Is DSG2 p.Arg773Lys (c.2318G>A) pathogenic?

DSG2 p.Arg773Lys (c.2318G>A) is classified Benign in DSG2 (ClinVar, Multiple submitters, 20 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0819); Common (popmax 54.9%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Cardiovascular phenotype.

What condition is associated with DSG2 p.Arg773Lys (c.2318G>A)?

DSG2 p.Arg773Lys (c.2318G>A) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic right ventricular dysplasia 10 (ClinVar).

What do computational predictors say about DSG2 p.Arg773Lys (c.2318G>A)?

AlphaMissense predicts likely benign (score 0.0819) — an in-silico prediction, not a clinical call.

DSG2 p.Arg773Lys

Q: How common is DSG2 p.Arg773Lys (c.2318G>A) in the general population?

DSG2 p.Arg773Lys (c.2318G>A) is common (popmax 54.9%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2318G>A · rs2278792 · VCV44300

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 20 submitters

AlphaMissense

likely benign

0.0819 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 54.9%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0819	likely benign
REVEL	0.092	moderately benign-leaning
SaProt	LLR -3.48	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 3.4	phastCons 0.53
Regional constraint	o/e 0.93	unconstrained · MANE · 48 kb · p 0.014 · regional, not allelic
Overall
CADD	18.1	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 54.9% East Asian · 20,919/38,118 alleles

Filtering AF 54.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 54%

Overall 29.2% 402,056/1,376,676 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	54.9%	2
Finnishnot grpmax-eligible	39.3%	3
Remaining individualsnot grpmax-eligible	30.6%	3
Admixed American	30.2%	3
European (non-Finnish)	29.4%	3
South Asian	24.6%	4
Ashkenazi Jewishnot grpmax-eligible	22.3%	4
Middle Eastern	20.5%	5
Amishnot grpmax-eligible	16.1%	6
African / African-American	8.47%	12

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.Arg773Lys
Coding: c.2318G>A
MANE Select: NM_001943
dbSNP: rs2278792
Type: single nucleotide variant
Location: chr18:31542836 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB
Residue 773: a UniProt-annotated variant site (in arvd10; uncertain significance; evidence of residual myocardium, fibrous tissue, fatty tissue, dysmetric and dysmorphic nuclei and prominent cytoplasmic vacuolization; decreases the number of desmosomes at intercalated disks also increases desmosome gap; smaller intercellular gaps, with repeating couplings, abnormally located desmosomes and pale internal plaques); a UniProt-annotated variant site (in arvd10; uncertain significance)

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.Arg773Gly 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
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-arg773lys (accessed [today's date]).

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