Is ADAMTS2 p.Ala199Val (c.596C>T) pathogenic?

ADAMTS2 p.Ala199Val (c.596C>T) is classified Benign/Likely benign in ADAMTS2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-04-15). AlphaMissense: likely benign (0.0965); Rare (popmax 0.983%, eas); Associated with Ehlers-Danlos syndrome, dermatosparaxis type.

What condition is associated with ADAMTS2 p.Ala199Val (c.596C>T)?

ADAMTS2 p.Ala199Val (c.596C>T) is associated with Ehlers-Danlos syndrome, dermatosparaxis type, Ehlers-Danlos syndrome (ClinVar).

How common is ADAMTS2 p.Ala199Val (c.596C>T) in the general population?

ADAMTS2 p.Ala199Val (c.596C>T) is rare (popmax 0.983%, eas) (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.Ala199Val (c.596C>T)?

AlphaMissense predicts likely benign (score 0.0965) — an in-silico prediction, not a clinical call.

ADAMTS2 p.Ala199Val

c.596C>T · rs76704342 · VCV469678

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0965 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.983%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ehlers-Danlos syndrome, dermatosparaxis type

Computational evidence

Protein change
AlphaMissense	0.0965	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -8.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.021	GERP -2.4
Regional constraint	o/e 1.21	unconstrained · MANE · 66 kb · p 0.0097 · regional, not allelic
Overall
CADD	12.18	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 0.983% East Asian · 441/44,840 alleles

Filtering AF 0.908% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.878%

Overall 0.058% 936/1,613,324 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.983%	102
Remaining individualsnot grpmax-eligible	0.0928%	1,078
European (non-Finnish)	0.034%	2,943
South Asian	0.0242%	4,140
African / African-American	0.0133%	7,504
Admixed American	0.005%	20,008
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608

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.Ala199Val
Coding: c.596C>T
MANE Select: NM_014244
dbSNP: rs76704342
Type: single nucleotide variant
Location: chr5:179273003 (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

Also linked: Ehlers-Danlos syndrome

For Dermatosparaxis Ehlers-Danlos syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ADAMTS2 p.Ala199= Likely benign ★★ same residue
ADAMTS2 p.Ala199Glu Uncertain significance ★ ⚠ same residue
ADAMTS2 p.Ala199Ser Uncertain significance ⚠ 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

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-ala199val (accessed [today's date]).

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