Arthrogryposis, distal, type 12

Summary

Arthrogryposis, distal, type 12 (MONDO:0957819) is a disease caused by ADAMTS15 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: ADAMTS15 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	arthrogryposis, distal, type 12
Mondo ID	MONDO:0957819
OMIM	620545
UMLS	C5882704
MedGen	1847896
GARD	0026879
Is cancer (heuristic)	no

Data availability: 5 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › distal arthrogryposis › arthrogryposis, distal, type 12

Related subtypes (22): arthrogryposis- oculomotor limitation-electroretinal anomalies syndrome, arthrogryposis-like hand anomaly-sensorineural deafness syndrome, Gordon syndrome, congenital contractural arachnodactyly, arthrogryposis, distal, type 2E, trismus-pseudocamptodactyly syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, Freeman-Sheldon syndrome, Sheldon-hall syndrome, Ehlers-Danlos syndrome, musculocontractural type, arthrogryposis-severe scoliosis syndrome, distal arthrogryposis type 5D, autism spectrum disorder - epilepsy - arthrogryposis syndrome, arthrogryposis, distal, with impaired proprioception and touch, digitotalar dysmorphism, distal arthrogryposis type 10, distal arthrogryposis Moore weaver type, arthrogryposis, distal, type 1C, arthrogryposis, distal, IIa 11, arthrogryposis-ectodermal dysplasia-other anomalies syndrome, ACTC1-related distal arthrogryposis with congenital heart disease, arthrogryposis, distal, type 2B4

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

5 retrieved; paginated sample, class counts are floors:

3 pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2584761	NM_139055.4(ADAMTS15):c.123C>G (p.Tyr41Ter)	ADAMTS15	Pathogenic	no assertion criteria provided
2584762	NM_139055.4(ADAMTS15):c.1903-2A>G	ADAMTS15	Pathogenic	no assertion criteria provided
2584763	NM_139055.4(ADAMTS15):c.2281G>A (p.Gly761Ser)	ADAMTS15	Pathogenic	no assertion criteria provided
2584764	NM_139055.4(ADAMTS15):c.2715C>G (p.Cys905Trp)	ADAMTS15	Likely pathogenic	criteria provided, single submitter
4277881	NM_139055.4(ADAMTS15):c.1903-2A>C	ADAMTS15	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 0 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ADAMTS15	Strong	Autosomal recessive	arthrogryposis, distal, type 12	2

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ADAMTS15	HGNC:16305	ENSG00000166106	Q8TE58	A disintegrin and metalloproteinase with thrombospondin motifs 15	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ADAMTS15	A disintegrin and metalloproteinase with thrombospondin motifs 15	Metalloprotease which has proteolytic activity against the proteoglycan VCAN, cleaving it at the ‘Glu-1428-|-1429-Ala’ site.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ADAMTS15	Protease	yes	3.4.24.B12	TSP1_rpt, Peptidase_M12B, Peptidase_M12B_N

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
decidua	1
kidney epithelium	1
left ventricle myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ADAMTS15	182		marker	decidua, left ventricle myocardium, kidney epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ADAMTS15	749

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ADAMTS15	Q8TE58	77.87

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective B3GALTL causes PpS	1	308.6×	0.014	ADAMTS15
O-glycosylation of TSR domain-containing proteins	1	300.5×	0.014	ADAMTS15
Diseases associated with O-glycosylation of proteins	1	215.5×	0.014	ADAMTS15
O-linked glycosylation	1	144.6×	0.014	ADAMTS15
Diseases of glycosylation	1	131.3×	0.014	ADAMTS15
Diseases of metabolism	1	80.4×	0.019	ADAMTS15
Post-translational protein modification	1	19.2×	0.067	ADAMTS15
Disease	1	13.1×	0.081	ADAMTS15
Metabolism of proteins	1	12.4×	0.081	ADAMTS15

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
myoblast fusion	1	601.9×	0.005	ADAMTS15
extracellular matrix disassembly	1	366.4×	0.005	ADAMTS15
extracellular matrix organization	1	122.1×	0.011	ADAMTS15
proteolysis	1	34.2×	0.029	ADAMTS15

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ADAMTS15	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ADAMTS15	3.4.24.B12

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ADAMTS15
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ADAMTS15	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.