Is ADAMTS2 p.Val954Met (c.2860G>A) pathogenic?

ADAMTS2 p.Val954Met (c.2860G>A) is classified Conflicting classifications of pathogenicity in ADAMTS2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-01-18). AlphaMissense: likely benign (0.2837); Rare (popmax 0.428%, mid); Associated with Ehlers-Danlos syndrome, dermatosparaxis type.

What condition is associated with ADAMTS2 p.Val954Met (c.2860G>A)?

ADAMTS2 p.Val954Met (c.2860G>A) is associated with Ehlers-Danlos syndrome, dermatosparaxis type (ClinVar).

How common is ADAMTS2 p.Val954Met (c.2860G>A) in the general population?

ADAMTS2 p.Val954Met (c.2860G>A) is rare (popmax 0.428%, mid) (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.Val954Met (c.2860G>A)?

AlphaMissense predicts likely benign (score 0.2837) — an in-silico prediction, not a clinical call.

ADAMTS2 p.Val954Met

c.2860G>A · rs368363548 · VCV972104

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2837 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.428%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ehlers-Danlos syndrome, dermatosparaxis type

Computational evidence

Protein change
AlphaMissense	0.2837	likely benign
REVEL	0.21	benign-leaning
SaProt	LLR -11.58	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 0.065, phastCons 0.61
Regional constraint	o/e 0.85	unconstrained · MANE · 40 kb · p 3.1e-07 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.428% Middle Eastern · 26/6,080 alleles

Filtering AF 0.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.257%

Overall 0.00596% 96/1,610,952 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.428%	234
African / African-American	0.0134%	7,478
Remaining individualsnot grpmax-eligible	0.0112%	8,912
Admixed American	0.00843%	11,869
European (non-Finnish)	0.00373%	26,807
South Asian	0.0033%	30,259
East Asian	0.00224%	44,672

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.Val954Met
Coding: c.2860G>A
MANE Select: NM_014244
dbSNP: rs368363548
Type: single nucleotide variant
Location: chr5:179125071 (GRCh38)
Gene constraint: LOEUF 0.568 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 71.59
Residue 954: the tsp type-1 3 domain

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 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
ADAMTS2 p.Cys659Ter Pathogenic/Likely pathogenic ★★ same condition
ADAMTS2 p.Gln225Ter 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-val954met (accessed [today's date]).

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