Is ADAMTS2 p.Pro4Gln (c.11C>A) pathogenic?

ADAMTS2 p.Pro4Gln (c.11C>A) is classified Uncertain significance in ADAMTS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-23). AlphaMissense: likely benign (0.1628); Very rare (popmax 0.000648%, nfe); Associated with Ehlers-Danlos syndrome, dermatosparaxis type.

What condition is associated with ADAMTS2 p.Pro4Gln (c.11C>A)?

ADAMTS2 p.Pro4Gln (c.11C>A) is associated with Ehlers-Danlos syndrome, dermatosparaxis type (ClinVar).

How common is ADAMTS2 p.Pro4Gln (c.11C>A) in the general population?

ADAMTS2 p.Pro4Gln (c.11C>A) is very rare (popmax 0.000648%, nfe) (gnomAD).

How is Dermatosparaxis Ehlers-Danlos syndrome inherited?

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

What do computational predictors say about ADAMTS2 p.Pro4Gln (c.11C>A)?

AlphaMissense predicts likely benign (score 0.1628) — an in-silico prediction, not a clinical call.

ADAMTS2 p.Pro4Gln

c.11C>A · rs2127463944 · VCV1314771

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1628 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000648%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ehlers-Danlos syndrome, dermatosparaxis type

Computational evidence

Protein change
AlphaMissense	0.1628	likely benign
REVEL	0.165	moderately benign-leaning
SaProt	LLR -9.79	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP -0.5, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 1,534 bp · p 0.83 · regional, not allelic
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000648% European (non-Finnish) · 6/926,510 alleles

Filtering AF 0.000233% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000153%

Overall 0.00061% 6/984,280 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.Pro4Gln
Coding: c.11C>A
MANE Select: NM_014244
dbSNP: rs2127463944
Type: single nucleotide variant
Location: chr5:179345318 (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.Pro4= Likely benign ★ same residue
ADAMTS2 p.Pro4fs Pathogenic ★ same residue
ADAMTS2 c.2085+1G>T Likely pathogenic ★★ same condition
ADAMTS2 c.3088+1G>A Likely pathogenic ★★ same condition
ADAMTS2 c.688+1G>A Likely pathogenic ★★ same condition
ADAMTS2 c.688+2T>C Likely pathogenic ★★ same condition
ADAMTS2 p.Arg1030Ter Pathogenic/Likely pathogenic ★★ same condition
ADAMTS2 p.Arg980Ter 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-pro4gln (accessed [today's date]).

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