Is DSG2 p.Ala764fs (c.2289del) pathogenic?

DSG2 p.Ala764fs (c.2289del) is classified Likely pathogenic in DSG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-19). Very rare (popmax 0.00179%, amr); Associated with Cardiovascular phenotype.

What condition is associated with DSG2 p.Ala764fs (c.2289del)?

DSG2 p.Ala764fs (c.2289del) is associated with Cardiovascular phenotype (ClinVar).

How common is DSG2 p.Ala764fs (c.2289del) in the general population?

DSG2 p.Ala764fs (c.2289del) is very rare (popmax 0.00179%, amr) (gnomAD).

DSG2 p.Ala764fs

c.2289del · VCV4015017

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00179%, amr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (14 of 15, 45 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.81	phastCons 0.009
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00179% Admixed American · 1/55,724 alleles

Overall 0.000126% 2/1,591,650 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00179%	55,724
African / African-American	0.00142%	70,496

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.Ala764fs
Coding: c.2289del
MANE Select: NM_001943
Type: Deletion
Location: chr18:31542807 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB
Residue 764: 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

Similar variants

DSG2 c.828_828+2del Uncertain significance ★★ same condition
DSG2 p.Arg1049fs Uncertain significance ★★ same condition
DSG2 p.Leu15del Uncertain significance ★★ same condition
DSG2 p.Asp162fs Pathogenic ★ same condition
DSG2 p.Leu150fs Pathogenic ★ same condition
DSG2 p.Phe388fs Pathogenic ★ same condition
DSG2 c.1014+3_1014+4del Uncertain significance ★ same condition
DSG2 c.1015del Conflicting classifications of pathogenicity ★ 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-ala764fs (accessed [today's date]).

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