Is ADAMTS2 p.His412= (c.1236C>T) pathogenic?

ADAMTS2 p.His412= (c.1236C>T) is classified Conflicting classifications of pathogenicity in ADAMTS2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-24). Very rare (popmax 0.00447%, eas); Associated with Ehlers-Danlos syndrome, dermatosparaxis type.

What condition is associated with ADAMTS2 p.His412= (c.1236C>T)?

ADAMTS2 p.His412= (c.1236C>T) is associated with Ehlers-Danlos syndrome, dermatosparaxis type (ClinVar).

How common is ADAMTS2 p.His412= (c.1236C>T) in the general population?

ADAMTS2 p.His412= (c.1236C>T) is very rare (popmax 0.00447%, eas) (gnomAD).

How is Dermatosparaxis Ehlers-Danlos syndrome inherited?

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

ADAMTS2 p.His412=

c.1236C>T · rs375556579 · VCV1094727

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00447%, eas)

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 Δ0.70 · evaluated, not missing
Constraint at this position
Conservation	phyloP -5.5	GERP -3.5
Overall
CADD	2.775	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00447% East Asian · 2/44,740 alleles

Filtering AF 0.000886% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000719%

Overall 0.00162% 26/1,609,476 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00481%	20,769
East Asiangrpmax	0.00447%	22,370
South Asian	0.00334%	29,969
European (non-Finnish)	0.00144%	69,305
African / African-American	0.00133%	75,016

Remaining individuals 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.His412=
Coding: c.1236C>T
MANE Select: NM_014244
dbSNP: rs375556579
Type: single nucleotide variant
Location: chr5:179154816 (GRCh38)
Gene constraint: LOEUF 0.568 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 71.59
Residue 412: a binding site; 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 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-his412 (accessed [today's date]).

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