Is DSG2 p.Val392Ile (c.1174G>A) pathogenic?

DSG2 p.Val392Ile (c.1174G>A) is classified Conflicting classifications of pathogenicity in DSG2 (ClinVar, Conflicting submitters, 20 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0707); Rare (popmax 0.615%, sas); Associated with Cardiovascular phenotype.

What condition is associated with DSG2 p.Val392Ile (c.1174G>A)?

DSG2 p.Val392Ile (c.1174G>A) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic right ventricular dysplasia 10 (ClinVar).

How common is DSG2 p.Val392Ile (c.1174G>A) in the general population?

DSG2 p.Val392Ile (c.1174G>A) is rare (popmax 0.615%, sas) (gnomAD).

What do computational predictors say about DSG2 p.Val392Ile (c.1174G>A)?

AlphaMissense predicts likely benign (score 0.0707) — an in-silico prediction, not a clinical call.

DSG2 p.Val392Ile

c.1174G>A · rs193922639 · VCV36009

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 20 submitters

AlphaMissense

likely benign

0.0707 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.615%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0707	likely benign
REVEL	0.27	benign-leaning
SaProt	LLR -7.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -2.3, phastCons 0.001
Regional constraint	o/e 0.93	unconstrained · MANE · 48 kb · p 0.014 · regional, not allelic
Overall
CADD	14.53	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 0.615% South Asian · 560/91,080 alleles

Filtering AF 0.573% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.556%

Overall 0.262% 4,233/1,614,094 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.615%	163
European (non-Finnish)	0.287%	349
Remaining individualsnot grpmax-eligible	0.194%	517
Finnishnot grpmax-eligible	0.125%	800
Middle Eastern	0.0825%	1,212
Admixed American	0.0716%	1,396
African / African-American	0.0413%	2,420
Ashkenazi Jewishnot grpmax-eligible	0.0372%	2,691
East Asian	0.00223%	44,866

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.Val392Ile
Coding: c.1174G>A
MANE Select: NM_001943
dbSNP: rs193922639
Type: single nucleotide variant
Location: chr18:31531146 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB
Residue 392: a β-strand; a UniProt-annotated variant site (in arvd10; uncertain significance; alters glycosylation pattern; no change in cell-cell adhesion strength); 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 arrhythmogenic right ventricular cardiomyopathy

Similar variants

DSG2 p.Val392= Likely benign ★ 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
DSG2 c.829-2A>T Likely pathogenic ★★ same condition
DSG2 p.Arg46Gln 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-val392ile (accessed [today's date]).

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