Is ADAMTS2 p.Pro34fs (c.100_130del) pathogenic?

ADAMTS2 p.Pro34fs (c.100130del) is classified Pathogenic/Likely pathogenic in ADAMTS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-30). Very rare (popmax 0.000109%, nfe); Associated with Ehlers-Danlos syndrome, dermatosparaxis type.

What condition is associated with ADAMTS2 p.Pro34fs (c.100_130del)?

ADAMTS2 p.Pro34fs (c.100_130del) is associated with Ehlers-Danlos syndrome, dermatosparaxis type (ClinVar).

How common is ADAMTS2 p.Pro34fs (c.100_130del) in the general population?

ADAMTS2 p.Pro34fs (c.100_130del) is very rare (popmax 0.000109%, nfe) (gnomAD).

How is Dermatosparaxis Ehlers-Danlos syndrome inherited?

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

ADAMTS2 p.Pro34fs

c.100_130del · rs1242279733 · VCV1936753

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000109%, nfe)

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 1 of 22
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.24	GERP 0.68, phastCons 0.23
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	(CGG)n simple repeat · ambiguous alignment · confidence, not pathogenicity

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000109% European (non-Finnish) · 1/915,450 alleles

Overall 0.000104% 1/961,706 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.Pro34fs
Coding: c.100_130del
MANE Select: NM_014244
dbSNP: rs1242279733
Type: Deletion
Location: chr5:179345199 (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.Pro34_Ala35insLeuProProProProProPro Uncertain significance ★ same residue
ADAMTS2 p.Pro34del Conflicting classifications of pathogenicity ★ same residue
ADAMTS2 p.Pro34dup Conflicting classifications of pathogenicity ★ same residue
ADAMTS2 p.Pro34= Likely benign ★ same residue
ADAMTS2 c.689-9_695del Likely pathogenic ★★ same condition
ADAMTS2 p.Ala89fs Pathogenic/Likely pathogenic ★★ same condition
ADAMTS2 p.Met791fs Pathogenic/Likely pathogenic ★★ same condition
ADAMTS2 p.Pro33fs 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/adamts2-p-pro34fs (accessed [today's date]).

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