Is DSG2 p.Glu331Lys (c.991G>A) pathogenic?

DSG2 p.Glu331Lys (c.991G>A) is classified Uncertain significance in DSG2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-11-26). AlphaMissense: ambiguous (0.5002); Very rare (popmax 0.00329%, sas); Associated with cardiomyopathy.

How common is DSG2 p.Glu331Lys (c.991G>A) in the general population?

DSG2 p.Glu331Lys (c.991G>A) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about DSG2 p.Glu331Lys (c.991G>A)?

AlphaMissense predicts ambiguous (score 0.5002) — an in-silico prediction, not a clinical call.

DSG2 p.Glu331Lys

Q: What condition is associated with DSG2 p.Glu331Lys (c.991G>A)?

DSG2 p.Glu331Lys (c.991G>A) is associated with cardiomyopathy, arrhythmogenic right ventricular dysplasia 10, arrhythmogenic right ventricular cardiomyopathy (ClinVar).

c.991G>A · rs121913012 · VCV16816

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

ambiguous

0.5002 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Conditions

cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.5002	ambiguous
REVEL	0.594	indeterminate
SaProt	LLR -14.27	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 48 kb · p 0.014 · regional, not allelic
Overall
CADD	26.9	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 0.00329% South Asian · 3/91,078 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00118% 19/1,614,044 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,359
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	0.00127%	78,668

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.Glu331Lys
Coding: c.991G>A
MANE Select: NM_001943
dbSNP: rs121913012
Type: single nucleotide variant
Location: chr18:31524865 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB
Residue 331: a β-strand; the 'interacts with human adenovirus b3 fiber protein' region; the cadherin 3 domain

Full DSG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: arrhythmogenic right ventricular dysplasia 10 arrhythmogenic right ventricular cardiomyopathy

Similar variants

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
DSG2 c.829-2A>T Likely pathogenic ★★ same condition
DSG2 p.Arg46Gln Pathogenic/Likely pathogenic ★★ same condition
DSG2 p.Arg46Trp 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/dsg2-p-glu331lys (accessed [today's date]).

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