THBS2

Summary

THBS2 (thrombospondin 2, HGNC:11786) is a protein-coding gene on chromosome 6q27, encoding Thrombospondin-2 (P35442). Adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions.

The protein encoded by this gene belongs to the thrombospondin family. It is a disulfide-linked homotrimeric glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. This protein has been shown to function as a potent inhibitor of tumor growth and angiogenesis. Studies of the mouse counterpart suggest that this protein may modulate the cell surface properties of mesenchymal cells and be involved in cell adhesion and migration.

Source: NCBI Gene 7058 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Ehlers-Danlos syndrome, classic-like, 3 (Moderate, GenCC)
• GWAS associations: 18
• Clinical variants (ClinVar): 217 total
• Phenotypes (HPO): 19
• MANE Select transcript: NM_003247

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11786
Approved symbol	THBS2
Name	thrombospondin 2
Location	6q27
Locus type	gene with protein product
Status	Approved
Aliases	TSP2
Ensembl gene	ENSG00000186340
Ensembl biotype	protein_coding
OMIM	188061
Entrez	7058

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 19 protein_coding, 5 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000366787, ENST00000435791, ENST00000461848, ENST00000472733, ENST00000488355, ENST00000617924, ENST00000649844, ENST00000676498, ENST00000676628, ENST00000676760, ENST00000676869, ENST00000676941, ENST00000677398, ENST00000677429, ENST00000678378, ENST00000906004, ENST00000906005, ENST00000927078, ENST00000927079, ENST00000927080, ENST00000927081, ENST00000969635, ENST00000969636, ENST00000969637, ENST00000969638, ENST00000969639

RefSeq mRNA: 4 — MANE Select: NM_003247 NM_001381939, NM_001381940, NM_001381942, NM_003247

CCDS: CCDS34574, CCDS94038

Canonical transcript exons

ENST00000617924 — 22 exons

Exon	Start	End
ENSE00001336843	169223248	169223475
ENSE00001336844	169225145	169225379
ENSE00001336846	169226180	169226298
ENSE00001336848	169228122	169228281
ENSE00001336849	169229572	169229679
ENSE00001336851	169231980	169232198
ENSE00001336852	169232664	169232816
ENSE00001336853	169232890	169233017
ENSE00001336854	169234734	169234907
ENSE00001336856	169237170	169237346
ENSE00001336857	169237625	169237795
ENSE00001336862	169239599	169239695
ENSE00001336864	169240452	169240592
ENSE00001336866	169241762	169241958
ENSE00001336868	169246197	169246281
ENSE00001336870	169248417	169248973
ENSE00001442629	169250733	169250806
ENSE00003475796	169221430	169221527
ENSE00003509884	169220198	169220337
ENSE00003666845	169222197	169222468
ENSE00003722126	169253724	169253846
ENSE00003913499	169215785	169217829

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 99.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 84.1563 / max 3412.4637, expressed in 1058 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
76783	84.1563	1058

Top tissues by expression

290 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
pericardium	UBERON:0002407	99.47	gold quality
right coronary artery	UBERON:0001625	99.30	gold quality
stromal cell of endometrium	CL:0002255	99.00	gold quality
saphenous vein	UBERON:0007318	99.00	gold quality
tibia	UBERON:0000979	98.82	gold quality
skin of hip	UBERON:0001554	98.73	gold quality
hair follicle	UBERON:0002073	98.73	gold quality
ascending aorta	UBERON:0001496	98.51	gold quality
thoracic aorta	UBERON:0001515	98.51	gold quality
descending thoracic aorta	UBERON:0002345	98.47	gold quality
synovial joint	UBERON:0002217	97.94	gold quality
vena cava	UBERON:0004087	97.93	gold quality
tendon of biceps brachii	UBERON:0008188	97.62	gold quality
mammalian vulva	UBERON:0000997	97.58	gold quality
coronary artery	UBERON:0001621	97.28	gold quality
mucosa of urinary bladder	UBERON:0001259	97.21	gold quality
visceral pleura	UBERON:0002401	97.16	gold quality
gall bladder	UBERON:0002110	97.13	gold quality
left coronary artery	UBERON:0001626	97.00	gold quality
nipple	UBERON:0002030	96.97	gold quality
mammary duct	UBERON:0001765	96.63	gold quality
periodontal ligament	UBERON:0008266	96.60	gold quality
upper leg skin	UBERON:0004262	96.51	gold quality
cartilage tissue	UBERON:0002418	96.04	gold quality
layer of synovial tissue	UBERON:0007616	95.99	gold quality
aorta	UBERON:0000947	95.86	gold quality
calcaneal tendon	UBERON:0003701	95.81	gold quality
ectocervix	UBERON:0012249	95.58	gold quality
endocervix	UBERON:0000458	95.53	gold quality
epithelium of mammary gland	UBERON:0003244	95.53	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	3221.55
E-ENAD-20	yes	1983.65
E-MTAB-10662	yes	265.53
E-MTAB-8410	yes	42.60
E-MTAB-9543	yes	15.20
E-MTAB-5061	yes	11.28
E-MTAB-6678	yes	10.96
E-ENAD-27	yes	6.83
E-GEOD-83139	yes	6.82
E-GEOD-130148	yes	4.12
E-GEOD-124858	no	3044.17
E-MTAB-10290	no	415.77
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, FOSL1, HOXA5, HOXB7, MYB, PITX2, SMAD2, SMAD3, SMAD4

miRNA regulators (miRDB)

144 targeting THBS2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4775	99.98	75.00	6394
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-548N	99.98	71.94	4170

Literature-anchored findings (GeneRIF, showing 40)

• Normal human adult corneal keratocytes have mRNA for this protein. (PMID:11943589)
• inhibits microvascular endothelial cell proliferation by a caspase-independent mechanism (PMID:12058057)
• All adrenal tissues (control adrenals, nonfunctional adenomas and ACTH-dependent aldosterone-producing adenomas) expressed both TSP1 and TSP2 mRNAs.both TSP1 and TSP2 mRNAs. Correlated closely with the expression of ACTH receptor. (PMID:12358136)
• Homozygosity for the THBS-2 variant allele is significantly associated with a lower risk of premature myocardial infarction. (PMID:12482844)
• Decreased thrombospondin-2 expression is associated with human salivary gland carcinomas (PMID:12824879)
• Thrombospondin 2 regulates cell proliferation induced by Rac1 redox-dependent signaling (PMID:12861025)
• thrombospondin-1 and thrombospondin-2 have N-terminal regions for binding to alpha6beta1 integrin (PMID:12909644)
• results indicate that transforming growth factor TGFbeta1 treatment may regulate angiogenesis in pituitary cells by initially increasing levels of pro-angiogenic growth factor VEGF-A and then stimulating anti-angiogenic thrombospondin -1 and 2 levels (PMID:15347840)
• The 2.6-A-resolution crystal structure of the glycosylated signature domain of human THBS2 was discribed. (PMID:16186819)
• biophysical analysis of roles of signature domains of thrombospondin-4 and thrombospondin-2 in calcium binding, fine structure, and inter-modular interactions (PMID:16246837)
• Gene-expression changes in human evolution that involve specific brain regions, including portions of cerebral cortex. (PMID:17182969)
• two mAbs that recognize epitopes that are optimally present when three elements of signature domains of TSP-1 and TSP-2, the EGF-like modules, wire, and the lectin-like module, are in the same protein. (PMID:17620335)
• EWS/FLI1 has a role in regulating tumor angiogenesis in Ewing’s sarcoma via suppression of thrombospondins TSP1 and TSP2 (PMID:17638877)
• TSP1 and TSP2, together with the VLDLR, initiate a nonapoptotic pathway for maintenance of the normal adult vascular endothelium in a quiescent state. (PMID:18032585)
• TSP-2 was inconsistently expressed in uterine fibroids. (PMID:18089612)
• The meta-analysis included 6388 (TSP-1), 4930 (TSP-2), and 6978 (TSP-4) cases; none of the polymorphisms was found to be linked with the risk of myocardial infarction. (PMID:18178577)
• regulation of intervertebral disc ECM metabolism by the THBS2-MMP system plays an essential role in the etiology and pathogenesis of LDH. (PMID:18455130)
• The variant allele of THBS2 is a risk factor for TAA in hypertensive patients, whereas the variant alleles of HSPA8, GPX1, AGT, and TNF are protective against this condition. (PMID:18600213)
• Mutations targeting intermodular interfaces or calcium binding destabilize the thrombospondin-2 signature domain. (PMID:18682400)
• TSP-2 was found to be present in some, but not all, annulus cells of the human annulus and the mouse annulus. (PMID:18718009)
• The expression of metastasis inhibitor genes PTEN and thrombospondin 2 was down-regulated in the supraglottic carcinoma tissue with lymph node metastasis. (PMID:18720079)
• A significant correlation between microvessel density and the expression of trombospondin-2 (p=0.009) was found. (PMID:18955754)
• When TSP-2 expression was reduced in tumor- derived pancreatic stellate cells using selective siRNAs, pancreatic cancer cell invasion was inhibited. (PMID:19592030)
• the thrombospondin gene 2 T>G single nucleotide polymorphism is decreased only in plaque erosion, with no difference in frequency between other coronary disease and controls (PMID:19631562)
• LRP1 and TSP2 stimulate Notch activity by driving trans-endocytosis of the Notch ectodomain into the signal-sending cell (PMID:20472562)
• Single-nucleotide polymorphism in THBS2 is associated with coronary atherosclerosis. (PMID:20485444)
• In patients with preeclampsia, we demonstrated 1.7-fold higher tsp-2 compared with control group. (PMID:21682699)
• Data suggests that the presence of thrombospondin-1 (rs2228262) and thrombospondin-2 (rs8089) variants need not be considered a risk for coronary artery disease or myocardial infarction among South Indians. (PMID:21762961)
• Endothelial nitric oxide synthase controls the expression of the angiogenesis inhibitor thrombospondin 2 (PMID:21949402)
• Calcific aortic stenosis in associated with upregulation of TSP-2 expression, and inactivation of Akt and NF-kappaB. (PMID:22035575)
• TSP-2 has a protective role against cardiac inflammation, injury, and dysfunction in acute viral myocarditis. (PMID:22308237)
• Upregulation of TSP-2 may be a protective mechanism against inflammation and angiogenesis associated with proliferative diabetic retinopathy (PDR). (PMID:23387388)
• TSP2 is down-regulated at PCa tissues and cell lines, especially at stroma compartment, which could be related to prostate cancer progression. (PMID:23470460)
• human cytomegalovirus infection induced time-dependent decreases in mRNA and protein expressions of both TSP1 and TSP2 in astrocytes (PMID:23660684)
• Although no SNPs in THBS2 were associated with lumbar spinal stenosis, two haplotypes were significantly associated with disease progression in the Korean population, whereas another haplotype may play a protective role. (PMID:23807322)
• TSP-2 haschondrogenic effects on chondroprogenitor cells via PKCA ERK, p38/MAPK, and Notch signaling pathways. (PMID:23843355)
• Variants within the thrombospondin 2 (THBS2) gene are not associated with Achilles tendinopathy (PMID:23875975)
• Estrogen receptor alpha in cancer-associated fibroblasts suppresses prostate cancer invasion via modulation of thrombospondin 2 and matrix metalloproteinase 3. (PMID:24374826)
• TSP-2 is a potentially useful biomarker for assessment of disease severity and prognosis in HFrEF. (PMID:24500070)
• THBS2 is a salivary biomarker of oral cavity squamous cell carcinoma. (PMID:24708169)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	thbs2a	ENSDARG00000060410
danio_rerio	thbs2b	ENSDARG00000073810
mus_musculus	Thbs2	ENSMUSG00000023885
rattus_norvegicus	Thbs2	ENSRNOG00000010529
drosophila_melanogaster	Tsp	FBGN0031850

Paralogs (5): ISM1 (ENSG00000101230), COMP (ENSG00000105664), THBS4 (ENSG00000113296), THBS1 (ENSG00000137801), THBS3 (ENSG00000169231)

Protein

Protein identifiers

Thrombospondin-2 — P35442 (reviewed: P35442)

All UniProt accessions (7): A0A3B3ITK0, A0A7I2V344, A0A7I2V585, A0A7I2YQ86, A0A7I2YQT6, P35442, Q5RI53

UniProt curated annotations — full annotation on UniProt →

Function. Adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. Ligand for CD36 mediating antiangiogenic properties.

Subunit / interactions. Homotrimer; disulfide-linked. Interacts (via the TSP type I repeats) with CD36; the interaction conveys an antiangiogenic effect. Interacts (via the TSP type I repeats) with HRG; the interaction blocks the antiangiogenic effect of THBS2 with CD36. Can bind to fibrinogen, fibronectin, laminin and type V collagen.

Tissue specificity. High expression in invertebral disk tissue.

Disease relevance. Intervertebral disc disease (IDD) [MIM:603932] A common musculo-skeletal disorder caused by degeneration of intervertebral disks of the lumbar spine. It results in low-back pain and unilateral leg pain. Disease susceptibility is associated with variants affecting the gene represented in this entry. Ehlers-Danlos syndrome, classic-like, 3 (EDSCLL3) [MIM:620865] A form of Ehlers-Danlos syndrome, a group of connective tissue disorders characterized by skin hyperextensibility, articular hypermobility, and tissue fragility. EDSCLL3 is an autosomal dominant form. Affected individuals have joint hypermobility, frequent joint dislocations, atrophic scarring, prolonged bleeding time and age-related aortic dilatation and rupture. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the thrombospondin family.

RefSeq proteins (3): NP_001368868, NP_001368871, NP_003238* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain
IPR000884	TSP1_rpt	Repeat
IPR001007	VWF_dom	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR003367	Thrombospondin_3-like_rpt	Repeat
IPR008859	Thrombospondin_C	Domain
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR017897	Thrombospondin_3_rpt	Repeat
IPR024731	NELL2-like_EGF	Domain
IPR028974	TSP_type-3_rpt	Homologous_superfamily
IPR036383	TSP1_rpt_sf	Homologous_superfamily
IPR048287	TSPN-like_N	Domain

Pfam: PF00090, PF00093, PF02412, PF05735, PF12947

UniProt features (134 total): strand 43, disulfide bond 29, turn 12, helix 11, repeat 8, domain 8, glycosylation site 7, sequence conflict 4, compositionally biased region 3, sequence variant 3, region of interest 2, signal peptide 1, chain 1, short sequence motif 1, mutagenesis site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1YO8	X-RAY DIFFRACTION	2.6
2RHP	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35442-F1	84.46	0.58

Functional residue map

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

Disulfide bonds (29): 266, 270, 393–425, 397–430, 408–415, 449–486, 453–491, 464–476, 506–543, 510–548, 521–533, 553–564, 558–574, 577–588, 594–610, 601–619, 622–646, 652–665, 659–678, 680–691 …

Glycosylation sites (7): 151, 316, 330, 457, 584, 710, 1069

Mutagenesis-validated functional residues (1):

Position	Phenotype
702	alters protein stability.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-186797	Signaling by PDGF
R-HSA-5083635	Defective B3GALTL causes PpS
R-HSA-5173214	O-glycosylation of TSR domain-containing proteins

MSigDB gene sets: 346 (showing top): TURASHVILI_BREAST_LOBULAR_CARCINOMA_VS_DUCTAL_NORMAL_UP, MODULE_52, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, BENPORATH_ES_WITH_H3K27ME3, BOYAULT_LIVER_CANCER_SUBCLASS_G56_DN, GOBP_SYNAPSE_ASSEMBLY, GOCC_SECRETORY_GRANULE, GOBP_POSITIVE_REGULATION_OF_SYNAPSE_ASSEMBLY, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GNF2_PTX3, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_POSITIVE_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, LIEN_BREAST_CARCINOMA_METAPLASTIC

GO Biological Process (3): cell adhesion (GO:0007155), negative regulation of angiogenesis (GO:0016525), positive regulation of synapse assembly (GO:0051965)

GO Molecular Function (4): calcium ion binding (GO:0005509), heparin binding (GO:0008201), extracellular matrix structural constituent (GO:0005201), protein binding (GO:0005515)

GO Cellular Component (4): extracellular region (GO:0005576), basement membrane (GO:0005604), extracellular matrix (GO:0031012), platelet alpha granule (GO:0031091)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Signaling by Receptor Tyrosine Kinases	1
Diseases associated with O-glycosylation of proteins	1
O-linked glycosylation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
extracellular matrix	2
cellular process	1
angiogenesis	1
regulation of angiogenesis	1
negative regulation of blood vessel morphogenesis	1
synapse assembly	1
positive regulation of nervous system development	1
regulation of synapse assembly	1
positive regulation of cell junction assembly	1
metal ion binding	1
glycosaminoglycan binding	1
sulfur compound binding	1
structural molecule activity	1
binding	1
cellular anatomical structure	1
external encapsulating structure	1
secretory granule	1

Protein interactions and networks

STRING

3368 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
THBS2	MMP9	P14780	954
THBS2	CD36	P16671	954
THBS2	SCARB2	Q14108	953
THBS2	SCARB1	Q8WTV0	950
THBS2	COL11A1	P12107	859
THBS2	FN1	P02751	821
THBS2	MMP2	P08253	788
THBS2	CD47	Q08722	788
THBS2	POSTN	Q15063	744
THBS2	PLG	P00747	740
THBS2	COL1A1	P02452	722
THBS2	COL1A2	P02464	716
THBS2	COL5A2	P05997	697
THBS2	COL3A1	P02461	694
THBS2	LUM	P51884	690

IntAct

9 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
THBS2	AP1G2	psi-mi:“MI:0914”(association)	0.530
THBS2	Cacna2d1	psi-mi:“MI:0915”(physical association)	0.400
Cacna2d1	THBS2	psi-mi:“MI:0915”(physical association)	0.400
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (28): THBS1 (Affinity Capture-MS), DPY19L3 (Affinity Capture-MS), B3GALTL (Affinity Capture-MS), ZWINT (Affinity Capture-MS), PPP1R21 (Affinity Capture-MS), PIGA (Affinity Capture-MS), AP1G2 (Affinity Capture-MS), EDEM2 (Affinity Capture-MS), FOXF2 (Affinity Capture-MS), ZNF696 (Affinity Capture-MS), DPY19L1 (Affinity Capture-MS), PPP1R21 (Affinity Capture-MS), B3GALTL (Affinity Capture-MS), DPY19L3 (Affinity Capture-MS), ZNF696 (Affinity Capture-MS)

ESM2 similar proteins: A0A096LNW5, B8JI71, D3ZHH1, G3I6Z6, O00548, O35516, O57409, P0DPK3, P0DPK4, P35442, P46531, P78504, P97677, Q01705, Q04721, Q05793, Q07008, Q08E66, Q2QI47, Q5G872, Q5ZQU0, Q61483, Q63722, Q66PY1, Q6DI48, Q6NZL8, Q70E20, Q7TQN3, Q7Z3S9, Q8IWY4, Q8IX30, Q8JZM4, Q8K3K1, Q8NFT8, Q8TER0, Q8TEU8, Q8UWJ4, Q8VHS2, Q90Y54, Q90Y57

Diamond homologs: A2VEC9, A6QNY1, B3EWZ3, B3EWZ8, C0HL12, C5IAW9, D3YXG0, D3ZTD8, F1LW30, O08721, O08722, O08747, O14514, O15072, O55225, O60241, O60242, O75173, O88783, O95185, O95450, P04275, P07358, P07996, P27918, P35441, P35442, P35448, P55314, P57110, P58397, P58459, P59384, P79331, P80012, P97857, P98088, P98092, P98160, P98164

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
THBS2	up-regulates	CD47	binding

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	136
Likely benign	28
Benign	27

Top pathogenic / likely-pathogenic (0)

SpliceAI

3551 predictions. Top by Δscore:

Variant	Effect	Δscore
6:169220351:T:C	acceptor_gain	1.0000
6:169222191:CCTCA:C	donor_loss	1.0000
6:169222192:CTCAC:C	donor_loss	1.0000
6:169222193:TCAC:T	donor_loss	1.0000
6:169222194:CA:C	donor_loss	1.0000
6:169222196:C:CA	donor_loss	1.0000
6:169223243:CTCA:C	donor_loss	1.0000
6:169223244:TCA:T	donor_loss	1.0000
6:169223245:CACC:C	donor_loss	1.0000
6:169223246:A:T	donor_loss	1.0000
6:169223472:TCAC:T	acceptor_gain	1.0000
6:169223473:CAC:C	acceptor_gain	1.0000
6:169223473:CACC:C	acceptor_gain	1.0000
6:169223474:ACCTA:A	acceptor_loss	1.0000
6:169223475:CCTA:C	acceptor_gain	1.0000
6:169223476:C:CC	acceptor_gain	1.0000
6:169223476:CTATG:C	acceptor_loss	1.0000
6:169223477:T:C	acceptor_loss	1.0000
6:169223478:A:AC	acceptor_gain	1.0000
6:169225156:T:TA	donor_gain	1.0000
6:169226175:CTCA:C	donor_loss	1.0000
6:169226177:CA:C	donor_loss	1.0000
6:169226178:ACCT:A	donor_loss	1.0000
6:169226179:C:A	donor_loss	1.0000
6:169226295:ACAT:A	acceptor_gain	1.0000
6:169226296:CAT:C	acceptor_gain	1.0000
6:169226296:CATC:C	acceptor_gain	1.0000
6:169226297:AT:A	acceptor_gain	1.0000
6:169226298:TC:T	acceptor_loss	1.0000
6:169226299:C:CA	acceptor_loss	1.0000

AlphaMissense

7863 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:169220244:G:C	F1155L	1.000
6:169220244:G:T	F1155L	1.000
6:169220246:A:G	F1155L	1.000
6:169221460:A:G	L1114P	1.000
6:169221467:A:G	W1112R	1.000
6:169221467:A:T	W1112R	1.000
6:169221489:C:A	W1104C	1.000
6:169221489:C:G	W1104C	1.000
6:169221490:C:G	W1104S	1.000
6:169221491:A:G	W1104R	1.000
6:169221491:A:T	W1104R	1.000
6:169222221:C:A	W1083C	1.000
6:169222221:C:G	W1083C	1.000
6:169222223:A:G	W1083R	1.000
6:169222223:A:T	W1083R	1.000
6:169222346:A:G	W1042R	1.000
6:169222346:A:T	W1042R	1.000
6:169222402:T:A	D1023V	1.000
6:169222402:T:G	D1023A	1.000
6:169223286:A:G	L988P	1.000
6:169223312:C:A	W979C	1.000
6:169223312:C:G	W979C	1.000
6:169223314:A:G	W979R	1.000
6:169223314:A:T	W979R	1.000
6:169225183:C:G	C912S	1.000
6:169225184:A:T	C912S	1.000
6:169228205:C:G	C779S	1.000
6:169228206:A:G	C779R	1.000
6:169228206:A:T	C779S	1.000
6:169228273:G:C	C756W	1.000

dbSNP variants (sampled 300 via entrez): RS1000097373 (6:169233850 C>T), RS1000163392 (6:169235143 A>C), RS1000178974 (6:169250253 T>C), RS1000196319 (6:169239069 G>A,T), RS1000231237 (6:169249955 G>A), RS1000251267 (6:169244606 A>G), RS1000307186 (6:169254171 A>C,G), RS1000403527 (6:169245526 C>G,T), RS1000528869 (6:169240165 C>A,G), RS1000706493 (6:169244323 C>A), RS1000744928 (6:169249538 T>A), RS1000751895 (6:169249222 C>A), RS1000753734 (6:169243929 G>A), RS1000863579 (6:169223693 T>C), RS1000916997 (6:169228448 C>A)

Disease associations

OMIM: gene MIM:188061 | disease phenotypes: MIM:620865, MIM:130000

GenCC curated gene-disease

Disease	Classification	Inheritance
Ehlers-Danlos syndrome, classic-like, 3	Moderate	Autosomal dominant

Mondo (3): lumbar disk herniation, susceptibility to (MONDO:0100202), Ehlers-Danlos syndrome, classic-like, 3 (MONDO:0971044), Ehlers-Danlos syndrome (MONDO:0020066)

Orphanet (1): Ehlers-Danlos syndrome (Orphanet:98249)

HPO phenotypes

19 total (19 of 19 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000974	Hyperextensible skin
HP:0000978	Bruising susceptibility
HP:0001075	Atrophic scars
HP:0001382	Joint hypermobility
HP:0001638	Cardiomyopathy
HP:0003010	Prolonged bleeding time
HP:0004970	Ascending tubular aorta aneurysm
HP:0005113	Aortic arch aneurysm
HP:0005293	Venous insufficiency
HP:0008330	Reduced von Willebrand factor activity
HP:0011873	Abnormal platelet count
HP:0011898	Abnormality of circulating fibrinogen
HP:0012095	Multiple joint dislocation
HP:0025509	Piezogenic pedal papules
HP:0030976	Abnormal factor VIII activity
HP:0032199	Abnormal prothrombin time
HP:0100550	Tendon rupture
HP:6000342	Thickened mitral valve cusp

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST001762_260	Obesity-related traits	5.000000e-06
GCST002938_39	Copper levels	8.000000e-06
GCST003616_1	Liver disease severity in Alagille syndrome	2.000000e-06
GCST003998_19	Joint mobility (Beighton score)	3.000000e-07
GCST004278_1	Pulse pressure	5.000000e-17
GCST005182_1	Common carotid intima-media thickness in HIV negative individuals	2.000000e-06
GCST005667_11	Central corneal thickness	1.000000e-08
GCST005760_8	Dimensional psychopathology (Cognitive)	6.000000e-07
GCST006585_2081	Blood protein levels	7.000000e-54
GCST007096_141	Pulse pressure	1.000000e-23
GCST007097_153	Pulse pressure	3.000000e-10
GCST007097_154	Pulse pressure	8.000000e-11
GCST007294_163	Body fat distribution (trunk fat ratio)	3.000000e-07
GCST007295_64	Body fat distribution (leg fat ratio)	1.000000e-07
GCST010151_15	Carotid intima media thickness x smoking interaction	2.000000e-06
GCST010206_4	Anorectal malformation	8.000000e-17
GCST90000654_41	Central corneal thickness	9.000000e-11
GCST90014033_78	Haemorrhoidal disease	5.000000e-12

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0005116	urinary metabolite measurement
EFO:0007905	joint hypermobility measurement
EFO:0005763	pulse pressure measurement
EFO:0005213	central corneal thickness
EFO:0009098	cognitive domain measurement
EFO:0004341	body fat distribution
EFO:0006527	smoking status measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D004535	Ehlers-Danlos Syndrome	C14.907.454.240; C15.378.463.515.240; C16.131.831.428; C16.320.850.260; C17.300.200.310; C17.800.804.428; C17.800.827.260

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

72 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, decreases expression, increases methylation, affects cotreatment	8
Estradiol	increases expression, affects expression, affects cotreatment	4
bisphenol A	increases expression, affects cotreatment, decreases methylation	3
sodium arsenite	affects methylation, decreases expression, increases abundance	3
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression, increases methylation	3
Tobacco Smoke Pollution	affects expression, decreases expression	3
arsenite	decreases expression, increases abundance, increases methylation	2
entinostat	increases expression, affects cotreatment	2
monomethylarsonous acid	decreases expression	2
Fulvestrant	decreases methylation, decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Doxorubicin	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Particulate Matter	increases abundance, increases expression	2
methylmercuric chloride	increases expression	1
pirinixic acid	increases activity, increases expression, affects binding	1
sodium arsenate	increases abundance, decreases expression	1
trichostatin A	increases expression	1
afimoxifene	decreases expression	1
monomethylarsonic acid	decreases expression	1
perfluorooctanoic acid	decreases expression	1
arsenic acid	decreases expression, increases abundance	1
didecyldimethylammonium	decreases expression	1
aflatoxin B2	increases methylation	1
nickel sulfate	affects cotreatment, increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
macrophage stimulatory lipopeptide 2	increases expression, affects cotreatment	1
3-nitrobenzanthrone	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

49 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04890431	PHASE4	UNKNOWN	Impact of Oxygen Therapy on Fatigue in Patients With Hypermobile-type Ehlers-Danlos Syndrome
NCT05603741	PHASE4	ACTIVE_NOT_RECRUITING	Local Anesthetic Response in Ehlers-Danlos Syndrome (EDS) and Healthy Volunteers
NCT05279937	PHASE3	NOT_YET_RECRUITING	The Ultrasound-Guided Dextrose Prolotherapy in Ehlers-Danlos Syndrome Patients
NCT00001966	PHASE2	COMPLETED	Mind-Body Therapy for Pain in Ehlers-Danlos Syndrome
NCT03686748	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Two Point Discrimination
NCT00001641	Not specified	COMPLETED	Study of Heritable Connective Tissue Disorders
NCT00270686	Not specified	COMPLETED	Studies of Heritable Disorders of Connective Tissue
NCT01322165	Not specified	COMPLETED	National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions
NCT01356134	Not specified	COMPLETED	Vascular Fundus Changes in Patients With High Probability of Chronic Cerebrospinal Venous Insufficiency (CCSVI)
NCT01367977	Not specified	COMPLETED	Head Circumference Growth in Children With Ehlers-Danlos Syndrome Who Develop Dysautonomia Later in Life
NCT02050113	Not specified	RECRUITING	Complex Aortic Aneurysm Repair Using Physician Modified Endografts and Custom Made Devices
NCT02435745	Not specified	COMPLETED	Obstructive Sleep Apnoea in Ehlers-Danlos Syndrome
NCT02721797	Not specified	UNKNOWN	Origins and Impact of EDS in Connective Tissues and Skin
NCT02985710	Not specified	COMPLETED	Assessment of Small Fiber Neuropathy in Rare Diseases Using Sudoscan
NCT03093493	Not specified	COMPLETED	Genetics of Ehlers-Danlos Syndrome
NCT03330977	Not specified	UNKNOWN	Efficiency Clinical Study of NOVATEX MEDICAL Compression Garments in Patients With Ehlers-Danlos Syndrome
NCT03575182	Not specified	UNKNOWN	Gait Retraining in Patients With Joint Hypermobility Syndrome/Hypermobile Ehlers Danlos Syndrome
NCT03596437	Not specified	UNKNOWN	Study of Arterial Properties by Ultra-high Frequency Ultrasound in Fibromuscular Dysplasia and Vascular Ehlers-Danlos Syndrome
NCT03602482	Not specified	COMPLETED	Standing Cognition and Co-morbidities of POTS Evaluation
NCT03681080	Not specified	COMPLETED	Concentration and Attentional Deficits in POTS and Other Autonomic Neuropathies
NCT03986229	Not specified	COMPLETED	Evaluation of the Effect of Custom Compression Garments on Standing Static Balance in Ehlers Danlos Syndrome
NCT04036305	Not specified	ACTIVE_NOT_RECRUITING	Local Anesthetic Response in Ehlers-Danlos Syndrome (EDS) and Healthy Volunteers
NCT04133272	Not specified	RECRUITING	Registry of Ehlers-Danlos Syndrome
NCT04437589	Not specified	COMPLETED	Opioid-Free Anesthesia for Patients With Joint Hypermobility Syndrome Undergoing Craneo-Cervical Fixation: A Case-series
NCT04680793	Not specified	COMPLETED	Effects of a Multidisciplinary Outpatient Rehabilitation Program in Patients With Ehlers-Danlos Syndrome.
NCT04734041	Not specified	COMPLETED	Integrative Medicine for Hypermobility Spectrum Disorder and Ehlers-Danlos Syndromes (IMforHSDandEDS)
NCT04742803	Not specified	COMPLETED	Straberi Epistamp Needling Treatment For Skin Rejuvenation
NCT04806620	Not specified	RECRUITING	Unhide® Project: A Digital Health Platform to Collect Lifestyle Data for Brain Inflammation Research
NCT05137379	Not specified	COMPLETED	Evaluation of a Cohort of Patients With Ehlers-Danlos Syndrome Treated With Orthopedic Surgery (SED-eval)
NCT05366114	Not specified	UNKNOWN	Vision-based Assessment of Joint Extensibility in Ehlers Danlos Syndrome
NCT05389865	Not specified	ACTIVE_NOT_RECRUITING	Proximal Aortopathy in Scotland - Epidemiology and Surgical Outcomes
NCT05429996	Not specified	UNKNOWN	Ultrastructural Collagen Markers in Ehlers Danlos Syndromes
NCT05434728	Not specified	UNKNOWN	Characterization of Bleeding Disorders in EDS
NCT05516043	Not specified	COMPLETED	Safety and Performance of POLYTHESE® Vascular Prosthesis
NCT05561270	Not specified	RECRUITING	Light Exposure on Pain in Hypermobile Ehlers-Danlos Syndrome
NCT05720923	Not specified	ACTIVE_NOT_RECRUITING	Analysis of Muscular Properties in Patients With MFS and EDS
NCT05871216	Not specified	RECRUITING	Functional Instability in Patients Suffering From Collagen Disease and Joint Hypermobility
NCT05945784	Not specified	COMPLETED	Exploring Accessible Beauty for Individuals With Upper Extremity Deficits
NCT06074276	Not specified	RECRUITING	The Effects of Almond on Facial Skin Collagen and Wrinkles
NCT06105541	Not specified	COMPLETED	Hypermobile Ehlers-Danlos Syndrome - Transcutaneous Auricular Neuromodulation