Is ADAMTS2 p.Pro224fs (c.669dup) pathogenic?

ADAMTS2 p.Pro224fs (c.669dup) is classified Pathogenic in ADAMTS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-11). Very rare (popmax 6.86e-05%); Associated with Ehlers-Danlos syndrome, dermatosparaxis type.

What condition is associated with ADAMTS2 p.Pro224fs (c.669dup)?

ADAMTS2 p.Pro224fs (c.669dup) is associated with Ehlers-Danlos syndrome, dermatosparaxis type (ClinVar).

How common is ADAMTS2 p.Pro224fs (c.669dup) in the general population?

ADAMTS2 p.Pro224fs (c.669dup) is very rare (popmax 6.86e-05%) (gnomAD).

How is Dermatosparaxis Ehlers-Danlos syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ADAMTS2 p.Pro224fs

c.669dup · VCV3629699

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 6.86e-05%)

Conditions

Ehlers-Danlos syndrome, dermatosparaxis type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 22
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.3	GERP -1, phastCons 0.99

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.86e-05%

Overall 6.86e-05% 1/1,458,052 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: ADAMTS2
Protein: p.Pro224fs
Coding: c.669dup
MANE Select: NM_014244
Type: Duplication
Location: chr5:179272929 (GRCh38)
Gene constraint: LOEUF 0.568 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 71.59

Full ADAMTS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Ehlers-Danlos syndrome, dermatosparaxis type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Dermatosparaxis Ehlers-Danlos syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ADAMTS2 p.Pro224= Likely benign ★★ same residue
ADAMTS2 p.Pro224Ser Uncertain significance ★ ⚠ same residue
ADAMTS2 p.Ala42fs Pathogenic/Likely pathogenic ★★ same condition
ADAMTS2 p.Asp535fs Pathogenic/Likely pathogenic ★★ same condition
ADAMTS2 p.Leu27_Pro34dup Uncertain significance ★★ same condition
ADAMTS2 p.Leu27_Pro33dup Benign/Likely benign ★★ same condition
ADAMTS2 p.Ala15fs Likely pathogenic ★ same condition
ADAMTS2 p.Ala43fs 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/adamts2-p-pro224fs (accessed [today's date]).

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