Is DSC2 p.Asn439Asp (c.1315A>G) pathogenic?

DSC2 p.Asn439Asp (c.1315A>G) is classified Conflicting classifications of pathogenicity in DSC2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-16). AlphaMissense: likely pathogenic (0.8934); Very rare (popmax 0.00508%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with DSC2 p.Asn439Asp (c.1315A>G)?

DSC2 p.Asn439Asp (c.1315A>G) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic right ventricular dysplasia 11 (ClinVar).

How common is DSC2 p.Asn439Asp (c.1315A>G) in the general population?

DSC2 p.Asn439Asp (c.1315A>G) is very rare (popmax 0.00508%, nfe) (gnomAD).

What do computational predictors say about DSC2 p.Asn439Asp (c.1315A>G)?

AlphaMissense predicts likely pathogenic (score 0.8934) — an in-silico prediction, not a clinical call.

DSC2 p.Asn439Asp

c.1315A>G · rs148712725 · VCV947676

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8934 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00508%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.8934	likely pathogenic
REVEL	0.507	indeterminate
SaProt	LLR -13.05	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.21	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 7.9	GERP 2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 34 kb · p 0.48 · regional, not allelic
Overall
CADD	24.0	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 0.00508% European (non-Finnish) · 60/1,179,972 alleles

Filtering AF 0.00402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00362%

Overall 0.00384% 62/1,613,932 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00508%	19,666
Remaining individualsnot grpmax-eligible	0.0016%	62,482
African / African-American	0.00133%	74,928

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.Asn439Asp
Coding: c.1315A>G
MANE Select: NM_024422
dbSNP: rs148712725
Type: single nucleotide variant
Location: chr18:31080301 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 439: a β-strand; the cadherin 3 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: cardiomyopathy arrhythmogenic right ventricular dysplasia 11

Similar variants

DSC2 p.Asn439= Likely benign ★★ same residue
DSC2 p.Asn439Ser Uncertain significance ★ ⚠ same residue
DSC2 p.Asn439Thr Uncertain significance ★ ⚠ same residue
DSC2 p.Asn439fs Pathogenic ★ 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

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-asn439asp (accessed [today's date]).

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