Is DSG2 p.Val334Met (c.1000G>A) pathogenic?

DSG2 p.Val334Met (c.1000G>A) is classified Conflicting classifications of pathogenicity in DSG2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-05-07). AlphaMissense: likely benign (0.2731); Very rare (popmax 0.000169%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with DSG2 p.Val334Met (c.1000G>A)?

DSG2 p.Val334Met (c.1000G>A) is associated with Cardiovascular phenotype, arrhythmogenic right ventricular dysplasia 10 (ClinVar).

How common is DSG2 p.Val334Met (c.1000G>A) in the general population?

DSG2 p.Val334Met (c.1000G>A) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about DSG2 p.Val334Met (c.1000G>A)?

AlphaMissense predicts likely benign (score 0.2731) — an in-silico prediction, not a clinical call.

DSG2 p.Val334Met

c.1000G>A · rs761360851 · VCV518615

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2731 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2731	likely benign
REVEL	0.08	moderately benign-leaning
SaProt	LLR -10.43	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP -2.3, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 48 kb · p 0.014 · regional, not allelic
Overall
CADD	22.6	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 0.000169% European (non-Finnish) · 2/1,180,026 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00131% 2/152,238 alleles · very rare

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.Val334Met
Coding: c.1000G>A
MANE Select: NM_001943
dbSNP: rs761360851
Type: single nucleotide variant
Location: chr18:31524874 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB
Residue 334: 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

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

Also linked: arrhythmogenic right ventricular dysplasia 10

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-val334met (accessed [today's date]).

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