Is ADAMTS2 p.Ala226= (c.678C>G) pathogenic?

ADAMTS2 p.Ala226= (c.678C>G) is classified Likely benign in ADAMTS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-01). Very rare (popmax 0.00669%, eas); Associated with Ehlers-Danlos syndrome, dermatosparaxis type.

What condition is associated with ADAMTS2 p.Ala226= (c.678C>G)?

ADAMTS2 p.Ala226= (c.678C>G) is associated with Ehlers-Danlos syndrome, dermatosparaxis type (ClinVar).

How common is ADAMTS2 p.Ala226= (c.678C>G) in the general population?

ADAMTS2 p.Ala226= (c.678C>G) is very rare (popmax 0.00669%, 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.Ala226=

c.678C>G · rs766547415 · VCV1111994

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00669%, 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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.88	GERP 0.16, phastCons 0.91
Overall
CADD	7.171	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00669% East Asian · 3/44,860 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000892%

Overall 0.000274% 4/1,457,630 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,953
European (non-Finnish)	8.47e-05%	1,179,956

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.Ala226=
Coding: c.678C>G
MANE Select: NM_014244
dbSNP: rs766547415
Type: single nucleotide variant
Location: chr5:179272921 (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 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-ala226 (accessed [today's date]).

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