COMP

Summary

COMP (cartilage oligomeric matrix protein, HGNC:2227) is a protein-coding gene on chromosome 19p13.11, encoding Cartilage oligomeric matrix protein (P49747). Plays a role in the structural integrity of cartilage via its interaction with other extracellular matrix proteins such as the collagens and fibronectin.

The protein encoded by this gene is a noncollagenous extracellular matrix (ECM) protein. It consists of five identical glycoprotein subunits, each with EGF-like and calcium-binding (thrombospondin-like) domains. Oligomerization results from formation of a five-stranded coiled coil and disulfides. Binding to other ECM proteins such as collagen appears to depend on divalent cations. Contraction or expansion of a 5 aa aspartate repeat and other mutations can cause pseudochondroplasia (PSACH) and multiple epiphyseal dysplasia (MED).

Source: NCBI Gene 1311 — RefSeq curated summary.

At a glance

• Gene–disease (curated): COMP-related skeletal dysplasia (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 888 total — 58 pathogenic, 86 likely-pathogenic
• Phenotypes (HPO): 93
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000095

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2227
Approved symbol	COMP
Name	cartilage oligomeric matrix protein
Location	19p13.11
Locus type	gene with protein product
Status	Approved
Aliases	MED, THBS5, TSP5, TSP-5
Ensembl gene	ENSG00000105664
Ensembl biotype	protein_coding
OMIM	600310
Entrez	1311

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 retained_intron

ENST00000222271, ENST00000425807, ENST00000542601, ENST00000612179, ENST00000944187, ENST00000944188

RefSeq mRNA: 1 — MANE Select: NM_000095 NM_000095

CCDS: CCDS12385

Canonical transcript exons

ENST00000222271 — 19 exons

Exon	Start	End
ENSE00000690352	18790562	18790613
ENSE00000690354	18790850	18790935
ENSE00002410667	18791191	18791305
ENSE00002990811	18789160	18789297
ENSE00002994550	18786532	18786650
ENSE00003077336	18788592	18788750
ENSE00003091449	18788839	18788913
ENSE00003103541	18789942	18790114
ENSE00003111278	18787491	18787650
ENSE00003116721	18788212	18788319
ENSE00003128675	18788410	18788514
ENSE00003143164	18782773	18782961
ENSE00003143260	18785498	18785546
ENSE00003146191	18785673	18785851
ENSE00003159325	18784191	18784363
ENSE00003190692	18783054	18783193
ENSE00003192317	18785965	18786146
ENSE00003218232	18784896	18785092
ENSE00003631787	18786239	18786291

Expression profiles

Bgee: expression breadth ubiquitous, 195 present calls, max score 99.87.

FANTOM5 (CAGE): breadth broad, TPM avg 50.3105 / max 11530.3989, expressed in 293 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
180094	49.7492	293
180067	0.2615	56
180066	0.1428	41
180064	0.0977	31
180065	0.0403	20
180093	0.0190	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	99.87	gold quality
cartilage tissue	UBERON:0002418	99.65	gold quality
calcaneal tendon	UBERON:0003701	99.59	gold quality
tendon of biceps brachii	UBERON:0008188	99.46	gold quality
synovial joint	UBERON:0002217	99.08	gold quality
tendon	UBERON:0000043	98.44	gold quality
popliteal artery	UBERON:0002250	98.37	gold quality
tibial artery	UBERON:0007610	98.36	gold quality
saphenous vein	UBERON:0007318	98.22	gold quality
aorta	UBERON:0000947	95.87	gold quality
urethra	UBERON:0000057	94.74	gold quality
ascending aorta	UBERON:0001496	92.97	gold quality
skin of leg	UBERON:0001511	92.93	gold quality
thoracic aorta	UBERON:0001515	92.91	gold quality
descending thoracic aorta	UBERON:0002345	92.29	gold quality
layer of synovial tissue	UBERON:0007616	92.16	gold quality
pericardium	UBERON:0002407	90.34	gold quality
left coronary artery	UBERON:0001626	89.76	gold quality
right coronary artery	UBERON:0001625	89.74	gold quality
trabecular bone tissue	UBERON:0002483	89.24	gold quality
coronary artery	UBERON:0001621	88.73	gold quality
tibial nerve	UBERON:0001323	87.95	gold quality
zone of skin	UBERON:0000014	87.08	gold quality
skin of abdomen	UBERON:0001416	85.76	gold quality
right atrium auricular region	UBERON:0006631	83.77	gold quality
gall bladder	UBERON:0002110	83.54	gold quality
hair follicle	UBERON:0002073	83.10	gold quality
periodontal ligament	UBERON:0008266	82.79	gold quality
subcutaneous adipose tissue	UBERON:0002190	81.67	gold quality
cardiac atrium	UBERON:0002081	81.43	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREBRF, GLI3, SON, SOX17, SOX5, SOX6, SOX9, SP1, TBXT, TCF3, ZBTB7A

miRNA regulators (miRDB)

3 targeting COMP, 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-216B-3P	98.55	67.19	1223
HSA-MIR-6852-3P	98.54	67.60	1468
HSA-MIR-3909	97.55	66.78	887

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Disease-causing mutations in cartilage oligomeric matrix protein cause an unstructured Ca2+ binding domain (PMID:11782471)
• Mutations effect the matrix around chondrocytes, causing osteochondrodysplasias (PMID:11891674)
• Matrix-matrix interaction of cartilage oligomeric matrix protein and fibronectin. (PMID:12225811)
• COMP gene mutations have been identified in patients with pseudochondrodysplasia and multiple epiphyseal dysplasia. (PMID:12768438)
• Mutations of the cartilage oligomeric matrix protein gene is associated with pseudoachondroplasia (PMID:12792737)
• Data show that mutated cartilage oligomeric matrix protein accumulated in the rough endoplasmic reticulum, and the affected cells were more likely to undergo apoptosis. (PMID:12819015)
• COMP expression is up-regulated by both GH and IGF-I in primary cultured human chondrocytes (PMID:15472220)
• COMP, type IX collagen and MATN3 play important roles in matrix assembly (PMID:15694129)
• COMP secretion is affected by the signal peptide (PMID:15749701)
• Mapping of all known COMP C-terminal domain (CTD) mutations on a three-dimensional model shows that the CTD mutations cluster in two distinct regions. (PMID:15880723)
• COMP/TSP5 can mediate chondrocyte attachment through interactions with integrins (PMID:16051604)
• expression pattern of both promoters recapitulates endogenous cartilage COMP expression in mice (PMID:16214313)
• COMP encodes a noncollagenous extracellular matrix protein in various musculoskeletal tissues {review} (PMID:16340129)
• COMP is overexpressed in scleroderma skin and cultured fibroblasts possibly due to autocrine TGFbeta stimulation, and COMP overexpression is sufficient to stimulate excess matrix deposition (PMID:16520029)
• COMP might be involved in human limb development, is upregulated in osteoarthritis (OA), and could play a role in the pathogenesis of OA as a factor secreted by chondrocytes to ameliorate the matrix breakdown. (PMID:16542502)
• This study showed that heritable factors influence serum levels of the cartilage matrix biomarker cartilage oligomeric matrix protein (COMP) in osteoarthritis. (PMID:16802351)
• May play an important role in an attempted repair of either traumatized or degenerated cartilage. (PMID:17033713)
• The results demonstrate that different COMP mutations in the T3 repeat domain have variable effects on intracellular transport, which correlate with clinical severity (PMID:17570134)
• DNA sequencing-based genetic diagnosis of pseudoachondroplasia revealed a heterozygous mutation for the nucleotide change 1532A>G in exon 14 of the COMP gene, resulting in a substitution of amino acid 511 from aspartic acid to glycine. (PMID:17579668)
• COMP/TSP5 may function to support matrix interactions with aggrecan in cartilage extracellular matrix (PMID:17588949)
• the authors consider serum COMP levels in different diseases…and discuss…whether COMP is able to predict a rapid and sustained clinical response to anti-TNF-alpha drugs. (PMID:17894003)
• Data show COMP protects cells against death by elevating members of the IAP family of survival proteins. (PMID:17993464)
• COMP mutations are associated with skeletal dysplasias (PMID:18193163)
• Recent studies highlighted in this review have identified molecular functions of cartilage oligomeric matrix protein that may contribute to its role in skeletal disease. (PMID:18855621)
• there is an inverse relationship between hypermobility and hand and knee osteoarthritis, and that hypermobility is associated with lower serum COMP levels (PMID:19035482)
• COMP, CXCL9 and KRT19 play an important role in the pathopoiesis of oral submucosal fibrosis. (PMID:19087608)
• Serum COMP was increased 1.6-fold at 10 km during a marathon race and declined to the pre-race level after 2 days recovery. (PMID:19125286)
• The crystal packing reveals an exposed potential metal-ion-dependent adhesion site on one edge of the beta-sandwich that is common to all TSPs and may serve as a binding site for collagens and other ligands. (PMID:19276170)
• Elevation of COMP may reflect joint damage that is dependent on the synovial inflammatory process in early-stage rheumatoid arthritis. (PMID:19447929)
• We found reduced COMP levels in children with juvenile idiopathic arthritis compared with healthy children (PMID:19605679)
• The structure of the mutant COMP growth plate recapitulated the findings of human pseudoachondroplasia growth plate morphology. (PMID:19762713)
• Serum COMP levels correlated with total-body joint disease severity as determined by bone scintigraphy, supporting the idea that whole-body bone scintigraphy quantifies the total-body burden of osteoarthritis for systemic biomarker validation. (PMID:19877068)
• Data show that cartilage oligomeric matrix protein (COMP) promotes cell attachment via independent mechanisms involving cell surface CD47 and alphaVbeta3 integrin and that cell attachment to COMP induces formation of fascin-stabilized actin microspikes. (PMID:20033473)
• Elevation of COMP serum concentration seems to depend on the loading mode of the physical activity and to reflect the extrusion of COMP fragments from the impact loaded articular cartilage or synovial fluid. (PMID:20544356)
• Mutations in COMP gene are responsible for the pseudoachondroplasia. Serum COMP concentration may be suggested as an additional diagnostic marker to aid clinical findings in suspected cases of pseudoachondroplasia. (PMID:20819661)
• Data revealed a strong induction of several genes encoding components of the extracellular matrix, such as collagens, COMP, IGFBP5 and biglycan. (PMID:21029365)
• We report an 81% mutation detection rate for pseudoachondroplasia, of which COMP+Col9A3 mutations were more prevalent (61%) than COMP mutations alone (30%). (PMID:21042783)
• The results suggest that uCTX-I, uCTX-II and sCOMP could identify patients with focal cartilage lesions from an early stage of osteoarthritis of the knee. (PMID:21221577)
• a c. 1352_1353ins TGTCCCTGG is a novel mutation in COMP responsible for severe familial pseudoachondroplasia (PMID:21599986)
• In vivo exercise interventions differentially regulate serum COMP concentrations and knee cartilage deformations. The relation between changes in COMP and in cartilage volume seems to depend on both mechanical and biochemical factors. (PMID:21616158)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	comp	ENSDARG00000098431
mus_musculus	Comp	ENSMUSG00000031849
rattus_norvegicus	Comp	ENSRNOG00000048472
drosophila_melanogaster	Tsp	FBGN0031850

Paralogs (5): ISM1 (ENSG00000101230), THBS4 (ENSG00000113296), THBS1 (ENSG00000137801), THBS3 (ENSG00000169231), THBS2 (ENSG00000186340)

Protein

Protein identifiers

Cartilage oligomeric matrix protein — P49747 (reviewed: P49747)

Alternative names: Thrombospondin-5

All UniProt accessions (2): P49747, G3XAP6

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in the structural integrity of cartilage via its interaction with other extracellular matrix proteins such as the collagens and fibronectin. Can mediate the interaction of chondrocytes with the cartilage extracellular matrix through interaction with cell surface integrin receptors. Could play a role in the pathogenesis of osteoarthritis. Potent suppressor of apoptosis in both primary chondrocytes and transformed cells. Suppresses apoptosis by blocking the activation of caspase-3 and by inducing the IAP family of survival proteins (BIRC3, BIRC2, BIRC5 and XIAP). Essential for maintaining a vascular smooth muscle cells (VSMCs) contractile/differentiated phenotype under physiological and pathological stimuli. Maintains this phenotype of VSMCs by interacting with ITGA7.

Subunit / interactions. Pentamer; disulfide-linked. Exists in a more compact conformation in the presence of calcium and shows a more extended conformation in the absence of calcium. Interacts with ITGB3, ITGA5 and FN1. Binding to FN1 requires the presence of divalent cations (Ca(2+), Mg(2+) or Mn(2+)). The greatest amount of binding is seen in the presence of Mn(2+). Interacts with MATN1, MATN3, MATN4 and ACAN. Binds heparin, heparan sulfate and chondroitin sulfate. EDTA dimishes significantly its binding to ACAN and abolishes its binding to MATN3, MATN4 and chondroitin sulfate. Interacts with collagen I, II and IX, and interaction with these collagens is dependent on the presence of zinc ions. Interacts with ADAMTS12. Interacts with ITGA7.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Abundantly expressed in the chondrocyte extracellular matrix, and is also found in bone, tendon, ligament and synovium and blood vessels. Increased amounts are produced during late stages of osteoarthritis in the area adjacent to the main defect.

Post-translational modifications. Proteolytically cleaved by metalloproteases ADAMTS4 and ADAMTS1 with ADAMTS4 showing more potent activity.

Disease relevance. Multiple epiphyseal dysplasia 1 (EDM1) [MIM:132400] A generalized skeletal dysplasia associated with significant morbidity. Joint pain, joint deformity, waddling gait, and short stature are the main clinical signs and symptoms. Radiological examination of the skeleton shows delayed, irregular mineralization of the epiphyseal ossification centers and of the centers of the carpal and tarsal bones. Multiple epiphyseal dysplasia is broadly categorized into the more severe Fairbank and the milder Ribbing types. The Fairbank type is characterized by shortness of stature, short and stubby fingers, small epiphyses in several joints, including the knee, ankle, hand, and hip. The Ribbing type is confined predominantly to the hip joints and is characterized by hands that are normal and stature that is normal or near-normal. The disease is caused by variants affecting the gene represented in this entry. Pseudoachondroplasia (PSACH) [MIM:177170] A skeletal dysplasia usually manifesting in the second year of life and characterized by moderate to severe disproportionate short stature, deformity of the lower limbs, brachydactyly, ligamentous laxity, and degenerative joint disease. The disease is caused by variants affecting the gene represented in this entry. Carpal tunnel syndrome 2 (CTS2) [MIM:619161] An autosomal dominant form of carpal tunnel syndrome, a condition characterized by entrapment of the median nerve within the carpal tunnel. Symptoms include burning pain and paresthesias involving the ventral surface of the hand and fingers which may radiate proximally. Impairment of sensation in the distribution of the median nerve and thenar muscle atrophy may occur. This condition may be associated with repetitive occupational trauma, wrist injuries, amyloid neuropathies, rheumatoid arthritis. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 11-14 calcium ions per subunit.

Domain organisation. The cell attachment motif mediates the attachment to chondrocytes. It mediates the induction of both the IAP family of survival proteins and the antiapoptotic response. The TSP C-terminal domain mediates interaction with FN1 and ACAN. Each of the eight TSP type-3 repeats binds two calcium ions. The TSP C-terminal domain binds three calcium ions.

Similarity. Belongs to the thrombospondin family.

Isoforms (2)

UniProt ID	Names	Canonical?
P49747-1	1	yes
P49747-2	2

RefSeq proteins (1): NP_000086* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR003367	Thrombospondin_3-like_rpt	Repeat
IPR008859	Thrombospondin_C	Domain
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR017897	Thrombospondin_3_rpt	Repeat
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR024665	TSP/COMP_CC	Domain
IPR028974	TSP_type-3_rpt	Homologous_superfamily
IPR039081	TSP-5_CC	Domain
IPR046970	TSP/COMP_CC_sf	Homologous_superfamily
IPR049883	NOTCH1_EGF-like	Domain

Pfam: PF02412, PF05735, PF07645, PF11598

UniProt features (184 total): sequence variant 81, strand 34, disulfide bond 23, helix 12, repeat 8, turn 6, domain 5, region of interest 3, compositionally biased region 3, sequence conflict 2, glycosylation site 2, signal peptide 1, chain 1, short sequence motif 1, site 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3FBY	X-RAY DIFFRACTION	3.15

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49747-F1	88.60	0.67

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): 77–78 (cleavage; by adamts4)

Disulfide bonds (23): 69, 72, 91–102, 96–111, 114–125, 131–142, 136–151, 154–178, 184–197, 191–206, 209–221, 229–243, 237–253, 255–266, 282–287, 292–312, 328–348, 351–371, 387–407, 410–430 …

Glycosylation sites (2): 121, 742

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-216083	Integrin cell surface interactions
R-HSA-3000178	ECM proteoglycans

MSigDB gene sets: 388 (showing top): TURASHVILI_BREAST_LOBULAR_CARCINOMA_VS_DUCTAL_NORMAL_UP, BENPORATH_ES_WITH_H3K27ME3, GOBP_COLLAGEN_FIBRIL_ORGANIZATION, GOBP_CARTILAGE_DEVELOPMENT, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_SMOOTH_MUSCLE_CELL_DIFFERENTIATION, GOBP_PLATELET_ACTIVATION, MODULE_45, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_GROWTH, SMID_BREAST_CANCER_RELAPSE_IN_LUNG_DN, GOBP_ARTERY_DEVELOPMENT, GOBP_MULTICELLULAR_ORGANISMAL_MOVEMENT

GO Biological Process (38): skeletal system development (GO:0001501), chondrocyte development (GO:0002063), growth plate cartilage development (GO:0003417), apoptotic process (GO:0006915), response to unfolded protein (GO:0006986), protein secretion (GO:0009306), animal organ morphogenesis (GO:0009887), regulation of gene expression (GO:0010468), vascular associated smooth muscle contraction (GO:0014829), protein processing (GO:0016485), collagen fibril organization (GO:0030199), bone mineralization (GO:0030282), regulation of bone mineralization (GO:0030500), BMP signaling pathway (GO:0030509), multicellular organism growth (GO:0035264), chondrocyte proliferation (GO:0035988), tendon development (GO:0035989), negative regulation of apoptotic process (GO:0043066), skin development (GO:0043588), artery morphogenesis (GO:0048844), musculoskeletal movement (GO:0050881), protein homooligomerization (GO:0051260), limb development (GO:0060173), platelet aggregation (GO:0070527), cellular senescence (GO:0090398), vascular associated smooth muscle cell development (GO:0097084), negative regulation of hemostasis (GO:1900047), positive regulation of chondrocyte proliferation (GO:1902732), cartilage homeostasis (GO:1990079), ossification (GO:0001503), endochondral bone growth (GO:0003416), cell adhesion (GO:0007155), blood coagulation (GO:0007596), neuromuscular process (GO:0050905), cartilage development (GO:0051216), muscle cell development (GO:0055001), bone morphogenesis (GO:0060349), bone growth (GO:0098868)

GO Molecular Function (10): protease binding (GO:0002020), integrin binding (GO:0005178), extracellular matrix structural constituent (GO:0005201), calcium ion binding (GO:0005509), collagen binding (GO:0005518), heparin binding (GO:0008201), BMP binding (GO:0036122), proteoglycan binding (GO:0043394), heparan sulfate proteoglycan binding (GO:0043395), protein binding (GO:0005515)

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), extracellular matrix (GO:0031012), protein-containing complex (GO:0032991), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Extracellular matrix organization	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
connective tissue development	2
animal organ development	2
protein-containing complex binding	2
system development	1
chondrocyte differentiation	1
cell development	1
endochondral bone growth	1
cartilage development involved in endochondral bone morphogenesis	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
response to topologically incorrect protein	1
protein transport	1
secretion by cell	1
establishment of protein localization to extracellular region	1
protein localization to extracellular region	1
anatomical structure morphogenesis	1
gene expression	1
regulation of macromolecule biosynthetic process	1
smooth muscle contraction	1
vasoconstriction	1
proteolysis	1
protein maturation	1
extracellular matrix organization	1
ossification	1
biomineral tissue development	1
regulation of ossification	1
bone mineralization	1
regulation of biomineral tissue development	1
cellular response to BMP stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
multicellular organismal process	1
developmental growth	1
cell population proliferation	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
blood vessel morphogenesis	1
artery development	1
enzyme binding	1

Protein interactions and networks

STRING

2153 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COMP	FN1	P02751	957
COMP	ACAN	P16112	954
COMP	ADAMTS7	Q9UKP4	912
COMP	MATN3	O15232	797
COMP	THBS4	P35443	792
COMP	FMOD	Q06828	791
COMP	DCN	P07585	786
COMP	ADAMTS12	P58397	786
COMP	BMP2	P12643	734
COMP	CFP	P27918	724
COMP	COL9A2	Q14055	717
COMP	COL9A3	Q14050	712
COMP	PRG4	Q92954	709
COMP	HAPLN1	P10915	703
COMP	COL2A1	P02458	691

IntAct

38 interactions, top by confidence:

A	B	Type	Score
OTX1	COMP	psi-mi:“MI:0915”(physical association)	0.780
COMP	OTX1	psi-mi:“MI:0915”(physical association)	0.780
ADAMTS12	COMP	psi-mi:“MI:0915”(physical association)	0.680
COMP	ADAMTS12	psi-mi:“MI:0570”(protein cleavage)	0.680
ADAMTS12	COMP	psi-mi:“MI:0570”(protein cleavage)	0.680
ATOX1	COMP	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	COMP	psi-mi:“MI:0915”(physical association)	0.560
COMP	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
COMP	NUFIP2	psi-mi:“MI:0915”(physical association)	0.560
AQP1	COMP	psi-mi:“MI:0915”(physical association)	0.560
COMP	SGTB	psi-mi:“MI:0915”(physical association)	0.560
MATN3	COMP	psi-mi:“MI:0407”(direct interaction)	0.440
ACAN	COMP	psi-mi:“MI:0407”(direct interaction)	0.440
COMP	ACAN	psi-mi:“MI:0407”(direct interaction)	0.440
ADAMTS7	COMP	psi-mi:“MI:0570”(protein cleavage)	0.440
COMP	VHL	psi-mi:“MI:0915”(physical association)	0.400
COMP	P4HB	psi-mi:“MI:0914”(association)	0.350
MATN2	CORO1A	psi-mi:“MI:0914”(association)	0.350
STAT3	COMP	psi-mi:“MI:0914”(association)	0.350
ATOX1	COMP	psi-mi:“MI:0915”(physical association)	0.000
AQP1	COMP	psi-mi:“MI:0915”(physical association)	0.000
COMP	CYSRT1	psi-mi:“MI:0915”(physical association)	0.000
COMP	MEOX2	psi-mi:“MI:0915”(physical association)	0.000
NUFIP2	COMP	psi-mi:“MI:0915”(physical association)	0.000
COMP	OTX1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (14): OTX1 (Two-hybrid), MEOX2 (Two-hybrid), NUFIP2 (Two-hybrid), OTX1 (Two-hybrid), ATOX1 (Two-hybrid), CYSRT1 (Two-hybrid), SGTB (Two-hybrid), AQP1 (Two-hybrid), COMP (Negative Genetic), COMP (Affinity Capture-MS), COMP (Affinity Capture-MS), VHL (Affinity Capture-MS), COMP (Affinity Capture-MS), COMP (Affinity Capture-MS)

ESM2 similar proteins: A0A1D5NSM8, A2AVA0, B3EWY9, B3EWZ3, B3EWZ8, G5E8Q8, O18733, O75445, O97827, P07996, P0C6B8, P14780, P22757, P28175, P34710, P35440, P35441, P35442, P35443, P35448, P41950, P49013, P49744, P49746, P49747, P91953, P97435, P98072, P98073, P98074, Q03350, Q05895, Q06441, Q17800, Q1L8P7, Q26422, Q26627, Q28178, Q38717, Q3SWW8

Diamond homologs: A0A1D0C023, A2ARV4, B3EWY9, B3NBB6, B4HVU2, B4PD96, B5DFC9, F1RRV3, O08523, O08710, O42182, O73775, O75095, O75197, O75443, O75581, O77469, O88322, O88572, P01130, P01131, P01266, P01267, P04233, P04441, P06882, P07522, P08460, P10247, P10493, P14543, P20063, P23142, P27590, P31226, P35442, P35443, P35444, P35445, P48960

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	58
Likely pathogenic	86
Uncertain significance	399
Likely benign	201
Benign	45

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1010194	NM_000095.3(COMP):c.1545C>G (p.Asp515Glu)	Pathogenic
1066799	NM_000095.3(COMP):c.1359C>G (p.Asn453Lys)	Pathogenic
1067222	NM_000095.3(COMP):c.1467C>A (p.Asn489Lys)	Pathogenic
1067975	NM_000095.3(COMP):c.949G>A (p.Asp317Asn)	Pathogenic
1074708	NM_000095.3(COMP):c.1526A>T (p.Asp509Val)	Pathogenic
1074709	NM_000095.3(COMP):c.1414G>C (p.Asp472His)	Pathogenic
1074710	NM_000095.3(COMP):c.1318G>A (p.Gly440Arg)	Pathogenic
1180714	NM_000095.3(COMP):c.1403G>T (p.Cys468Phe)	Pathogenic
1360065	NM_000095.3(COMP):c.1553A>G (p.Asp518Gly)	Pathogenic
1372994	NM_000095.3(COMP):c.1520A>G (p.Asp507Gly)	Pathogenic
1404709	NM_000095.3(COMP):c.905A>T (p.Asp302Val)	Pathogenic
1415145	NM_000095.3(COMP):c.1126G>C (p.Asp376His)	Pathogenic
1427648	NM_000095.3(COMP):c.1045G>A (p.Asp349Asn)	Pathogenic
1455152	NM_000095.3(COMP):c.1132G>A (p.Asp378Asn)	Pathogenic
1457556	NM_000095.3(COMP):c.1280G>A (p.Gly427Glu)	Pathogenic
1679945	NM_000095.3(COMP):c.868G>T (p.Asp290Tyr)	Pathogenic
1683450	NM_000095.3(COMP):c.1309G>C (p.Asp437His)	Pathogenic
1723871	NM_000095.3(COMP):c.1045G>C (p.Asp349His)	Pathogenic
2005884	NM_000095.3(COMP):c.1527T>A (p.Asp509Glu)	Pathogenic
2138261	NM_000095.3(COMP):c.1552G>A (p.Asp518Asn)	Pathogenic
2138262	NM_000095.3(COMP):c.1511G>A (p.Cys504Tyr)	Pathogenic
2138263	NM_000095.3(COMP):c.1423G>A (p.Asp475Asn)	Pathogenic
2138265	NM_000095.3(COMP):c.1052G>A (p.Cys351Tyr)	Pathogenic
2709843	NM_000095.3(COMP):c.1373A>G (p.Asp458Gly)	Pathogenic
2736852	NM_000095.3(COMP):c.1544A>G (p.Asp515Gly)	Pathogenic
2736857	NM_000095.3(COMP):c.1220G>A (p.Cys407Tyr)	Pathogenic
280393	NM_000095.3(COMP):c.875G>T (p.Cys292Phe)	Pathogenic
2862149	NM_000095.3(COMP):c.1402T>C (p.Cys468Arg)	Pathogenic
3066042	NM_000095.3(COMP):c.1359del (p.Asn453fs)	Pathogenic
3666755	NM_000095.3(COMP):c.1810C>G (p.Gln604Glu)	Pathogenic

SpliceAI

2454 predictions. Top by Δscore:

Variant	Effect	Δscore
19:18783048:GCTCA:G	donor_loss	1.0000
19:18783049:CTCAC:C	donor_loss	1.0000
19:18783050:TCAC:T	donor_loss	1.0000
19:18783051:CA:C	donor_loss	1.0000
19:18783052:A:AC	donor_gain	1.0000
19:18783052:ACCA:A	donor_loss	1.0000
19:18783053:C:CC	donor_gain	1.0000
19:18783053:C:T	donor_loss	1.0000
19:18783192:CC:C	acceptor_gain	1.0000
19:18783193:CC:C	acceptor_gain	1.0000
19:18783194:C:CC	acceptor_gain	1.0000
19:18784883:ACGGC:A	donor_gain	1.0000
19:18784884:CGGCC:C	donor_gain	1.0000
19:18784887:C:A	donor_gain	1.0000
19:18784891:GGCAC:G	donor_loss	1.0000
19:18784892:GCACC:G	donor_loss	1.0000
19:18784893:CACCT:C	donor_loss	1.0000
19:18784894:A:C	donor_loss	1.0000
19:18784895:CCT:C	donor_loss	1.0000
19:18784943:G:A	donor_gain	1.0000
19:18784967:T:TA	donor_gain	1.0000
19:18784967:TCC:T	donor_gain	1.0000
19:18785088:GTAAC:G	acceptor_gain	1.0000
19:18785089:TAAC:T	acceptor_gain	1.0000
19:18785090:AAC:A	acceptor_gain	1.0000
19:18785091:AC:A	acceptor_gain	1.0000
19:18785091:ACC:A	acceptor_loss	1.0000
19:18785092:CC:C	acceptor_gain	1.0000
19:18785093:C:CC	acceptor_gain	1.0000
19:18785099:A:AC	acceptor_gain	1.0000

AlphaMissense

5062 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:18783100:G:C	F727L	1.000
19:18783100:G:T	F727L	1.000
19:18783102:A:G	F727L	1.000
19:18784250:C:A	W676C	1.000
19:18784250:C:G	W676C	1.000
19:18784252:A:G	W676R	1.000
19:18784252:A:T	W676R	1.000
19:18784313:C:A	W655C	1.000
19:18784313:C:G	W655C	1.000
19:18784315:A:G	W655R	1.000
19:18784315:A:T	W655R	1.000
19:18784944:C:A	W622C	1.000
19:18784944:C:G	W622C	1.000
19:18784970:A:G	W614R	1.000
19:18784970:A:T	W614R	1.000
19:18785688:C:A	W551C	1.000
19:18785688:C:G	W551C	1.000
19:18785690:A:G	W551R	1.000
19:18785690:A:T	W551R	1.000
19:18783081:A:G	W734R	0.999
19:18783081:A:T	W734R	0.999
19:18783103:G:C	C726W	0.999
19:18783114:C:A	G723W	0.999
19:18784221:A:G	L686P	0.999
19:18784228:A:G	W684R	0.999
19:18784228:A:T	W684R	0.999
19:18784251:C:G	W676S	0.999
19:18784900:A:G	L637P	0.999
19:18784946:A:G	W622R	0.999
19:18784946:A:T	W622R	0.999

dbSNP variants (sampled 300 via entrez): RS1000230900 (19:18788212 C>G,T), RS1000620272 (19:18782605 AC>A), RS1000738967 (19:18782425 CCGAA>C), RS1001137977 (19:18790782 C>T), RS1001170842 (19:18791537 G>T), RS1001402764 (19:18790464 C>T), RS1001694143 (19:18785754 G>A,T), RS1002242685 (19:18789762 G>A), RS1002435798 (19:18792734 A>G), RS1002875535 (19:18793132 G>A), RS1003270019 (19:18782958 G>A), RS1003649690 (19:18788558 A>C,G), RS1004112824 (19:18783283 C>G), RS1004139467 (19:18783651 C>A,T), RS1004616053 (19:18788137 C>G,T)

Disease associations

OMIM: gene MIM:600310 | disease phenotypes: MIM:177170, MIM:132400, MIM:619161

GenCC curated gene-disease

Disease	Classification	Inheritance
pseudoachondroplasia	Definitive	Autosomal dominant
multiple epiphyseal dysplasia type 1	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
COMP-related skeletal dysplasia	Definitive	AD

Mondo (5): pseudoachondroplasia (MONDO:0008322), multiple epiphyseal dysplasia type 1 (MONDO:0007561), carpal tunnel syndrome 2 (MONDO:0030883), multiple epiphyseal dysplasia (MONDO:0016648), connective tissue disorder (MONDO:0003900)

Orphanet (3): Pseudoachondroplasia (Orphanet:750), Multiple epiphyseal dysplasia type 1 (Orphanet:93308), Multiple epiphyseal dysplasia (Orphanet:251)

HPO phenotypes

93 total (30 of 93 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000763	Sensory neuropathy
HP:0000926	Platyspondyly
HP:0001156	Brachydactyly
HP:0001249	Intellectual disability
HP:0001288	Gait disturbance
HP:0001376	Limitation of joint mobility
HP:0001377	Limited elbow extension
HP:0001382	Joint hypermobility
HP:0001385	Hip dysplasia
HP:0001387	Joint stiffness
HP:0001498	Carpal bone hypoplasia
HP:0001763	Pes planus
HP:0002341	Cervical cord compression
HP:0002515	Waddling gait
HP:0002650	Scoliosis
HP:0002656	Epiphyseal dysplasia
HP:0002663	Delayed epiphyseal ossification
HP:0002758	Osteoarthritis
HP:0002761	Generalized joint hypermobility
HP:0002808	Kyphosis
HP:0002812	Coxa vara
HP:0002816	Genu recurvatum
HP:0002829	Arthralgia
HP:0002834	Flared femoral metaphysis
HP:0002857	Genu valgum
HP:0002938	Lumbar hyperlordosis
HP:0002970	Genu varum
HP:0003015	Flared metaphysis
HP:0003016	Metaphyseal widening

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002540_3	Osteoarthritis biomarkers	7.000000e-06
GCST004199_2	Osteoarthritis (with total hip replacement)	4.000000e-12
GCST005171_14	QT interval	3.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005890	osteoarthritis biomarker measurement
EFO:0007942	hip osteoarthritis symptom severity measurement
EFO:0004682	QT interval

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D003240	Connective Tissue Diseases	C17.300
C535819	Pseudoachondroplasia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	affects expression, increases expression	4
Valproic Acid	affects expression, increases expression	4
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	3
Estradiol	increases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
N-((3,5-difluorophenyl)acetyl)alanyl-2-phenylglycine-1,1-dimethylethyl ester	increases expression	1
2,4,6-tribromophenol	increases expression	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
HT-2 toxin	decreases expression	1
butyraldehyde	increases expression	1
tetrabromobisphenol A	increases expression	1
corosolic acid	increases expression	1
abrine	increases expression	1
hexabrominated diphenyl ether 153	increases expression	1
incobotulinumtoxinA	increases expression	1
Zoledronic Acid	increases expression	1
Acetaminophen	increases expression	1
Aluminum Oxide	increases expression	1
Calcitriol	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Ivermectin	decreases expression	1
Urethane	increases expression	1
Zinc	increases expression	1
Cyclosporine	increases expression	1
Asbestos, Crocidolite	increases expression	1
Cadmium Chloride	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04197050	PHASE4	UNKNOWN	Effect of Sacubitril/Valsartan on Reduced Right Ventricular Ejection Fraction in Patients With CTD
NCT04928586	PHASE4	UNKNOWN	Immunosuppressant Combined With Pirfenidone in CTD-ILD
NCT05440240	PHASE4	RECRUITING	Percutaneous Needle Fasciotomy +/- Corticosteroid Injection for Dupuytren’s Contracture
NCT05505409	PHASE4	UNKNOWN	Efficacy and Safety of Pirfenidone in CTD-ILD
NCT06499233	PHASE4	RECRUITING	Efficacy and Safety of Prophylactic Treatment for Pneumocystis Jirovecii Pneumonia in Patients With Autoimmune Inflammatory Rheumatic Disease
NCT00864201	PHASE3	UNKNOWN	A Study to Evaluate the Use of Bosentan in Patients With Exercise Induced Pulmonary Arterial Hypertension Associated With Connective Tissue Disease
NCT01196091	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01205438	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01488708	PHASE3	TERMINATED	On Open-Label Study in Participants With Systemic Lupus Erythematosus
NCT03626688	PHASE3	COMPLETED	A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients
NCT03683186	PHASE3	ENROLLING_BY_INVITATION	A Study Evaluating the Long-Term Efficacy and Safety of Ralinepag in Subjects With PAH Via an Open-Label Extension
NCT04084678	PHASE3	TERMINATED	A Study of Ralinepag to Evaluate Effects on Exercise Capacity by CPET in Subjects With WHO Group 1 PH
NCT06716606	PHASE3	RECRUITING	A Study to Investigate the Long-term Safety and Efficacy of Belimumab in Adults With Interstitial Lung Disease (ILD) Associated With Systemic Sclerosis (SSc) and Other Connective Tissue Diseases (CTD) (BLISSconneCTD-OLE)
NCT06917690	PHASE3	RECRUITING	A Study to Learn About the Safety and Efficacy of the Drug Oleogel-S10 in Japanese Patients With Epidermolysis Bullosa
NCT03866200	PHASE2	TERMINATED	Resveratrol Trial for Relief of Pain in Pseudoachondroplasia
NCT00004357	PHASE2	COMPLETED	Absorption of Corticosteroids in Children With Juvenile Dermatomyositis
NCT00005675	PHASE2	COMPLETED	Oral Type I Collagen for Relieving Scleroderma
NCT01808196	PHASE2	COMPLETED	Testing Effectiveness of Losartan in Patients With EoE With or Without a CTD
NCT02682511	PHASE2	ACTIVE_NOT_RECRUITING	Oral Ifetroban to Treat Diffuse Cutaneous Systemic Sclerosis (SSc) or SSc-associated Pulmonary Arterial Hypertension
NCT04993885	PHASE2	RECRUITING	Avatrombopag in the Treatment of Adult Immune Thrombocytopenia With Autoantibodies
NCT05516758	PHASE2	TERMINATED	A Study of Peresolimab (LY3462817) in Participants With Moderately-to-Severely Active Rheumatoid Arthritis
NCT05998759	PHASE2	RECRUITING	Telitacicept for the Treatment of Connective Tissue Disease-associated Thrombocytopenia
NCT06104228	PHASE2	RECRUITING	129 Xenon MRI as a Biomarker for Diagnosis and Response to Therapy in Pulmonary Arterial Hypertension (PAH)
NCT01093911	PHASE1	COMPLETED	Safety Study of CDP7657 in Healthy Volunteers and Patients With Systemic Lupus Erythematosus (SLE)
NCT01764594	PHASE1	COMPLETED	Safety Study of CDP7657 in Patients With Systemic Lupus Erythematosus
NCT02392130	PHASE1	COMPLETED	A Clinical Trial to Assess the Potential of LEO 130852A Gel to Reduce Steroid Induced Skin Atrophy on Healthy Skin
NCT03337165	PHASE1	COMPLETED	Autologous Tolerogenic Dendritic Cells for Treatment of Patients With Rheumatoid Arthritis
NCT03929120	PHASE1	COMPLETED	Allogeneic Bone Marrow Mesenchymal Stem Cells for Patients With Interstitial Lung Disease (ILD) & Connective Tissue Disorders (CTD)
NCT01424033	PHASE2/PHASE3	TERMINATED	A Clinical Trial for CTD-ILD Treatment
NCT04915482	PHASE2/PHASE3	UNKNOWN	TPO-RAs Combined With Anti-CD20 Antibody in the Treatment of Adult Immune Thrombocytopenia With Autoantibodies
NCT06574581	PHASE1/PHASE2	RECRUITING	ADSCs Therapy in Patients With CTD-ILD
NCT00001330	Not specified	COMPLETED	Study of Silicone-Associated Connective Tissue Diseases
NCT00001641	Not specified	COMPLETED	Study of Heritable Connective Tissue Disorders
NCT00001978	Not specified	TERMINATED	Determination of Kidney Function
NCT00076830	Not specified	COMPLETED	Evaluation and Treatment of Patients With Connective Tissue Disease
NCT00341679	Not specified	COMPLETED	Studies of the Natural History and Pathogenesis of Autoimmune/Connective Tissue Diseases
NCT00470327	Not specified	RECRUITING	A Study of the Natural Progression of Interstitial Lung Disease (ILD)