Is DSG2 p.Ser999= (c.2997G>A) pathogenic?

DSG2 p.Ser999= (c.2997G>A) is classified Likely benign in DSG2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-27). Very rare (popmax 0.00833%, amr); Associated with Cardiovascular phenotype.

What condition is associated with DSG2 p.Ser999= (c.2997G>A)?

DSG2 p.Ser999= (c.2997G>A) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic right ventricular dysplasia 10 (ClinVar).

How common is DSG2 p.Ser999= (c.2997G>A) in the general population?

DSG2 p.Ser999= (c.2997G>A) is very rare (popmax 0.00833%, amr) (gnomAD).

DSG2 p.Ser999=

c.2997G>A · rs763888499 · VCV466338

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.4
Overall
CADD	0.443	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00833% Admixed American · 5/59,996 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000929% 15/1,613,956 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	11,999
East Asian	0.00446%	22,446
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)	0.000593%	168,570

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.Ser999=
Coding: c.2997G>A
MANE Select: NM_001943
dbSNP: rs763888499
Type: single nucleotide variant
Location: chr18:31546383 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB
Residue 999: 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.Ser999Leu Uncertain significance ★★ ⚠ same residue
DSG2 p.Ser999Ala Uncertain significance ★ ⚠ same residue
DSG2 p.Ser999Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
DSG2 p.Ser999Trp 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

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-ser999 (accessed [today's date]).

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