Is ADAMTS2 p.His286= (c.858C>T) pathogenic?

ADAMTS2 p.His286= (c.858C>T) is classified Benign in ADAMTS2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 23.3%, mid) — too common for a highly-penetrant pathogenic allele; Associated with Ehlers-Danlos syndrome, dermatosparaxis type.

What condition is associated with ADAMTS2 p.His286= (c.858C>T)?

ADAMTS2 p.His286= (c.858C>T) is associated with Ehlers-Danlos syndrome, dermatosparaxis type (ClinVar).

How is Dermatosparaxis Ehlers-Danlos syndrome inherited?

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

ADAMTS2 p.His286=

Q: How common is ADAMTS2 p.His286= (c.858C>T) in the general population?

ADAMTS2 p.His286= (c.858C>T) is common (popmax 23.3%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.858C>T · rs66565583 · VCV353129

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 23.3%, mid) — too common for a highly-penetrant pathogenic allele

Conditions

Ehlers-Danlos syndrome, dermatosparaxis type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.98 · evaluated, not missing
Constraint at this position
Conservation	phyloP -2.3	GERP -3.9
Overall
CADD	2.65	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 23.3% Middle Eastern · 1,350/5,790 alleles

Filtering AF 22.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 21.9%

Overall 19.2% 298,649/1,556,148 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	35.7%	3
Ashkenazi Jewishnot grpmax-eligible	24.3%	4
Middle Easterngrpmax	23.3%	4
Finnishnot grpmax-eligible	21.5%	5
South Asian	20.7%	5
European (non-Finnish)	20.2%	5
Remaining individualsnot grpmax-eligible	19.5%	5
African / African-American	13.1%	8
Admixed American	11.1%	9
East Asian	0.312%	320

Amish 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.His286=
Coding: c.858C>T
MANE Select: NM_014244
dbSNP: rs66565583
Type: single nucleotide variant
Location: chr5:179207546 (GRCh38)
Gene constraint: LOEUF 0.568 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 71.59
Residue 286: 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 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-his286 (accessed [today's date]).

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