ADAMTS13

Summary

ADAMTS13 (ADAM metallopeptidase with thrombospondin type 1 motif 13, HGNC:1366) is a protein-coding gene on chromosome 9q34.2, encoding A disintegrin and metalloproteinase with thrombospondin motifs 13 (Q76LX8). Cleaves the vWF multimers in plasma into smaller forms thereby controlling vWF-mediated platelet thrombus formation.

This gene encodes a member of a family of proteins containing several distinct regions, including a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. The enzyme encoded by this gene specifically cleaves von Willebrand Factor (vWF). Defects in this gene are associated with thrombotic thrombocytopenic purpura. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 11093 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital thrombotic thrombocytopenic purpura (Definitive, ClinGen)
• GWAS associations: 18
• Clinical variants (ClinVar): 1,253 total — 62 pathogenic, 71 likely-pathogenic (top 2% of genes corpus-wide)
• GTEx eGene: eQTL in 46 tissues, sQTL in 19 (q < 0.05)
• Phenotypes (HPO): 21
• Drug target: yes — 1 curated mechanism-of-action drug
• Approved drugs (ChEMBL mechanism of action): 1 — Apadamtase Alfa
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.92 (unconstrained)
• MANE Select transcript: NM_139027

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1366
Approved symbol	ADAMTS13
Name	ADAM metallopeptidase with thrombospondin type 1 motif 13
Location	9q34.2
Locus type	gene with protein product
Status	Approved
Aliases	VWFCP, TTP, vWF-CP, FLJ42993, MGC118899, MGC118900, DKFZp434C2322
Ensembl gene	ENSG00000160323
Ensembl biotype	protein_coding
OMIM	604134
Entrez	11093

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 8 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000355699

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 6, TSL 5: 3

ENST00000355699, ENST00000356589, ENST00000371910, ENST00000371911, ENST00000371916, ENST00000371929, ENST00000474918, ENST00000485925, ENST00000495234, ENST00000908290, ENST00001134857

RefSeq mRNA: 3 — MANE Select: NM_139027 NM_139025, NM_139026, NM_139027

CCDS: CCDS6970, CCDS6971, CCDS6972

Canonical transcript exons

ENST00000355699 — 29 exons

Exon	Start	End
ENSE00001135494	133429939	133430101
ENSE00001668874	133428634	133428771
ENSE00003466340	133442614	133442743
ENSE00003503578	133439366	133439446
ENSE00003507978	133425938	133426062
ENSE00003510596	133426199	133426345
ENSE00003515051	133443376	133443561
ENSE00003530088	133425529	133425612
ENSE00003537605	133436829	133436955
ENSE00003539970	133433378	133433529
ENSE00003543257	133432588	133432692
ENSE00003552932	133423101	133423167
ENSE00003556187	133455285	133455435
ENSE00003559969	133442399	133442534
ENSE00003561184	133457910	133458094
ENSE00003561950	133437749	133437897
ENSE00003579270	133424321	133424478
ENSE00003581683	133458974	133459386
ENSE00003581763	133444863	133445052
ENSE00003613557	133445699	133445819
ENSE00003627054	133454415	133454619
ENSE00003634854	133456543	133456719
ENSE00003650188	133449783	133449965
ENSE00003653630	133438246	133438366
ENSE00003659551	133440344	133440525
ENSE00003676185	133448599	133448728
ENSE00003684694	133456069	133456215
ENSE00003688033	133433641	133433704
ENSE00003904238	133422367	133422548

Expression profiles

Bgee: expression breadth ubiquitous, 132 present calls, max score 94.10.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2127 / max 48.4695, expressed in 84 samples.

Highest expression (Bgee): lobe of liver, liver, hemisphere of cerebellum, uterine tube, cerebellar hemisphere.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ADAMTS13 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 46 tissues and its splicing (sQTL) in 19 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 65 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Skin Sun Exposed Lower leg	eqtl	7.7e-35	+0.61	9:133418269:T:C
Thyroid	eqtl	1.6e-34	+0.49	9:133418269:T:C
Nerve Tibial	eqtl	1.3e-32	+0.55	9:133418269:T:C
Esophagus Mucosa	eqtl	5.3e-29	+0.56	9:133418269:T:C
Skin Not Sun Exposed Suprapubic	eqtl	1.3e-28	+0.61	9:133418269:T:C
Adipose Subcutaneous	eqtl	8.7e-28	+0.55	9:133418269:T:C
Artery Tibial	eqtl	1.5e-26	+0.50	9:133418269:T:C
Heart Atrial Appendage	eqtl	9.8e-23	+0.56	9:133418269:T:C
Esophagus Muscularis	eqtl	1.5e-22	+0.39	9:133418930:G:T
Artery Aorta	eqtl	8.2e-21	+0.51	9:133418269:T:C
Brain Cerebellum	eqtl	2.1e-20	+1.00	9:133347372:C:T
Adipose Visceral Omentum	eqtl	2.9e-20	+0.49	9:133418269:T:C
Brain Cerebellum	sqtl	7.3e-20	+1.01	9:133425943:T:C
Pituitary	eqtl	2.2e-19	-0.62	9:133469936:TGGGAGTGGCATCTGAGGCC:T
Esophagus Gastroesophageal Junction	eqtl	3.8e-18	+0.54	9:133418269:T:C
Whole Blood	eqtl	4.8e-18	+0.39	9:133418269:T:C
Brain Cerebellar Hemisphere	sqtl	6.4e-18	+0.80	9:133425943:T:C
Colon Sigmoid	eqtl	3.0e-17	+0.49	9:133418269:T:C
Cells Cultured fibroblasts	eqtl	5.7e-17	+0.25	9:133418269:T:C
Breast Mammary Tissue	eqtl	9.4e-15	+0.35	9:133418930:G:T

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
99274	0.0982	31
99276	0.0964	37
99275	0.0182	8

Top tissues by expression

showing 100 of 134 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	94.10	gold quality
liver	UBERON:0002107	90.06	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.31	gold quality
right uterine tube	UBERON:0001302	87.50	gold quality
cerebellar hemisphere	UBERON:0002245	87.18	gold quality
cerebellar cortex	UBERON:0002129	87.05	gold quality
cerebellum	UBERON:0002037	86.98	gold quality
right frontal lobe	UBERON:0002810	85.74	gold quality
right testis	UBERON:0004534	85.69	gold quality
left testis	UBERON:0004533	85.64	gold quality
testis	UBERON:0000473	84.52	gold quality
primary visual cortex	UBERON:0002436	84.14	gold quality
pituitary gland	UBERON:0000007	84.05	gold quality
apex of heart	UBERON:0002098	83.52	gold quality
Brodmann (1909) area 9	UBERON:0013540	83.22	gold quality
putamen	UBERON:0001874	82.97	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	82.56	gold quality
adenohypophysis	UBERON:0002196	82.49	gold quality
Ammon’s horn	UBERON:0001954	82.40	gold quality
brain	UBERON:0000955	82.16	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.90	gold quality
anterior cingulate cortex	UBERON:0009835	81.80	gold quality
cerebral cortex	UBERON:0000956	81.73	gold quality
temporal lobe	UBERON:0001871	81.56	gold quality
amygdala	UBERON:0001876	81.53	gold quality
nucleus accumbens	UBERON:0001882	81.52	gold quality
caudate nucleus	UBERON:0001873	81.40	gold quality
frontal cortex	UBERON:0001870	81.35	gold quality
body of stomach	UBERON:0001161	80.49	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	80.09	gold quality
hypothalamus	UBERON:0001898	79.73	gold quality
fundus of stomach	UBERON:0001160	79.72	gold quality
mucosa of transverse colon	UBERON:0004991	79.61	gold quality
substantia nigra	UBERON:0002038	79.53	gold quality
prefrontal cortex	UBERON:0000451	78.85	gold quality
superior frontal gyrus	UBERON:0002661	78.52	gold quality
stomach	UBERON:0000945	78.04	gold quality
left ovary	UBERON:0002119	77.91	gold quality
metanephros cortex	UBERON:0010533	76.84	gold quality
duodenum	UBERON:0002114	76.57	gold quality
right lobe of thyroid gland	UBERON:0001119	76.51	gold quality
right ovary	UBERON:0002118	76.40	gold quality
ovary	UBERON:0000992	76.25	gold quality
heart left ventricle	UBERON:0002084	76.20	gold quality
thyroid gland	UBERON:0002046	75.78	gold quality
right atrium auricular region	UBERON:0006631	75.75	gold quality
cortex of kidney	UBERON:0001225	75.66	gold quality
left lobe of thyroid gland	UBERON:0001120	75.58	gold quality
cortical plate	UBERON:0005343	75.41	gold quality
body of pancreas	UBERON:0001150	75.22	gold quality
lower esophagus mucosa	UBERON:0035834	75.19	gold quality
gastrocnemius	UBERON:0001388	75.17	gold quality
body of uterus	UBERON:0009853	75.09	gold quality
muscle of leg	UBERON:0001383	74.81	gold quality
hindlimb stylopod muscle	UBERON:0004252	74.75	gold quality
prostate gland	UBERON:0002367	74.53	gold quality
heart	UBERON:0000948	74.43	gold quality
transverse colon	UBERON:0001157	74.29	gold quality
myometrium	UBERON:0001296	73.74	gold quality
small intestine Peyer’s patch	UBERON:0003454	73.59	gold quality
muscle layer of sigmoid colon	UBERON:0035805	73.54	gold quality
stromal cell of endometrium	CL:0002255	73.20	gold quality
small intestine	UBERON:0002108	73.14	gold quality
multicellular organism	UBERON:0000468	73.00	gold quality
fallopian tube	UBERON:0003889	72.96	gold quality
right adrenal gland	UBERON:0001233	72.86	gold quality
adult mammalian kidney	UBERON:0000082	72.58	gold quality
colon	UBERON:0001155	72.54	gold quality
right adrenal gland cortex	UBERON:0035827	72.39	gold quality
tibial nerve	UBERON:0001323	72.34	gold quality
intestine	UBERON:0000160	72.24	gold quality
endocervix	UBERON:0000458	72.07	gold quality
right coronary artery	UBERON:0001625	71.90	gold quality
left uterine tube	UBERON:0001303	71.73	gold quality
lower esophagus	UBERON:0013473	71.63	gold quality
lower esophagus muscularis layer	UBERON:0035833	71.63	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	71.63	gold quality
left adrenal gland cortex	UBERON:0035825	71.34	gold quality
ascending aorta	UBERON:0001496	71.16	gold quality
ventricular zone	UBERON:0003053	71.06	gold quality
thoracic aorta	UBERON:0001515	71.03	gold quality
mucosa of stomach	UBERON:0001199	70.98	gold quality
vagina	UBERON:0000996	70.90	gold quality
left adrenal gland	UBERON:0001234	70.78	gold quality
ganglionic eminence	UBERON:0004023	70.72	gold quality
kidney	UBERON:0002113	70.43	gold quality
thoracic mammary gland	UBERON:0005200	70.40	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	70.37	gold quality
ectocervix	UBERON:0012249	70.30	gold quality
esophagus	UBERON:0001043	70.28	gold quality
pancreas	UBERON:0001264	70.15	gold quality
omental fat pad	UBERON:0010414	69.97	gold quality
skin of abdomen	UBERON:0001416	69.96	gold quality
left coronary artery	UBERON:0001626	69.89	gold quality
right lung	UBERON:0002167	69.86	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	69.71	gold quality
descending thoracic aorta	UBERON:0002345	69.58	gold quality
esophagus mucosa	UBERON:0002469	69.57	gold quality
muscle tissue	UBERON:0002385	69.55	gold quality
minor salivary gland	UBERON:0001830	69.48	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-130473	yes	502.60
E-ANND-3	no	0.86

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Pituitary gland	tissue	12.4
Liver	tissue	12.2	not detected
Hippocampus	tissue	5.1	not detected
Postcentral gyrus	tissue	4.6
Stomach 1	tissue	4.4	not detected
Nucleus accumbens	tissue	4.2
Locus coeruleus	tissue	3.9
Vagina	tissue	3.0	not detected
Duodenum	tissue	3.0	not detected
Epididymis	tissue	2.8	not detected
Testis	tissue	2.4	high
Skin 1	tissue	2.3	not detected
Skeletal muscle	tissue	2.1	not detected
Hypothalamus	tissue	1.9
Small intestine	tissue	1.7	not detected
Choroid plexus	tissue	1.6
Ovary	tissue	1.5	not detected
Fallopian tube	tissue	1.5	medium
Parathyroid gland	tissue	1.4	not detected
Pancreas	tissue	1.4	not detected
Heart muscle	tissue	1.3	not detected
Seminal vesicle	tissue	1.3	not detected
Endometrium 1	tissue	1.3	not detected
Tongue	tissue	1.3
Thyroid gland	tissue	1.3	not detected
Septum	tissue	1.3
Salivary gland	tissue	1.2	not detected
Basal ganglia	tissue	1.2	not detected
Putamen	tissue	1.2
Gallbladder	tissue	1.2	not detected
Periaqueductal gray	tissue	1.2
Colon	tissue	1.1	not detected
Prostate	tissue	1.1	not detected
Ventral forebrain	tissue	1.1
Retina	tissue	1.0
Pons	tissue	1.0
Lymph node	tissue	0.9	not detected
Rectum	tissue	0.9	not detected
Medulla oblongata	tissue	0.9
Cerebellum	tissue	0.9	not detected
Adipose tissue	tissue	0.8	not detected
Midbrain	tissue	0.8
Thalamus	tissue	0.8
Spinal cord	tissue	0.8
Adrenal gland	tissue	0.8	not detected
Cerebral cortex	tissue	0.7	not detected
Amygdala	tissue	0.7
Placenta	tissue	0.7	not detected
Substantia nigra	tissue	0.7
Lung	tissue	0.7	not detected
Kidney	tissue	0.7	not detected
Corpus callosum	tissue	0.7
Thymus	tissue	0.7
Insular cortex	tissue	0.7
Prefrontal cortex	tissue	0.6
Esophagus	tissue	0.6	not detected
Smooth muscle	tissue	0.6	not detected
Urinary bladder	tissue	0.6	not detected
Motor cortex	tissue	0.6
Superior colliculi	tissue	0.6

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Precentral gyrus (7.7), Inferior frontal gyrus, opercular (6.7), Vermis (6.4), Temporo-occipital transitional zone (6.3), Supplementary motor cortex (6.2).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EGR1, ELK1, SP1, STAT3

miRNA regulators (miRDB)

Targeting ADAMTS13 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

12 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-3978	99.24	68.39	2201
HSA-MIR-4520-2-3P	99.14	69.28	1009
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-5703	99.10	67.09	2053
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-1263	98.13	69.18	459
HSA-MIR-7850-5P	98.12	67.28	1111
HSA-MIR-596	97.48	63.13	469
HSA-MIR-4462	95.10	66.27	172

Functional genomics

gnomAD constraint: pLI 1e-29, LOEUF 0.917, missense Z 0.927 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000355699 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
9:133,422,444–133,438,248	733 / 749.6	0.98	no
9:133,438,249–133,438,326	13 / 34.2	0.38	no
9:133,438,327–133,459,177	961 / 1107.9	0.87	no
ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• incodes a zinc proteinase involved in thrombotic thrombocytopenic purpura (PMID:11586344)
• mutation of gene causes thrombotic thrombocytopenic purpura (PMID:11586351)
• VWF-CPis composed of a single polypeptide with a molecular mass of approx. 190 kD,and cDNA cloning indicated it is uniquely produced in the liver. Its gene is on chromosome 9q34. (PMID:11843286)
• role of the vWF protease and vWF proteolysis in the pathogenesis of bone marrow transplant-associated thrombotic microangiopathy of the fulminant type (PMID:11920264)
• Complete defect in vWF-cleaving protease activity is associated with increased shear-induced platelet aggregation in thrombotic microangiopathy. (PMID:12038781)
• An acquired deficiency of vWF-CP due to an autoantibody is associated with responsiveness to plasma exchange therapy in TTP. Patients whose TTP is not caused by autoimmunity to vWF-CP may not respond to PE. (PMID:12084165)
• Deficiency of vWF-cp activity in patients with colon cancer was shown to be associated with the progression of the disease and metastasis. (PMID:12091044)
• A severely deficient activity is specific for thrombotic thrombocytopenic purpura. (PMID:12091372)
• ADAMTS13 is deficient in recurrent and familial thrombotic thrombocytopenic purpura and hemolytic uremic syndrome; its activity level cannot be used to distingush between TTP and HUS. (PMID:12130486)
• REVIEW: role of ADAMTS13 mutations and deficiencies in thrombotic microangiopathies (PMID:12172456)
• mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity (PMID:12181489)
• role of variation in modulating risk of thrombosis in cardiovascular disorders (PMID:12195022)
• a sensitive blood indicator for diagnosing thrombocytopenic thrombotic purpura (PMID:12223999)
• ADAMTS-13 rapidly cleaves newly secreted ultralarge VWF multimers on the vascular endothelial surface under flowing conditions (PMID:12393397)
• Cloning, expression, and functional characterization of the von Willebrand factor-cleaving protease (ADAMTS13). (PMID:12393399)
• Mutation analysis of the ADAMTS13 gene in the childhood TTP patients deficient in VWF-CP by direct sequencing of all 29 exons identified 8 different mutations. (PMID:12393505)
• vWF proteolysis by ADAMTS13 is critical in regulating vWF-platelet interaction and set the stage for improving the diagnosis and treatment of thrombotic thrombocytopenic purpura. (PMID:12395148)
• This article reviews the role of this cleavage in regulating vWF-platelet interaction and proposes a scheme for understanding how a deficiency of ADAMTS13 results in the development of microthrombi in patients with thrombotic thrombocytopenic purpura. (PMID:12615692)
• deficiency of ADAMTS13 is a molecular mechanism responsible for familial thrombotic thrombocytopenic purpura (PMID:12753286)
• high titers of IgM and IgG antibodies that bound to ADAMTS-13, but did not neutralize protease activity, in a patient with thrombotic thrombocytopenic purpura probably influenced the half-life of ADAMTS-13 or its binding to the endothelial cell surface. (PMID:12855569)
• truncation of the cysteine-rich/spacer domains caused a remarkable reduction in VWF-CP activity (PMID:12869506)
• REVIEW: mechanisms by which defects in ADAMTS13 cause TTP (PMID:12871390)
• REVIEW: defects in ADAMTS13 cause TTP and HUS (PMID:12871391)
• Acquired deficiency of this enzyme causes Schistocytic anaemia, severe thrombocytopenia, and renal dysfunction (PMID:12923577)
• The ADAMTS13 propeptide is not required for folding or secretion, and does not perform the common function of maintaining enzyme latency. (PMID:12975358)
• VWF73 is a specific substrate for ADAMTS-13 (PMID:14512308)
• Severe deficiency of the von Willebrand Factor (VWF)-cleaving proteinase, ADAMTS13, is associated with the development of thrombotic thrombocytopenic purpura (PMID:14512317)
• an amino acid polymorphism in VWF may influence susceptibility to ADAMTS13 proteolysis (PMID:14525793)
• Molecular models of the metalloprotease, fifth domain of thrombospondin 1 (Tsp1-5), and Tsp1-8 domains of ADAMTS13 suggest that the missense mutations could cause structural defects in the mutants. (PMID:14563640)
• No significant difference in ADAMTS-13 activity between the age- and sex-matched patients with benign and malignant brain tumors nor between the age matched patients with prostatic cancer. (PMID:14644076)
• REVIEW: role in thrombotic thrombocytopenic purpura (PMID:14727254)
• REVIEW: processing of von Willebrand factor by ADAMTS-13 on endothelial cells (PMID:14727255)
• REVIEW: recent advances in cell culture expression and functional characterization of human rADAMTS-13 (PMID:14727256)
• REVIEW: mutations in hereditary thrombotic thrombocytopenic purpura (PMID:14727257)
• the substitution of ADAMTS-13 by means of recombinant drug instead of plasma (PMID:14727259)
• REVIEW: ADAMTS-13 deficiency in childhood (PMID:14727263)
• thrombotic microangiopathy with severe ADAMTS13 deficiency is a distinct pathologic process. (PMID:14962303)
• ADAMTS13 auto-antibodies from 25 patients with severe ADAMTS13 deficiency (acquired thrombotic thrombocytopenia purpura) was evaluated in vitro (PMID:14976043)
• Role of ADAMTS13 mutations in the pathogenesis of congenital thrombotic thrombocytopenic purpura. (PMID:15009458)
• The metalloprotease ADAMTS-13 cleaves von Willebrand factor (VWF) at the Y842/M843 peptide bond located in the A2 domain. (PMID:15009467)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	adamts13	ENSDARG00000076270
mus_musculus	Adamts13	ENSMUSG00000014852
rattus_norvegicus	Adamts13	ENSRNOG00000005780

Paralogs (25): ADAMTS6 (ENSG00000049192), ADAMTS2 (ENSG00000087116), PAPLN (ENSG00000100767), ADAMTS8 (ENSG00000134917), ADAMTS7 (ENSG00000136378), ADAMTS14 (ENSG00000138316), ADAMTS17 (ENSG00000140470), ADAMTS18 (ENSG00000140873), ADAMTS10 (ENSG00000142303), ADAMTSL4 (ENSG00000143382), ADAMTS16 (ENSG00000145536), ADAMTS19 (ENSG00000145808), ADAMTS12 (ENSG00000151388), ADAMTS1 (ENSG00000154734), ADAMTS5 (ENSG00000154736), ADAMTS3 (ENSG00000156140), ADAMTSL3 (ENSG00000156218), ADAMTS4 (ENSG00000158859), ADAMTS9 (ENSG00000163638), ADAMTS15 (ENSG00000166106), ADAMTS20 (ENSG00000173157), ADAMTSL1 (ENSG00000178031), ADAMTSL5 (ENSG00000185761), THSD4 (ENSG00000187720), ADAMTSL2 (ENSG00000197859)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2685556) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 10 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal thrombosis	2
increased susceptibility to induced thrombosis	2
premature death	1
increased susceptibility to bacterial infection	1
abnormal erythrocyte morphology	1
abnormal blood coagulation	1
thrombocytopenia	1
abnormal platelet physiology	1
abnormal platelet activation	1
increased circulating von Willebrand factor level	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pongo abelii	Q5RFQ8	98.7%	Diamond
Bos taurus	Q9TT92	98.1%	Diamond
Xenopus laevis	C5IAW9	96.9%	Diamond
Oryctolagus cuniculus	P98137	83.2%	Diamond
Gallus gallus	P35440	80.4%	Diamond
Oncorhynchus mykiss	Q90X85	70.2%	Diamond
Paralichthys olivaceus	Q9PVW7	70.2%	Diamond
Acropora millepora	B3EWZ3	58.7%	Diamond
Drosophila melanogaster	Q9VTT0	52.0%	Diamond
Caenorhabditis elegans	Q20930	44.6%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
SLC2A6	protein-coding	11182
STKLD1	protein-coding	169436
REXO4	protein-coding	57109
SURF4	protein-coding	6836
CACFD1	protein-coding	11094
MYMK	protein-coding	389827
SURF1	protein-coding	6834
SURF2	protein-coding	6835
SNORD36C	snoRNA	26813
RPL7A	protein-coding	6130

Protein

Protein identifiers

A disintegrin and metalloproteinase with thrombospondin motifs 13 — Q76LX8 (reviewed: Q76LX8)

Alternative names: von Willebrand factor-cleaving protease

All UniProt accessions (5): A0A0B4J229, A0A0C4DFV8, E7EV88, Q76LX8, F6V803

UniProt curated annotations — full annotation on UniProt →

Function. Cleaves the vWF multimers in plasma into smaller forms thereby controlling vWF-mediated platelet thrombus formation.

Subcellular location. Secreted.

Tissue specificity. Plasma. Expressed primarily in liver.

Post-translational modifications. Glycosylated. O-fucosylated by POFUT2 on a serine or a threonine residue found within the consensus sequence C1-X(2)-(S/T)-C2-G of the TSP type-1 repeat domains where C1 and C2 are the first and second cysteine residue of the repeat, respectively. Fucosylated repeats can then be further glycosylated by the addition of a beta-1,3-glucose residue by the glucosyltransferase, B3GALTL. Fucosylation mediates the efficient secretion of ADAMTS13. May also be C-glycosylated on tryptophan residues within the consensus sequence W-X-X-W of the TPRs, and also N-glycosylated. These other glycosylations can also facilitate secretion. The precursor is processed by a furin endopeptidase which cleaves off the pro-domain.

Disease relevance. Thrombotic thrombocytopenic purpura, hereditary (TTP) [MIM:274150] An autosomal recessive hematologic disease characterized by hemolytic anemia with fragmentation of erythrocytes, thrombocytopenia, diffuse and non-focal neurologic findings, decreased renal function and fever. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Zinc and calcium ions cooperatively modulate enzyme activity. The cleavage of the pro-domain is not required for protease activity. Dependence on calcium for proteolytic activity is mediated by the high affinity site.

Cofactor. Binds 1 zinc ion per subunit. Binds 4 Ca(2+) ions.

Domain organisation. The pro-domain is not required for folding or secretion and does not perform the common function of maintening enzyme latency. The globular cysteineless spacer domain adopts a jelly-roll topology, and is necessary to recognize and cleave vWF. The C-terminal TSP type-1 and CUB domains may modulate this interaction.

Polymorphism. Genetic variations in ADAMTS13 coding region influence plasmatic ADAMTS13 activity levels. Dependent on the sequence context, the same polymorphisms might be either positive or negative modifiers of gene expression, thereby altering the phenotype of ADAMTS13 deficiency.

Isoforms (4)

UniProt ID	Names	Canonical?
Q76LX8-1	1	yes
Q76LX8-2	2
Q76LX8-3	3
Q76LX8-4	4

RefSeq proteins (3): NP_620594, NP_620595, NP_620596* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000884	TSP1_rpt	Repeat
IPR001590	Peptidase_M12B	Domain
IPR006586	ADAM_Cys-rich	Domain
IPR010294	ADAMTS_spacer1	Domain
IPR013273	ADAMTS/ADAMTS-like	Family
IPR024079	MetalloPept_cat_dom_sf	Homologous_superfamily
IPR035914	Sperma_CUB_dom_sf	Homologous_superfamily
IPR036383	TSP1_rpt_sf	Homologous_superfamily
IPR041645	ADAMTS_CR_2	Domain
IPR045371	ADAMTS_CR_3	Domain
IPR050439	ADAMTS_ADAMTS-like	Family

Pfam: PF00090, PF01421, PF05986, PF17771, PF19030, PF19236

Enzyme classification (BRENDA)

• EC 3.4.24.87 — ADAMTS13 endopeptidase (BRENDA: 8 organisms, 140 substrates, 55 inhibitors, 28 Km, 22 kcat entries)

Substrate kinetics (BRENDA)

9 substrates with measured Km, best-characterized 9. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
VWF73 PEPTIDE	0.0017–0.022	8
VWF115	0.0009–0.59	4
FRET-VWF115 PEPTIDE	0.0013–0.0043	2
VON WILLEBRAND FACTOR 115	0.0006–0.0016	2
VWF115 D1614A MUTANT	0.37–0.47	2
DREQAPNLVYMVTGNPASDEIKRLPGDIQVVPIGVGPNANVQELERIG	0.0066	1
FRETS-VON WILLEBRAND FACTOR 73	0.0032	1
FRETSVWF73 PEPTIDE	0.0058	1
HRPH-A2-B	0.0003	1

UniProt features (227 total): sequence variant 61, strand 55, helix 23, glycosylation site 18, disulfide bond 15, mutagenesis site 14, domain 12, binding site 11, splice variant 5, turn 4, region of interest 3, signal peptide 1, propeptide 1, sequence conflict 1, short sequence motif 1, active site 1, chain 1

Structure

Experimental structures (PDB)

5 structures by resolution:

PDB	Title	Method	Resolution (Å)
3GHM	Crystal structure of the exosite-containing fragment of human ADAMTS13 (form-1)	X-RAY DIFFRACTION	2.6
3GHN	Crystal structure of the exosite-containing fragment of human ADAMTS13 (form-2)	X-RAY DIFFRACTION	2.8
3VN4	Crystal structure of the exosite-containing fragment of human ADAMTS13 (P475S mutant)	X-RAY DIFFRACTION	2.8
6QIG	Metalloproteinase	X-RAY DIFFRACTION	2.8
7B01	ADAMTS13-CUB12	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q76LX8-F1	76.00	0.31

Antibody-complex structures (SAbDab)

1 antibodies co-crystallized with this protein: 6QIG

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Predicted secreted proteins, Predicted intracellular proteins, Plasma proteins, Disease related genes, Potential drug targets, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): vesicles

Antibody reliability (HPA): IH approved · IF uncertain

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1)

Position	Role
225

Ligand- & substrate-binding residues (11)

Position	Role
83	Ca(2+)
173	Ca(2+)
182	Ca(2+)
184	Ca(2+)
187	Ca(2+)
212	Ca(2+)
224	Zn(2+)
228	Zn(2+)
234	Zn(2+)
281	Ca(2+)
284	Ca(2+)

Disulfide bonds (15)

Type	Positions
Disulfide bond	155–208, 202–281, 242–265, 311–337, 322–347, 332–366, 360–371, 396–433, 400–438, 411–423, 450–487, 483–522, 508–527, 532–548, 545–555

Glycosylation sites (18)

Type	Positions
N-linked (glcnac…) asparagine	142, 146, 552, 579, 614, 828, 1235, 1354
C-linked (man) tryptophan	387
O-linked (fuc…) serine	399, 698, 757, 907, 965, 1027, 1087
N-linked (glcnac…) (complex) asparagine	667, 707

Mutagenesis-validated functional residues (14)

Position	Phenotype
71	abolishes pro-domain removal but no loss of proteolytic activity; when associated with d-73.
73	abolishes pro-domain removal but no loss of proteolytic activity; when associated with k-71.
83	no change in calcium dependence for proteolysis.
173	no change in calcium dependence for proteolysis.
184	dramatically reduced affinity for calcium.
187	dramatically reduced affinity for calcium.
212	dramatically reduced affinity for calcium.
399	no effect on cleavage of vwf and little change in secretion of adamts13. abolishes secretion of adamts13; when associated with a-698.
698	no effect on cleavage of vwf and greatly reduced secretion of adamts13. abolishes secretion of adamts13; when associated with a-399.
757	no effect on cleavage of vwf and little change in secretion of adamts13.
907	no effect on cleavage of vwf and greatly reduced secretion of adamts13. abolishes most of the secretion of adamts13; when associated with …
965	no effect on cleavage of vwf and little change in secretion of adamts13. abolishes most of the secretion of adamts13; when associated with …
1027	no effect on cleavage of vwf and little change in secretion of adamts13. abolishes most of the secretion of adamts13; when associated with …
1087	no effect on cleavage of vwf and little change in secretion of adamts13. abolishes most of the secretion of adamts13; when associated with …

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 16; 9 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

16 pathways:

ID	Pathway	Evidence
R-HSA-9769739	Regulation of clotting cascade	curated
R-HSA-5083635	Defective B3GALTL causes PpS ⚕	—
R-HSA-9845621	Defective VWF cleavage by ADAMTS13 variant ⚕	—
R-HSA-9823587	Defects of platelet adhesion to exposed collagen ⚕	—
R-HSA-1643685	Disease ⚕	—
R-HSA-3906995	Diseases associated with O-glycosylation of proteins ⚕	—
R-HSA-3781865	Diseases of glycosylation ⚕	—
R-HSA-9671793	Diseases of hemostasis ⚕	—
R-HSA-5668914	Diseases of metabolism ⚕	—
R-HSA-9845619	Enhanced cleavage of VWF variant by ADAMTS13 ⚕	—
R-HSA-109582	Hemostasis	—
R-HSA-392499	Metabolism of proteins	—
R-HSA-5173214	O-glycosylation of TSR domain-containing proteins	—
R-HSA-5173105	O-linked glycosylation	—
R-HSA-75892	Platelet Adhesion to exposed collagen	—
R-HSA-597592	Post-translational protein modification	—

MSigDB gene sets: 151 (showing top): GCACCTT_MIR18A_MIR18B, TGGTGCT_MIR29A_MIR29B_MIR29C, RNGTGGGC_UNKNOWN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, FREAC2_01, GOBP_RESPONSE_TO_AMINE, GOMF_METALLOPEPTIDASE_ACTIVITY, GOBP_RESPONSE_TO_INTERLEUKIN_4, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_PLATELET_ACTIVATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOCC_CELL_SURFACE, GOBP_RESPONSE_TO_POTASSIUM_ION

GO Biological Process (21): proteolysis (GO:0006508), cell-matrix adhesion (GO:0007160), integrin-mediated signaling pathway (GO:0007229), blood coagulation (GO:0007596), glycoprotein metabolic process (GO:0009100), response to toxic substance (GO:0009636), response to amine (GO:0014075), protein processing (GO:0016485), protein catabolic process (GO:0030163), platelet activation (GO:0030168), extracellular matrix organization (GO:0030198), response to potassium ion (GO:0035864), peptide catabolic process (GO:0043171), cellular response to lipopolysaccharide (GO:0071222), cellular response to type II interferon (GO:0071346), cellular response to interleukin-4 (GO:0071353), cellular response to tumor necrosis factor (GO:0071356), hemostasis (GO:0007599), response to type II interferon (GO:0034341), response to tumor necrosis factor (GO:0034612), response to interleukin-4 (GO:0070670)

GO Molecular Function (10): metalloendopeptidase activity (GO:0004222), integrin binding (GO:0005178), calcium ion binding (GO:0005509), metallopeptidase activity (GO:0008237), zinc ion binding (GO:0008270), endopeptidase activity (GO:0004175), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (4): extracellular region (GO:0005576), endoplasmic reticulum lumen (GO:0005788), cell surface (GO:0009986), extracellular matrix (GO:0031012)

Reactome top-level categories

11 top-level categories:

Category	Pathways
Defects of platelet adhesion to exposed collagen	2
Disease	2
Diseases associated with O-glycosylation of proteins	1
O-linked glycosylation	1
Hemostasis	1
Coagulation pathway	1
Diseases of metabolism	1
Diseases of glycosylation	1
Post-translational protein modification	1
Metabolism of proteins	1
Diseases of hemostasis	1

GO top-level categories

47 GO namespaces:

Category	Terms
protein metabolic process	3
cellular response to cytokine stimulus	3
response to cytokine	2
peptidase activity	2
cellular anatomical structure	2
cell-substrate adhesion	1
cell surface receptor signaling pathway	1
hemostasis	1
wound healing	1
coagulation	1
carbohydrate derivative metabolic process	1
response to chemical	1
response to nitrogen compound	1
proteolysis	1
protein maturation	1
macromolecule catabolic process	1
cell activation	1
blood coagulation	1
extracellular structure organization	1
external encapsulating structure organization	1
response to metal ion	1
peptide metabolic process	1
catabolic process	1
response to lipopolysaccharide	1
cellular response to molecule of bacterial origin	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
response to type II interferon	1
response to interleukin-4	1
response to tumor necrosis factor	1
regulation of body fluid levels	1
innate immune response	1
endopeptidase activity	1
metallopeptidase activity	1
signaling receptor binding	1
protein-containing complex binding	1
cell adhesion molecule binding	1
metal ion binding	1
transition metal ion binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
cation binding	1
endoplasmic reticulum	1
intracellular organelle lumen	1
external encapsulating structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 3 of 36 annotations. The rest are phylogenetic / computational / electronic (IEA).

3 experimentally-supported GO terms:

GO term	NS	Evidence
peptide catabolic process	BP	direct assay
proteolysis	BP	direct assay
metalloendopeptidase activity	MF	experiment

Protein interactions and networks

STRING

showing 15 of 840 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADAMTS13	VWF	P04275	981
ADAMTS13	F8	P00451	929
ADAMTS13	GP1BA	P07359	887
ADAMTS13	CFHR1	Q03591	841
ADAMTS13	CFH	P08603	840
ADAMTS13	CFHR3	Q02985	827
ADAMTS13	HP	P00737	769
ADAMTS13	DGKE	P52429	747
ADAMTS13	THBD	P07204	730
ADAMTS13	C3	P01024	724
ADAMTS13	F3	P13726	720
ADAMTS13	F2	P00734	717
ADAMTS13	CFI	P05156	717
ADAMTS13	CD46	P15529	702
ADAMTS13	CFHR5	Q9BXR6	655

IntAct

Human interaction partners of ADAMTS13 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

3 partners by confidence:

Partner	Interaction type	MIscore	Records
VWF	protein cleavage	0.790	19
F8	direct interaction	0.440	1
C2CD4B	association	0.350	1

BioGRID (24 interactions; top human partners by supporting records): AGGF1 (Affinity Capture-MS), ALDH18A1 (Affinity Capture-MS), ARMCX3 (Affinity Capture-MS), B3GALTL (Affinity Capture-MS), C2CD4B (Affinity Capture-MS), CELSR1 (Affinity Capture-MS), CELSR2 (Affinity Capture-MS), DICER1 (Affinity Capture-MS), FAT3 (Affinity Capture-MS), FAT4 (Affinity Capture-MS), FREM2 (Affinity Capture-MS), FZD3 (Affinity Capture-MS), HERC1 (Affinity Capture-MS), KIAA0232 (Affinity Capture-MS), KIAA0754 (Affinity Capture-MS)

SIGNOR signaling

3 signaling interactions:

A	Effect	B	Mechanism
HBB	“down-regulates activity”	ADAMTS13
HBA1	“down-regulates activity”	ADAMTS13
ADAMTS13	“down-regulates activity”	VWF	cleavage

Disease & clinical

Genetic variants

Variant evidence for ADAMTS13: 1,253 ClinVar records (133 pathogenic / likely pathogenic); 18 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

1,253 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	62
Likely pathogenic	71
Uncertain significance	495
Likely benign	355
Benign	68

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 133 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
5807	NM_139027.6(ADAMTS13):c.3975dup (p.Glu1326fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	8
5801	NM_139027.6(ADAMTS13):c.587C>T (p.Thr196Ile)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
68805	NM_139027.6(ADAMTS13):c.1787C>T (p.Ala596Val)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
2636095	NM_139027.6(ADAMTS13):c.1456_1457del (p.Met486fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
5809	NM_139027.6(ADAMTS13):c.2074C>T (p.Arg692Cys)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
68802	NM_139027.6(ADAMTS13):c.1520G>A (p.Arg507Gln)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
1804165	NM_139027.6(ADAMTS13):c.1169G>A (p.Trp390Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
2004982	NM_139027.6(ADAMTS13):c.2920_2938del (p.Ile974fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
2136834	NM_139027.6(ADAMTS13):c.3198_3199del (p.Cys1067fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1163512	NM_139027.6(ADAMTS13):c.3488G>A (p.Arg1163Gln)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
1323853	NM_139027.6(ADAMTS13):c.1492C>T (p.Arg498Cys)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
1700239	NM_139027.6(ADAMTS13):c.1192C>T (p.Arg398Cys)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
2683660	NM_139027.6(ADAMTS13):c.305G>A (p.Arg102His)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
1163035	NM_139027.6(ADAMTS13):c.2068G>A (p.Ala690Thr)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
2500705	NM_139027.6(ADAMTS13):c.1705+1G>A	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2

Per-variant reference — Sugi Variant

Explore ADAMTS13’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 28 predictions of 2,490):

Position(s)	Effect	Δscore	Sites
9:133426346–133426347	donor_loss	1.0000	4
9:133440419–133440420	acceptor_gain	1.0000	2
9:133440526	donor_loss	1.0000	2
9:133440535	donor_gain	1.0000
9:133454620–133454621	donor_loss	1.0000	2
9:133422549–133422550	donor_loss	0.9900	4
9:133424319–133424320	acceptor_loss	0.9900	6
9:133424479–133424480	donor_loss	0.9900	5
9:133424483	donor_loss	0.9900
9:133426195	acceptor_gain	0.9900

AlphaMissense

1,722 missense substitutions predicted likely pathogenic (of 8,881 scored), across 452 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M249	9	0.834	0.971
D213	8	0.947	0.991
H228	8	0.944	0.972
H224	8	0.935	0.970
D543	8	0.905	0.968
D235	8	0.888	0.950
D173	8	0.884	0.941
F573	8	0.871	0.976
H234	8	0.849	0.934
F530	8	0.838	0.974
C337	7	0.979	0.990
C155	7	0.976	0.989
C208	7	0.976	0.987
C311	7	0.973	0.992
C322	7	0.970	0.983
C332	7	0.968	0.988
C522	7	0.967	0.985
C360	7	0.965	0.989
C366	7	0.963	0.986
C202	7	0.960	0.981

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Pancreatic Adenocarcinoma (TCGA)	favorable	0.000239
Glioblastoma Multiforme (validation)	favorable	0.000715

Disease associations

OMIM: gene MIM:604134 | disease phenotypes: MIM:274150

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
congenital thrombotic thrombocytopenic purpura	Strong	Autosomal recessive	4

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

1 validity classifications:

Disease	Classification	Inheritance
congenital thrombotic thrombocytopenic purpura	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (8 panels, 5 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

8 panels:

Panel	Rating
Bleeding and platelet disorders	green
Cytopenias and congenital anaemias	green
Inherited bleeding disorders	green
Thrombophilia with a likely monogenic cause	green
Vascular skin disorders	green
Atypical haemolytic uraemic syndrome	amber
Cytopenia - NOT Fanconi anaemia	amber
Unexplained young onset end-stage renal disease	amber

Mondo (3): congenital thrombotic thrombocytopenic purpura (MONDO:0010122), thrombotic thrombocytopenic purpura (MONDO:0018896), thrombocytopenia (MONDO:0002049)

Orphanet (2): Congenital thrombotic thrombocytopenic purpura (Orphanet:93583), Thrombotic thrombocytopenic purpura (Orphanet:54057)

HPO phenotypes

21 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000093	Proteinuria
HP:0000952	Jaundice
HP:0001289	Confusion
HP:0001297	Stroke
HP:0001337	Tremor
HP:0001658	Myocardial infarction
HP:0001873	Thrombocytopenia
HP:0001923	Reticulocytosis
HP:0001937	Microangiopathic hemolytic anemia
HP:0001945	Fever
HP:0001981	Schistocytosis
HP:0002098	Respiratory distress
HP:0002151	Increased circulating lactate concentration
HP:0002326	Transient ischemic attack
HP:0002907	Microscopic hematuria
HP:0003138	Increased blood urea nitrogen
HP:0003259	Elevated circulating creatinine concentration
HP:0005575	Hemolytic-uremic syndrome
HP:0006579	Prolonged neonatal jaundice
HP:0012211	Abnormal renal physiology

GWAS associations

18 associations:

Study	Trait	p-value
GCST001793_4	Coagulation factor levels	1e-128
GCST001574_9	Activated partial thromboplastin time	9e-100
GCST002881_3	ADAMTS13 activity	1e-63
GCST005945_1	ADAMTS13 levels	1e-57
GCST001793_1	Coagulation factor levels	4e-34
GCST005945_3	ADAMTS13 levels	1e-30
GCST000248_5	Liver enzyme levels	8e-21
GCST010725_6	Malaria	9e-21
GCST002881_1	ADAMTS13 activity	1e-20
GCST010725_73	Malaria	1e-19
GCST002553_4	Pancreatic cancer	2e-16
GCST010725_94	Malaria	9e-11
GCST90002389_406	Lymphocyte percentage of white cells	9e-11
GCST005945_4	ADAMTS13 levels	9e-9
GCST004598_3	vWF levels in ischaemic stroke and hyperhomocysteinaemia	6e-8
GCST006491_13	Circulating fibroblast growth factor 23 levels	1e-7
GCST003854_55	Gut microbiota (functional units)	3e-6
GCST002930_12	Cobalt levels	5e-6

EFO canonical traits (from GWAS)

5 canonical traits:

EFO ID	Trait name
EFO:0004533	alkaline phosphatase measurement
EFO:0006955	ADAMTS13 activity measurement
EFO:0007874	gut microbiome measurement
EFO:0008011	a disintegrin and metalloproteinase with thrombospondin motifs 13 measurement
EFO:0007993	lymphocyte percentage of leukocytes

MeSH disease descriptors

2 disease descriptors:

Descriptor	Name	Tree numbers
D011697	Purpura, Thrombotic Thrombocytopenic	C15.378.100.802.687.680; C15.378.140.855.925.750.680; C15.378.243.937.925.750.680; C15.378.925.850; C23.550.414.950.687.680; C23.888.885.687.687.680
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2346492 (SINGLE PROTEIN)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the ADAMTS13 protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

1 curated-mechanism drugs:

Drug	Modality	Max phase
APADAMTASE ALFA	Enzyme	4

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — M12: Astacin/Adamalysin

Binding affinities (BindingDB)

1 measured of 4 human assays (4 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(5S)-5-cyclopropyl-5-[3-[(3S)-4-(3,5-difluorophenyl)-3-methylpiperazin-1-yl]-3-oxopropyl]imidazolidine-2,4-dione	IC50	1160 nM	US-9926281: 5-[(piperazin-1-yl)-3-oxo-propyl]-imidazolidine-2,4-dione derivatives as ADAMTS inhibitors for the treatment of osteoarthritis

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases mutagenesis, affects expression	2
Cisplatin	affects cotreatment, increases expression, decreases expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
afuresertib	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
benzo(e)pyrene	decreases methylation	1
bisphenol Z	increases expression	1
jinfukang	affects cotreatment, increases expression	1
Air Pollutants	increases abundance, increases expression	1
Methapyrilene	decreases methylation	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Toluene	decreases expression, increases methylation	1
Paclitaxel	affects cotreatment, decreases expression	1
Okadaic Acid	decreases expression	1
Acrylamide	decreases expression	1
Particulate Matter	increases abundance, increases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2352582	Binding	Inhibition of ADAMTS-13 (unknown origin)	A series of thiazole derivatives bearing thiazolidin-4-one as non-competitive ADAMTS-5 (aggrecanase-2) inhibitors. — *Bioorg Med Chem Lett*

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 82 trials:

NCT	Phase	Status	Title
NCT04767828	Phase 4	UNKNOWN	A Single Arm Study of Brain Metastasis in Patients With HER2-positive Breast Cancer
NCT02574403	Phase 4	COMPLETED	Study Assessing an Algorithm-based Strategy of Eculizumab Discontinuation in Children and Adults With aHUS
NCT07308574	Phase 4	RECRUITING	Post-Marketing Clinical Study of Ravulizumab in Participants With Clinical aHUS
NCT00411801	Phase 3	TERMINATED	Safety and Efficacy Study to Compare Uniplas With Cryosupernatant Plasma in Thrombotic Thrombocytopenic Purpura (TTP)
NCT00713193	Phase 3	COMPLETED	Study of Cyclosporine or Corticosteroids as an Adjunct to Plasma Exchange in Thrombotic Thrombocytopenic Purpura (TTP)
NCT00799773	Phase 3	TERMINATED	Evaluating the Effectiveness of Adding Rituximab to Standard Treatment for Thrombotic Thrombocytopenic Purpura (TTP)
NCT03237819	Phase 3	UNKNOWN	Magnesium Sulfate in Thrombotic Thrombocytopenic Purpura in Intensive Care
NCT03393975	Phase 3	COMPLETED	A Study of BAX 930 in Children, Teenagers, and Adults Born With Thrombotic Thrombocytopenic Purpura (TTP)
NCT04683003	Phase 3	ACTIVE_NOT_RECRUITING	A Study of TAK-755 in Participants With Congenital Thrombotic Thrombocytopenic Purpura
NCT05468320	Phase 3	COMPLETED	Caplacizumab and Immunosuppressive Therapy Without Firstline Therapeutic Plasma Exchange in Adults With Immune-mediated Thrombotic Thrombocytopenic Purpura
NCT02949128	Phase 3	COMPLETED	Study of ALXN1210 in Complement Inhibitor Treatment-Naïve Adult and Adolescent Participants With Atypical Hemolytic Uremic Syndrome (aHUS)
NCT03131219	Phase 3	COMPLETED	Study of Ravulizumab in Children and Adolescents With Atypical Hemolytic Uremic Syndrome (aHUS)
NCT03205995	Phase 3	TERMINATED	Safety and Efficacy Study of OMS721 in Patients With Atypical Hemolytic Uremic Syndrome
NCT04861259	Phase 3	ACTIVE_NOT_RECRUITING	A Study Evaluating the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Crovalimab in Adult and Adolescent Participants With Atypical Hemolytic Uremic Syndrome (aHUS)
NCT04889430	Phase 3	COMPLETED	Efficacy and Safety of Iptacopan (LNP023) in Adult Patients With Atypical Hemolytic Uremic Syndrome Naive to Complement Inhibitor Therapy
NCT04958265	Phase 3	ACTIVE_NOT_RECRUITING	A Study Evaluating the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Crovalimab in Pediatric Participants With Atypical Hemolytic Uremic Syndrome (aHUS)
NCT05795140	Phase 3	RECRUITING	Evaluate Long-term Safety, Tolerability and Efficacy of Iptacopan in Study Participants With aHUS
NCT05935215	Phase 3	RECRUITING	Efficacy and Safety of Switching From Anti-C5 Antibody Treatment to Iptacopan Treatment in Study Participants With Atypical Hemolytic Uremic Syndrome (aHUS)
NCT00531089	Phase 2	UNKNOWN	Rituximab in Patients With Relapsed or Refractory TTP-HUS
NCT00726544	Phase 2	TERMINATED	Clinical Outcome Study of ARC1779 Injection in Patients With Thrombotic Microangiopathy
NCT00907751	Phase 2	COMPLETED	Rituximab in Adult Acquired Idiopathic Thrombotic Thrombocytopenic Purpura
NCT00937131	Phase 2	COMPLETED	The Use of Rituximab in Acute Thrombotic Thrombocytopenic Purpura (TTP)
NCT00953771	Phase 2	TERMINATED	Safety Study of Danazol With Plasma Exchange and Steroids for the Treatment of Thrombotic Thrombocytopenic Purpura (TTP)
NCT01554514	Phase 2	COMPLETED	Low Dose Rituximab in Thrombotic Thrombocytopenic Purpura
NCT04588194	Phase 2	UNKNOWN	Romiplostim, Rituximab and Dexamethasone as Frontline Treatment for Immune Thrombocytopenia
NCT05393999	Phase 2	WITHDRAWN	SABRE: A Single-arm Prospective Study Measuring Safety and Tolerability of SARS-CoV-2 Neutralising Antibodies in High-risk Populations
NCT05714969	Phase 2	COMPLETED	A Study of TAK-755 (rADAMTS13) With Little to No Plasma Exchange (PEX) Treatment in Adults With Immune-mediated Thrombotic Thrombocytopenic Purpura (iTTP)
NCT00838513	Phase 2	COMPLETED	Open Label Controlled Trial of Eculizumab in Adult Patients With Plasma Therapy-sensitive Atypical Hemolytic Uremic Syndrome (aHUS)
NCT00844428	Phase 2	COMPLETED	Open Label Controlled Trial of Eculizumab in Adolescent Patients With Plasma Therapy-Sensitive aHUS
NCT00844545	Phase 2	COMPLETED	Open Label Controlled Trial of Eculizumab in Adult Patients With Plasma Therapy-Resistant aHUS
NCT00844844	Phase 2	COMPLETED	Open Label Controlled Trial of Eculizumab in Adolescent Patients With Plasma Therapy-Resistant aHUS
NCT01193348	Phase 2	COMPLETED	An Open-Label, Multi-Center Clinical Trial of Eculizumab in Pediatric Patients With Atypical Hemolytic-Uremic Syndrome
NCT01194973	Phase 2	COMPLETED	An Open-label, Multi-center Clinical Trial of Eculizumab in Adult Patients With Atypical Hemolytic-uremic Syndrome
NCT01757431	Phase 2	COMPLETED	The Safety and Efficacy of Eculizumab in Japanese Patients With Atypical Hemolytic Uremic Syndrome (aHUS)
NCT02464891	Phase 2	TERMINATED	Complement Inhibition in aHUS Dialysis Patients
NCT03303313	Phase 2	WITHDRAWN	A Study of an Investigational Drug, Cemdisiran (ALN-CC5), in Patients With Atypical Hemolytic Uremic Syndrome
NCT03518203	Phase 2	COMPLETED	Eculizumab to Treat Thrombotic Microangiopathy/Atypical Hemolytic Uremic Syndrome -Associated Multiple Organ Dysfunction Syndrome in Hematopoietic Stem Cell Transplant Recipients
NCT03999840	Phase 2	WITHDRAWN	Eculizumab to Cemdisiran Switch in aHUS
NCT04725812	Phase 2	TERMINATED	Complement Regulation to Undo Systemic Harm in Preeclampsia
NCT02216084	Phase 1	COMPLETED	Phase 1 Dose Escalation, Single Dose Study to Assess Safety and Pharmacokinetics of BAX930 in Hereditary Thrombotic Thrombocytopenic Purpura (TTP)
NCT01808521	Early Phase 1	COMPLETED	A Pilot Study of N-acetylcysteine in Thrombotic Thrombocytopenia Purpura
NCT01257269	Not specified	RECRUITING	Genotype and Phenotype Correlation in Hereditary Thrombotic Thrombocytopenic Purpura (Upshaw-Schulman Syndrome)
NCT03519672	Not specified	COMPLETED	Prospective Psychometric Evaluation Study of a Patient-reported Outcomes (PRO) Instrument for Congenital Thrombotic Thrombocytopenic Purpura (cTTP, Upshaw-Schulman Syndrome [USS], Hereditary Thrombotic Thrombocytopenic Purpura [hTTP]
NCT05004493	Not specified	RECRUITING	Biorepository and Registry for Plasma Exchange Patients
NCT04074187	Phase 2/3	COMPLETED	A Trial of Caplacizumab in Japanese Patients With Acquired Thrombotic Thrombocytopenic Purpura (aTTP)
NCT05568147	Phase 2/3	NOT_YET_RECRUITING	Aspirin for Prophylaxis of TTP
NCT00251277	Phase 1/2	WITHDRAWN	Use of Rituximab Treatment in Addition to Standard Care for Newly Presenting Thrombotic Thrombocytopenic Purpura
NCT00426686	Not specified	COMPLETED	ADAMTS13 in Thrombotic Thrombocytopenic Purpura
NCT00593229	Not specified	TERMINATED	International Registry and Biorepository for TMA(Thrombotic Microangiopathy)
NCT01931644	Not specified	COMPLETED	At-Home Research Study for Patients With Autoimmune, Inflammatory, Genetic, Hematological, Infectious, Neurological, CNS, Oncological, Respiratory, Metabolic Conditions
NCT01938404	Not specified	TERMINATED	Octaplas Adult TTP Trial
NCT02134171	Not specified	COMPLETED	Early Predictive Factors of Cardiac and Cerebral Involvement in TMA
NCT02626663	Not specified	WITHDRAWN	The Role of Microparticles as a Biomarker
NCT03187652	Not specified	UNKNOWN	A Prospective Study on the Long-Term Vascular Burden in Thrombotic Thrombocytopenic Purpura Patients
NCT03369314	Not specified	COMPLETED	Observational Study of the Use of octaplasLG®.
NCT03605511	Not specified	UNKNOWN	TTP and aHUS in Complicated Pregnancies
NCT04981028	Not specified	UNKNOWN	The ConNeCT Study: Neurological Complications of TTP
NCT05389007	Not specified	UNKNOWN	.German TTP-Registry (Thrombotic Thrombocytopenic Purpura)
NCT05770219	Not specified	APPROVED_FOR_MARKETING	Expanded Access Program of TAK-755 for Congenital Thrombotic Thrombocytopenic Purpura (cTTP)
NCT05785468	Not specified	UNKNOWN	A Retrospective, Observational Study on the Response to Caplacizumab Treatment in aTTP Patients: the Italian Experience (ROSCAPLI)

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for ADAMTS13 across ~30M SureChEMBL compounds — explore on Sugi Predict.