Is ADAMTS2 p.Arg214Trp (c.640C>T) pathogenic?

ADAMTS2 p.Arg214Trp (c.640C>T) is classified Uncertain significance in ADAMTS2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-04). AlphaMissense: likely benign (0.1654); Very rare (popmax 0.0022%, sas); Associated with Inborn genetic diseases.

What condition is associated with ADAMTS2 p.Arg214Trp (c.640C>T)?

ADAMTS2 p.Arg214Trp (c.640C>T) is associated with Inborn genetic diseases, Ehlers-Danlos syndrome, dermatosparaxis type (ClinVar).

How common is ADAMTS2 p.Arg214Trp (c.640C>T) in the general population?

ADAMTS2 p.Arg214Trp (c.640C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about ADAMTS2 p.Arg214Trp (c.640C>T)?

AlphaMissense predicts likely benign (score 0.1654) — an in-silico prediction, not a clinical call.

ADAMTS2 p.Arg214Trp

c.640C>T · rs144732073 · VCV286306

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1654 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1654	likely benign
REVEL	0.269	benign-leaning
SaProt	LLR -12.79	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 0.33, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 66 kb · p 0.0097 · regional, not allelic
Overall
CADD	25.6	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 0.0022% South Asian · 2/91,066 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00124% 20/1,612,252 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,233
South Asiangrpmax	0.0022%	45,533
African / African-American	0.00134%	74,870
European (non-Finnish)	0.00127%	78,665

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.Arg214Trp
Coding: c.640C>T
MANE Select: NM_014244
dbSNP: rs144732073
Type: single nucleotide variant
Location: chr5:179272959 (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

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

Also linked: Ehlers-Danlos syndrome, dermatosparaxis type

Similar variants

ADAMTS2 p.Arg214Gln Uncertain significance ★★ ⚠ same residue
ADAMTS2 p.Arg214= Likely benign ★ 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
ADAMTS2 p.Arg980Ter 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-arg214trp (accessed [today's date]).

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