Is ADAMTS2 p.Arg827Trp (c.2479C>T) pathogenic?

ADAMTS2 p.Arg827Trp (c.2479C>T) is classified Uncertain significance in ADAMTS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-14). AlphaMissense: likely benign (0.1634); Ultra-rare (popmax 0.0417%, sas); Associated with Ehlers-Danlos syndrome, dermatosparaxis type.

What condition is associated with ADAMTS2 p.Arg827Trp (c.2479C>T)?

ADAMTS2 p.Arg827Trp (c.2479C>T) is associated with Ehlers-Danlos syndrome, dermatosparaxis type (ClinVar).

How common is ADAMTS2 p.Arg827Trp (c.2479C>T) in the general population?

ADAMTS2 p.Arg827Trp (c.2479C>T) is ultra-rare (popmax 0.0417%, sas) (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.Arg827Trp (c.2479C>T)?

AlphaMissense predicts likely benign (score 0.1634) — an in-silico prediction, not a clinical call.

ADAMTS2 p.Arg827Trp

c.2479C>T · rs376995938 · VCV653861

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1634 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0417%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Ehlers-Danlos syndrome, dermatosparaxis type

Computational evidence

Protein change
AlphaMissense	0.1634	likely benign
REVEL	0.295	indeterminate
SaProt	LLR -9.86	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.3	GERP 0.33, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 40 kb · p 3.1e-07 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0417% South Asian · 38/91,064 alleles

Filtering AF 0.0312% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0276%

Overall 0.00502% 81/1,613,482 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0417%	2,396
Remaining individualsnot grpmax-eligible	0.0064%	15,619
East Asian	0.00446%	22,440
European (non-Finnish)	0.00297%	33,714
African / African-American	0.00267%	37,432

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.Arg827Trp
Coding: c.2479C>T
MANE Select: NM_014244
dbSNP: rs376995938
Type: single nucleotide variant
Location: chr5:179128097 (GRCh38)
Gene constraint: LOEUF 0.568 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 71.59
Residue 827: the 'spacer' region; a UniProt-annotated variant site (in)

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 p.Arg827Gln Benign/Likely benign ★★ same residue
ADAMTS2 p.Arg827= 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-arg827trp (accessed [today's date]).

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