3.51%	29
European (non-Finnish)grpmax	1.27%	79
Finnishnot grpmax-eligible	1.01%	99
Remaining individualsnot grpmax-eligible	0.914%	109
Admixed American	0.567%	176
Middle Eastern	0.561%	178
South Asian	0.333%	301
African / African-American	0.176%	569
Ashkenazi Jewishnot grpmax-eligible	0.162%	617
East Asian	0.00223%	44,848

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala897fs
Coding: c.2686_2687dup
MANE Select: NM_024422
dbSNP: rs200056085
Type: Duplication
Location: chr18:31068033 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 897: a UniProt-annotated variant site (in arvd11; likely pathogenic; mislocalization of dsc2 to the cytoplasm within intercalated disks of the heart)

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 arrhythmogenic right ventricular cardiomyopathy

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

DSC2 p.Ala897= Likely benign ★★ same residue
DSC2 p.Leu396fs Pathogenic ★★ same condition
DSC2 p.Gly12_Ala13insGly Uncertain significance ★★ same condition
DSC2 c.2126-15dup Likely benign ★★ same condition
DSC2 c.631-13dup Benign/Likely benign ★★ same condition
DSC2 c.70-18dup Benign/Likely benign ★★ same condition
DSC2 c.70-8dup Benign/Likely benign ★★ same condition
DSC2 c.942+13_942+15dup Benign/Likely benign ★★ 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-ala897fs (accessed [today's date]).

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