Is ADAMTS2 p.Arg390His (c.1169G>A) pathogenic?

ADAMTS2 p.Arg390His (c.1169G>A) is classified Uncertain significance in ADAMTS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: likely pathogenic (0.7982); Very rare (popmax 0.000678%, nfe); Associated with Ehlers-Danlos syndrome, dermatosparaxis type.

What condition is associated with ADAMTS2 p.Arg390His (c.1169G>A)?

ADAMTS2 p.Arg390His (c.1169G>A) is associated with Ehlers-Danlos syndrome, dermatosparaxis type (ClinVar).

How common is ADAMTS2 p.Arg390His (c.1169G>A) in the general population?

ADAMTS2 p.Arg390His (c.1169G>A) is very rare (popmax 0.000678%, 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.Arg390His (c.1169G>A)?

AlphaMissense predicts likely pathogenic (score 0.7982) — an in-silico prediction, not a clinical call.

ADAMTS2 p.Arg390His

c.1169G>A · rs768623482 · VCV1447191

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7982 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ehlers-Danlos syndrome, dermatosparaxis type

Computational evidence

Protein change
AlphaMissense	0.7982	likely pathogenic
REVEL	0.91	moderately pathogenic-leaning
SaProt	LLR -11.24	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 4,610 bp · p 2.1e-06 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000678% European (non-Finnish) · 8/1,179,924 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000616% 9/1,461,334 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00157%	63,808
European (non-Finnish)grpmax	0.000678%	147,490

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg390His
Coding: c.1169G>A
MANE Select: NM_014244
dbSNP: rs768623482
Type: single nucleotide variant
Location: chr5:179154883 (GRCh38)
Gene constraint: LOEUF 0.568 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 71.59
Residue 390: a disulfide bond; the peptidase m12b 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 p.Arg390= Likely benign ★ 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
ADAMTS2 p.Cys659Ter 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-arg390his (accessed [today's date]).

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