Is DSG2 p.Asn493Ser (c.1478A>G) pathogenic?

DSG2 p.Asn493Ser (c.1478A>G) is classified Conflicting classifications of pathogenicity in DSG2 (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2025-12-17). AlphaMissense: ambiguous (0.4179); Ultra-rare (popmax 0.036%, afr); Associated with Cardiovascular phenotype.

What condition is associated with DSG2 p.Asn493Ser (c.1478A>G)?

DSG2 p.Asn493Ser (c.1478A>G) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic right ventricular dysplasia 10 (ClinVar).

How common is DSG2 p.Asn493Ser (c.1478A>G) in the general population?

DSG2 p.Asn493Ser (c.1478A>G) is ultra-rare (popmax 0.036%, afr) (gnomAD).

What do computational predictors say about DSG2 p.Asn493Ser (c.1478A>G)?

AlphaMissense predicts ambiguous (score 0.4179) — an in-silico prediction, not a clinical call.

DSG2 p.Asn493Ser

c.1478A>G · rs375679311 · VCV163212

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 14 submitters

AlphaMissense

ambiguous

0.4179 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.036%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.4179	ambiguous
REVEL	0.546	indeterminate
SaProt	LLR -13.86	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 48 kb · p 0.014 · regional, not allelic
Overall
CADD	23.2	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 0.036% African / African-American · 27/74,944 alleles

Filtering AF 0.0254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0219%

Overall 0.00384% 62/1,614,094 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.036%	2,776
Admixed American	0.00833%	12,002
European (non-Finnish)	0.00237%	42,144
East Asian	0.00223%	44,886
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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: DSG2
Protein: p.Asn493Ser
Coding: c.1478A>G
MANE Select: NM_001943
dbSNP: rs375679311
Type: single nucleotide variant
Location: chr18:31536256 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB
Residue 493: the cadherin 4 domain

Full DSG2 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 10 dilated cardiomyopathy 1BB arrhythmogenic right ventricular cardiomyopathy

Similar variants

DSG2 p.Asn493Asp Uncertain significance ★★ ⚠ same residue
DSG2 p.Asn493= Conflicting classifications of pathogenicity ★ same residue
DSG2 p.Asn493del Uncertain significance ★ same residue
DSG2 c.1423+1G>T Likely pathogenic ★★ same condition
DSG2 c.1424-1G>A Likely pathogenic ★★ same condition
DSG2 c.523+1G>T Pathogenic/Likely pathogenic ★★ same condition
DSG2 c.690+1G>A Pathogenic ★★ same condition
DSG2 c.81+1G>T 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/dsg2-p-asn493ser (accessed [today's date]).

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