Is DSG2 p.Ser1111Arg (c.3333C>G) pathogenic?

DSG2 p.Ser1111Arg (c.3333C>G) is classified Uncertain significance in DSG2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-03-11). AlphaMissense: likely pathogenic (0.5664); Very rare (popmax 0.00178%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with DSG2 p.Ser1111Arg (c.3333C>G)?

DSG2 p.Ser1111Arg (c.3333C>G) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy (ClinVar).

How common is DSG2 p.Ser1111Arg (c.3333C>G) in the general population?

DSG2 p.Ser1111Arg (c.3333C>G) is very rare (popmax 0.00178%, nfe) (gnomAD).

What do computational predictors say about DSG2 p.Ser1111Arg (c.3333C>G)?

AlphaMissense predicts likely pathogenic (score 0.5664) — an in-silico prediction, not a clinical call.

DSG2 p.Ser1111Arg

c.3333C>G · rs143867223 · VCV1171476

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.5664 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00178%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.5664	likely pathogenic
REVEL	0.407	indeterminate
SaProt	LLR -6.81	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.44	GERP -1.3, phastCons 0.49
Regional constraint	o/e 0.93	unconstrained · MANE · 48 kb · p 0.014 · regional, not allelic
Overall
CADD	19.01	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 0.00178% European (non-Finnish) · 21/1,180,016 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00144% 21/1,461,842 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.Ser1111Arg
Coding: c.3333C>G
MANE Select: NM_001943
dbSNP: rs143867223
Type: single nucleotide variant
Location: chr18:31546719 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB
Residue 1111: the 'disordered' region; 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 cardiomyopathy

Similar variants

DSG2 p.Arg46Gln Pathogenic/Likely pathogenic ★★ same condition
DSG2 p.Arg46Trp Pathogenic/Likely pathogenic ★★ same condition
DSG2 p.Arg49His Pathogenic/Likely pathogenic ★★ same condition
DSG2 p.Asn266Ser Likely pathogenic ★★ same condition
DSG2 p.Gln873Ter Pathogenic/Likely pathogenic ★★ same condition
DSG2 p.Ser314Ter Pathogenic/Likely pathogenic ★★ same condition
DSG2 p.Ser404Ter Pathogenic/Likely pathogenic ★★ same condition
DSG2 p.Tyr130Ter 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-ser1111arg (accessed [today's date]).

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