Is ADAMTS2 p.Pro1177Ser (c.3529C>T) pathogenic?

ADAMTS2 p.Pro1177Ser (c.3529C>T) is classified Benign in ADAMTS2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.128); Common (popmax 39%, amr) — too common for a highly-penetrant pathogenic allele; Associated with Ehlers-Danlos syndrome, dermatosparaxis type.

What condition is associated with ADAMTS2 p.Pro1177Ser (c.3529C>T)?

ADAMTS2 p.Pro1177Ser (c.3529C>T) is associated with Ehlers-Danlos syndrome, dermatosparaxis type (ClinVar).

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.Pro1177Ser (c.3529C>T)?

AlphaMissense predicts likely benign (score 0.128) — an in-silico prediction, not a clinical call.

ADAMTS2 p.Pro1177Ser

Q: How common is ADAMTS2 p.Pro1177Ser (c.3529C>T) in the general population?

ADAMTS2 p.Pro1177Ser (c.3529C>T) is common (popmax 39%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3529C>T · rs1054480 · VCV353083

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.128 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 39%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ehlers-Danlos syndrome, dermatosparaxis type

Computational evidence

Protein change
AlphaMissense	0.128	likely benign
REVEL	0.101	moderately benign-leaning
SaProt	LLR -6.16	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 8.4	GERP 1.4, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 40 kb · p 3.1e-07 · regional, not allelic
Overall
CADD	16.86	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 39% Admixed American · 23,431/60,004 alleles

Filtering AF 38.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 38.5%

Overall 29.1% 468,924/1,613,916 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	43.3%	2
Admixed Americangrpmax	39%	3
South Asian	36.8%	3
East Asian	35.2%	3
Middle Eastern	31.5%	3
Ashkenazi Jewishnot grpmax-eligible	31.1%	3
European (non-Finnish)	29%	3
Finnishnot grpmax-eligible	28.8%	3
Remaining individualsnot grpmax-eligible	28.6%	3
African / African-American	7.69%	13

Amish 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.Pro1177Ser
Coding: c.3529C>T
MANE Select: NM_014244
dbSNP: rs1054480
Type: single nucleotide variant
Location: chr5:179113974 (GRCh38)
Gene constraint: LOEUF 0.568 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 71.59
Residue 1177: the 'disordered' 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.Pro1177Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
ADAMTS2 p.Pro1177Phe Uncertain significance ★ same residue
ADAMTS2 p.Pro1177= 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-pro1177ser (accessed [today's date]).

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