Is ADAMTS2 p.Pro733Arg (c.2198C>G) pathogenic?

ADAMTS2 p.Pro733Arg (c.2198C>G) is classified Uncertain significance in ADAMTS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-22). AlphaMissense: likely benign (0.2753); Very rare (popmax 0.00329%, sas); Associated with Inborn genetic diseases.

What condition is associated with ADAMTS2 p.Pro733Arg (c.2198C>G)?

ADAMTS2 p.Pro733Arg (c.2198C>G) is associated with Inborn genetic diseases, Ehlers-Danlos syndrome, dermatosparaxis type (ClinVar).

How common is ADAMTS2 p.Pro733Arg (c.2198C>G) in the general population?

ADAMTS2 p.Pro733Arg (c.2198C>G) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about ADAMTS2 p.Pro733Arg (c.2198C>G)?

AlphaMissense predicts likely benign (score 0.2753) — an in-silico prediction, not a clinical call.

ADAMTS2 p.Pro733Arg

c.2198C>G · rs1581143324 · VCV972123

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2753 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2753	likely benign
REVEL	0.334	indeterminate
SaProt	LLR -10.02	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 40 kb · p 3.1e-07 · regional, not allelic
Overall
CADD	23.9	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 0.00329% South Asian · 3/91,076 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000205% 3/1,461,808 alleles · very rare

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.Pro733Arg
Coding: c.2198C>G
MANE Select: NM_014244
dbSNP: rs1581143324
Type: single nucleotide variant
Location: chr5:179132788 (GRCh38)
Gene constraint: LOEUF 0.568 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 71.59
Residue 733: the 'spacer' region

Full ADAMTS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Ehlers-Danlos syndrome, dermatosparaxis type

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-pro733arg (accessed [today's date]).

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