COL2A1

Summary

COL2A1 (collagen type II alpha 1 chain, HGNC:2200) is a protein-coding gene on chromosome 12q13.11, encoding Collagen alpha-1(II) chain (P02458). Type II collagen is specific for cartilaginous tissues. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes the alpha-1 chain of type II collagen, a fibrillar collagen found in cartilage and the vitreous humor of the eye. Mutations in this gene are associated with achondrogenesis, chondrodysplasia, early onset familial osteoarthritis, SED congenita, Langer-Saldino achondrogenesis, Kniest dysplasia, Stickler syndrome type I, and spondyloepimetaphyseal dysplasia Strudwick type. In addition, defects in processing chondrocalcin, a calcium binding protein that is the C-propeptide of this collagen molecule, are also associated with chondrodysplasia. There are two transcripts identified for this gene.

Source: NCBI Gene 1280 — RefSeq curated summary.

At a glance

• Gene–disease (curated): achondrogenesis type II (Definitive, ClinGen) — +23 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 3,518 total — 625 pathogenic, 406 likely-pathogenic
• Phenotypes (HPO): 360
• Druggable target: yes
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001844

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2200
Approved symbol	COL2A1
Name	collagen type II alpha 1 chain
Location	12q13.11
Locus type	gene with protein product
Status	Approved
Aliases	STL1
Ensembl gene	ENSG00000139219
Ensembl biotype	protein_coding
OMIM	120140
Entrez	1280

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 4 retained_intron, 3 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000337299, ENST00000380518, ENST00000465743, ENST00000466884, ENST00000474996, ENST00000483376, ENST00000490609, ENST00000493991, ENST00000546974, ENST00000928357

RefSeq mRNA: 2 — MANE Select: NM_001844 NM_001844, NM_033150

CCDS: CCDS41778, CCDS8759

Canonical transcript exons

ENST00000380518 — 54 exons

Exon	Start	End
ENSE00001521209	47972967	47973553
ENSE00001598832	47993994	47994047
ENSE00001606284	47993809	47993862
ENSE00001626662	47995255	47995308
ENSE00001641870	47995710	47995763
ENSE00001713001	47997606	47997707
ENSE00001716055	47994424	47994477
ENSE00001729865	47992878	47992931
ENSE00001749051	47996548	47996625
ENSE00001752481	47993458	47993502
ENSE00001763552	47989228	47989281
ENSE00001774985	47989761	47989805
ENSE00001805624	47995875	47995919
ENSE00003463788	47983093	47983137
ENSE00003467659	47975963	47976070
ENSE00003480196	47974675	47974862
ENSE00003482255	47998415	47998431
ENSE00003490773	47983683	47983736
ENSE00003495045	47986835	47986888
ENSE00003505036	47980554	47980661
ENSE00003506481	47981776	47981829
ENSE00003507992	47977320	47977427
ENSE00003517693	47977600	47977653
ENSE00003518710	47981343	47981396
ENSE00003519572	47980915	47980968
ENSE00003522191	47977102	47977155
ENSE00003522717	48004237	48004476
ENSE00003525342	47976812	47976919
ENSE00003527270	47998032	47998064
ENSE00003528225	47997871	47997924
ENSE00003530628	47985534	47985587
ENSE00003536261	47983385	47983438
ENSE00003539119	47976514	47976567
ENSE00003539340	47987269	47987313
ENSE00003542545	47982107	47982160
ENSE00003549194	47984995	47985093
ENSE00003566920	47980009	47980062
ENSE00003578663	47987078	47987176
ENSE00003579490	47985728	47985826
ENSE00003590489	47982848	47982946
ENSE00003597965	47984546	47984599
ENSE00003598556	47987611	47987709
ENSE00003598704	47999919	48000125
ENSE00003625148	47998169	47998201
ENSE00003625527	47978291	47978398
ENSE00003636434	47978010	47978117
ENSE00003641845	47984087	47984140
ENSE00003654556	47982502	47982609
ENSE00003660329	47974089	47974331
ENSE00003677477	47985912	47985965
ENSE00003680424	47986336	47986443
ENSE00003684678	47975317	47975605
ENSE00003688064	47978597	47978758
ENSE00003692946	47979511	47979564

Expression profiles

Bgee: expression breadth ubiquitous, 145 present calls, max score 99.99.

FANTOM5 (CAGE): breadth broad, TPM avg 9.1572 / max 2785.5725, expressed in 234 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
130715	6.3849	211
130716	2.7723	188

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	99.99	gold quality
cartilage tissue	UBERON:0002418	99.95	gold quality
corpus epididymis	UBERON:0004359	94.17	gold quality
trachea	UBERON:0003126	93.82	gold quality
sperm	CL:0000019	85.17	gold quality
trabecular bone tissue	UBERON:0002483	83.20	gold quality
adrenal tissue	UBERON:0018303	82.48	gold quality
male germ cell	CL:0000015	82.20	gold quality
cauda epididymis	UBERON:0004360	78.70	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.66	silver quality
pituitary gland	UBERON:0000007	77.30	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	76.50	gold quality
tendon of biceps brachii	UBERON:0008188	74.60	gold quality
adenohypophysis	UBERON:0002196	73.41	gold quality
periodontal ligament	UBERON:0008266	73.38	silver quality
ventricular zone	UBERON:0003053	73.10	gold quality
body of stomach	UBERON:0001161	72.28	gold quality
stomach	UBERON:0000945	71.71	gold quality
embryo	UBERON:0000922	71.68	gold quality
left testis	UBERON:0004533	69.24	gold quality
right testis	UBERON:0004534	69.07	gold quality
caput epididymis	UBERON:0004358	68.42	gold quality
testis	UBERON:0000473	68.20	gold quality
fundus of stomach	UBERON:0001160	66.69	gold quality
stromal cell of endometrium	CL:0002255	63.22	gold quality
endometrium epithelium	UBERON:0004811	62.35	gold quality
mammary duct	UBERON:0001765	60.60	gold quality
pancreatic ductal cell	CL:0002079	60.03	silver quality
cardia of stomach	UBERON:0001162	58.97	silver quality
rectum	UBERON:0001052	57.21	gold quality

Single-cell (SCXA)

Detected in 15 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	11943.47
E-MTAB-8221	yes	7861.32
E-HCAD-56	yes	3733.68
E-MTAB-11121	yes	442.87
E-MTAB-10018	yes	243.46
E-GEOD-130473	yes	240.62
E-GEOD-124472	yes	179.80
E-MTAB-7008	yes	144.65
E-GEOD-93593	yes	121.13
E-GEOD-75140	yes	120.31
E-HCAD-4	yes	117.39
E-HCAD-10	yes	46.64
E-MTAB-6108	no	208.50
E-GEOD-75367	no	86.61
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AIRE, ARID5A, BHLHE40, CEBPA, CEBPG, DLX2, EGR1, EHF, ELF3, ESR1, ETS1, FOS, FOXC1, HAND2, HBP1, HES1, HEY1, HIF1A, HIVEP1, KAT5, LEF1, MAF, MEF2C, MSX2, NCOA2, NFAT5, NFIB, NFIC, NFKB1, NONO, NOTCH1, RELA, RUNX2, SCX, SMAD2, SMAD3, SNAI1, SNAI2, SOX10, SOX17

miRNA regulators (miRDB)

49 targeting COL2A1, 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-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-5692A	100.00	74.40	6850
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-18A-3P	99.56	65.68	1092
HSA-MIR-4677-3P	99.49	67.91	1246
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-6871-3P	99.43	68.85	741
HSA-MIR-889-3P	99.40	69.76	2103
HSA-MIR-4797-5P	99.39	68.01	1354
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-622	98.99	66.48	1050
HSA-MIR-3074-5P	98.82	66.56	1414
HSA-MIR-11399	98.71	65.69	869

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• The first paper to show that mutations in exon 2 result in a predominantly ocular form of Stickler syndrome (PMID:10729292)
• Sp3 represses the Sp1-mediated transactivation of the human COL2A1 gene in primary and de-differentiated chondrocytes (PMID:11447232)
• This form of premature osteoarthritis may present in childhood and should be considered in the differential diagnosis of childhood arthropathy presenting in the context of a positive family history. (PMID:11708863)
• COL2A1 gene expression in differentiating chondrocytes can be modulated by culture conditions so that its transcriptional activity is repressed in monolayer cultures and rescued to some extent when the cells are switched to polyHEMA substrata. (PMID:11716775)
• TGF-beta1 inhibition of COL2A1 gene transcription in articular chondrocytes is mediated by an increase of the Sp3/Sp1 ratio and by the repression of Sp1 transactivating effects on that gene (PMID:12186868)
• Upstream elements present in the 3’-untranslated region of the gene influence the processing efficiency of overlapping polyadenylation signals. (PMID:12200454)
• identification of TATA-containing core promoter as target of interferon-gamma-mediated inhibition in human chondrocytes (PMID:12223098)
• Linkage of stop codon mutation in exon 2 of the collagen 2A1 gene in a large stickler syndrome family. (PMID:12429249)
• A variant of Stickler syndrome, caused by mutations in exon 2 of COL2A1, may present in families (PMID:12429250)
• Posterior chorioretinal atrophy and vitreous phenotype in a family with Stickler syndrome from a mutation in the COL2A1 gene. (PMID:12511349)
• Mutations of Col2a1 result in Stickler syndrome. (PMID:12544472)
• Egr-1 represses COL2A1 by preventing interactions between Sp1 and the general transcriptional machinery (PMID:12637574)
• SOX9 exerts a bifunctional effect on COL2A1 gene expression in chondrocytes depending on the differentiation state. (PMID:12713737)
• In promoter assays, CBP/p300 enhances Col2a1, which encodes cartilage-specific type II collagen gene promoter activity via Sox9. (PMID:12732631)
• SOX9 is not the key regulator of COL2A1 promoter activity in human adult articular chondrocytes (PMID:12935820)
• Kniest dysplasia with retinal detachment associated with a novel type II collagen gene (COL2A1) mutation. (PMID:14644246)
• A missense mutation in a lethal type case and a 4-base pair deletion in a non-lethal case in COL2A1 of platyspondylic skeletal dysplasia, Torrance type patients. (PMID:14729840)
• BMP2 or 4 in pilomatricoma is responsible for induction of proalpha(1)(II) collagen mRNA in overlying epidermal cells resulting in deposition of type II collagen in dermo-epidermal junction (PMID:15102076)
• a prototypical chordin-like cysteine-rich repeat (von Willebrand Factor type C module) from collagen IIA may be evolutionarily conserved (PMID:15466413)
• single amino acid substitution positions in the collagen triple helix determine their effect on structure of collagen fibrils (PMID:15522781)
• Mutations outside the alternatively spliced exon 2 region of COL2A1 can also result in an ocular only phenotype. There was no evidence that missplicing modifies the phenotype of these mutations (PMID:15671297)
• The presence of type II collagen in the extracellular tumor matrix significantly facilitates the diagnosis of mesenchymal chondrosarcomas in the absence of histologically visible chondroid matrix formation. (PMID:15731776)
• identification of COL2A1 mutations in 56 families that were suspected of having type II collagenopathies, and 38 mutations in 41 families were found (PMID:15895462)
• In families with avascular necrosis of the femoral head, haplotype and sequence analysis of the COL2A1 gene can be used to identify carriers of the mutant allele before the onset of clinical symptoms (PMID:15930420)
• Data demonstrate a significant reduction of collagens I, II and aggrecan mRNA after the initiation of culture compared with mRNA levels in fresh tissue. (PMID:16001263)
• cis elements in the COL2A1 gene modulate the cell type-specific alternative splicing switch of exon 2 during cartilage development (PMID:16076844)
• Trypsin degrades COL2A1 and is expressed and activated in mesenchymally transformed rheumatoid arthritis synovitis tissue. (PMID:16192646)
• When modified by conditions found within the inflamed joint, CII acts as an autoantigen in rheumatoid arthritis (PMID:16329077)
• An 8-year-old boy with type 1 Stickler syndrome showed a novel mutation in intron 11 of the COL2A1 gene (PMID:16395149)
• Mechanical compression increases the level of type II mRNA expression by transcriptional activation possibly through the Sp1 binding sites residing in the proximal region of the COL2A1 gene promoter. (PMID:16650379)
• In comparison with healthy cartilage, Osteoarthritis articular chondrocytes exhibit increased in vivo synthesis of collagen prolyl-4-hydroxylase type II, a pivotal enzyme in collagen triple helix formation. (PMID:16877351)
• Premature induction of hypertrophy-related molecules (type X collagen and matrix metalloproteinase 13) occurred before production of type II collagen and was followed by up-regulation of alkaline phosphatase activity. (PMID:17009260)
• COL2A1 mutations associated with marked metaphyseal dysplasia with only mild epiphyseal and spondylar changes. (PMID:17163530)
• The expression of collagen type II and TGF-beta1, bFGF in adolescent idiopathic scoliosis was similar to congenital scoliosis. (PMID:17217840)
• type II collagen expression was observed very focally within advanced atherosclerotic plaques in crural arteries (PMID:17335825)
• Study found a missense mutation (p.G1170S) in COL2A1 in a Japanese family with an autosomal dominant hip disorder manifesting as Legg-Calve-Perthes disease and showing considerable intra-familial phenotypic variation. (PMID:17394019)
• We present two missense mutations and one apparently silent mutation that each result in Stickler syndrome, but via different molecular mechanisms. (PMID:17437277)
• Familial mutation of G504S of collagen type II alpha (COL2A1) gene results in distinctive spondyloepiphyseal dysplasia congenita. (PMID:17509551)
• Human cells cultured over 5 days increased expression of aggrecan and collagen II in both nucleus and annulus cells under increasing osmolarity. (PMID:17568421)
• dual role for TIA-1 in shuttling between DNA and RNA ligands to co-regulate COL2A1 expression at the level of transcription and pre-mRNA alternative splicing. (PMID:17580305)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	col2a1b	ENSDARG00000011407
danio_rerio	col2a1a	ENSDARG00000069093
mus_musculus	Col2a1	ENSMUSG00000022483
rattus_norvegicus	Col2a1	ENSRNOG00000058560

Paralogs (37): COL9A2 (ENSG00000049089), COL23A1 (ENSG00000050767), COL11A1 (ENSG00000060718), COL17A1 (ENSG00000065618), COL5A3 (ENSG00000080573), COL4A4 (ENSG00000081052), COL16A1 (ENSG00000084636), COL9A3 (ENSG00000092758), COL20A1 (ENSG00000101203), COL1A1 (ENSG00000108821), COL9A1 (ENSG00000112280), COL7A1 (ENSG00000114270), COL21A1 (ENSG00000124749), COL5A1 (ENSG00000130635), COL4A2 (ENSG00000134871), COL6A1 (ENSG00000142156), COL6A2 (ENSG00000142173), EDA (ENSG00000158813), COL26A1 (ENSG00000160963), COL1A2 (ENSG00000164692), COL3A1 (ENSG00000168542), COL4A3 (ENSG00000169031), COL22A1 (ENSG00000169436), COL24A1 (ENSG00000171502), COL18A1 (ENSG00000182871), EMID1 (ENSG00000186998), COL4A1 (ENSG00000187498), COL4A5 (ENSG00000188153), COL25A1 (ENSG00000188517), COL27A1 (ENSG00000196739), COL13A1 (ENSG00000197467), COL4A6 (ENSG00000197565), COL11A2 (ENSG00000204248), COL5A2 (ENSG00000204262), COL15A1 (ENSG00000204291), COLQ (ENSG00000206561), COL28A1 (ENSG00000215018)

Protein

Protein identifiers

Collagen alpha-1(II) chain — P02458 (reviewed: P02458)

Alternative names: Alpha-1 type II collagen

All UniProt accessions (1): P02458

UniProt curated annotations — full annotation on UniProt →

Function. Type II collagen is specific for cartilaginous tissues. It is essential for the normal embryonic development of the skeleton, for linear growth and for the ability of cartilage to resist compressive forces.

Subunit / interactions. Homotrimers of alpha 1(II) chains.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Isoform 2 is highly expressed in juvenile chondrocyte and low in fetal chondrocyte.

Post-translational modifications. The N-telopeptide is covalently linked to the helical COL2 region of alpha 1(IX), alpha 2(IX) and alpha 3(IX) chain. The C-telopeptide is covalently linked to an another site in the helical region of alpha 3(IX) COL2. Contains mostly 4-hydroxyproline. Prolines at the third position of the tripeptide repeating unit (G-X-P) are 4-hydroxylated in some or all of the chains. Contains 3-hydroxyproline at a few sites. This modification occurs on the first proline residue in the sequence motif Gly-Pro-Hyp, where Hyp is 4-hydroxyproline. Lysine residues at the third position of the tripeptide repeating unit (G-X-Y) are 5-hydroxylated in some or all of the chains. O-glycosylated on hydroxylated lysine residues. The O-linked glycan consists of a Glc-Gal disaccharide.

Disease relevance. Spondyloepiphyseal dysplasia congenital type (SEDC) [MIM:183900] Disorder characterized by disproportionate short stature and pleiotropic involvement of the skeletal and ocular systems. The disease is caused by variants affecting the gene represented in this entry. Spondyloepiphyseal dysplasia, Stanescu type (SEDSTN) [MIM:616583] An autosomal dominant spondyloepiphyseal dysplasia characterized by glycoproteins accumulation in chondrocytes. Clinical features include progressive joint contractures, premature degenerative joint disease particularly in the knee, hip and finger joints, and osseous distention of the metaphyseal ends of the phalanges causing swolling of interphalangeal joints of the hands. Radiological features include generalized platyspondyly, hypoplastic pelvis, epiphyseal flattening with metaphyseal splaying of the long bones, and enlarged phalangeal epimetaphyses of the hands. The disease is caused by variants affecting the gene represented in this entry. Spondyloepimetaphyseal dysplasia, Strudwick type (SEMDSTWK) [MIM:184250] A bone disease characterized by disproportionate short stature from birth, with a very short trunk and shortened limbs, and skeletal abnormalities including lordosis, scoliosis, flattened vertebrae, pectus carinatum, coxa vara, clubfoot, and abnormal epiphyses or metaphyses. A distinctive radiographic feature is irregular sclerotic changes, described as dappled in the metaphyses of the long bones. The disease is caused by variants affecting the gene represented in this entry. Achondrogenesis 2 (ACG2) [MIM:200610] An autosomal dominant disease characterized by the absence of ossification in the vertebral column, sacrum and pubic bones. The disease is caused by variants affecting the gene represented in this entry. Legg-Calve-Perthes disease (LCPD) [MIM:150600] Characterized by loss of circulation to the femoral head, resulting in avascular necrosis in a growing child. Clinical pictures of the disease vary, depending on the phase of disease progression through ischemia, revascularization, fracture and collapse, and repair and remodeling of the bone. The disease is caused by variants affecting the gene represented in this entry. Kniest dysplasia (KD) [MIM:156550] Moderately severe chondrodysplasia phenotype that results from mutations in the COL2A1 gene. Characteristics of the disorder include a short trunk and extremities, mid-face hypoplasia, cleft palate, myopia, retinal detachment, and hearing loss. The disease is caused by variants affecting the gene represented in this entry. Avascular necrosis of femoral head, primary, 1 (ANFH1) [MIM:608805] A disease characterized by mechanical failure of the subchondral bone, and degeneration of the hip joint. It usually leads to destruction of the hip joint in the third to fifth decade of life. The clinical manifestations, such as pain on exertion, a limping gait, and a discrepancy in leg length, cause considerable disability. ANFH1 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry. Osteoarthritis with mild chondrodysplasia (OSCDP) [MIM:604864] Osteoarthritis is a common disease that produces joint pain and stiffness together with radiologic evidence of progressive degeneration of joint cartilage. The disease is caused by variants affecting the gene represented in this entry. Platyspondylic lethal skeletal dysplasia Torrance type (PLSD-T) [MIM:151210] Platyspondylic lethal skeletal dysplasias (PLSDs) are a heterogeneous group of chondrodysplasias characterized by severe platyspondyly and limb shortening. PLSD-T is characterized by varying platyspondyly, short ribs with anterior cupping, hypoplasia of the lower ilia with broad ischial and pubic bones, and shortening of the tubular bones with splayed and cupped metaphyses. Histology of the growth plate typically shows focal hypercellularity with slightly enlarged chondrocytes in the resting cartilage and relatively well-preserved columnar formation and ossification at the chondro-osseous junction. PLSD-T is generally a perinatally lethal disease, but a few long-term survivors have been reported. The disease is caused by variants affecting the gene represented in this entry. Multiple epiphyseal dysplasia with myopia and conductive deafness (EDMMD) [MIM:132450] A generalized skeletal dysplasia associated with significant morbidity. Joint pain, joint deformity, waddling gait, and short stature are the main clinical signs and symptoms. EDMMD is an autosomal dominant disorder characterized by epiphyseal dysplasia associated with progressive myopia, retinal thinning, crenated cataracts, conductive deafness. The disease is caused by variants affecting the gene represented in this entry. Spondyloperipheral dysplasia (SPD) [MIM:271700] SPD patients manifest short stature, midface hypoplasia, sensorineural hearing loss, spondyloepiphyseal dysplasia, platyspondyly and brachydactyly. The disease is caused by variants affecting the gene represented in this entry. Stickler syndrome 1 (STL1) [MIM:108300] An autosomal dominant form of Stickler syndrome, an inherited disorder that associates ocular signs with more or less complete forms of Pierre Robin sequence, bone disorders and sensorineural deafness. Ocular disorders may include juvenile cataract, myopia, strabismus, vitreoretinal or chorioretinal degeneration, retinal detachment, and chronic uveitis. Pierre Robin sequence includes an opening in the roof of the mouth (a cleft palate), a large tongue (macroglossia), and a small lower jaw (micrognathia). Bones are affected by slight platyspondylisis and large, often defective epiphyses. Juvenile joint laxity is followed by early signs of arthrosis. The degree of hearing loss varies among affected individuals and may become more severe over time. Syndrome expressivity is variable. The disease is caused by variants affecting the gene represented in this entry. Stickler syndrome 1 non-syndromic ocular (STL1O) [MIM:609508] An autosomal dominant form of Stickler syndrome characterized by the ocular signs typically seen in Stickler syndrome type 1 such as cataract, myopia, retinal detachment. Systemic features of premature osteoarthritis, cleft palate, hearing impairment, and craniofacial abnormalities are either absent or very mild. The disease is caused by variants affecting the gene represented in this entry. Rhegmatogenous retinal detachment autosomal dominant (DRRD) [MIM:609508] A eye disease that most frequently results from a break or tear in the retina that allows fluid from the vitreous humor to enter the potential space beneath the retina. It is often associated with pathologic myopia and in most cases leads to visual impairment or blindness if untreated. The disease is caused by variants affecting the gene represented in this entry. Czech dysplasia (CZECHD) [MIM:609162] A skeletal dysplasia characterized by early-onset, progressive pseudorheumatoid arthritis, platyspondyly, and short third and fourth toes. The disease is caused by variants affecting the gene represented in this entry. Vitreoretinopathy with phalangeal epiphyseal dysplasia (VPED) [MIM:619248] An autosomal dominant disorder characterized by rhegmatogenous retinal detachment, premature arthropathy, and development of phalangeal epiphyseal dysplasia resulting in brachydactyly. The disease is caused by variants affecting the gene represented in this entry. Spondylometaphyseal dysplasia, Algerian type (SMDALG) [MIM:184253] A form of spondylometaphyseal dysplasia, a group of short stature disorders distinguished by abnormalities in the vertebrae and the metaphyses of the tubular bones. SMDALG is an autosomal dominant form characterized by short trunk and severe genu valgum. Myopia may be a syndromic component. SMDALG radiological hallmarks include moderate platyspondyly, particularly with dorsal vertebral flattening, short ilia with narrow greater sciatic notches and generalized metaphyseal dysplasia of the long bones. The metaphyseal changes are most conspicuous in the hip and knee, and are associated with coxa vara and severe genu valgum. The short tubular bones are mildly affected. The epiphyses of the tubular bones are said to be normal. The disease may be caused by variants affecting the gene represented in this entry.

Domain organisation. The C-terminal propeptide, also known as COLFI domain, have crucial roles in tissue growth and repair by controlling both the intracellular assembly of procollagen molecules and the extracellular assembly of collagen fibrils. It binds a calcium ion which is essential for its function.

Similarity. Belongs to the fibrillar collagen family.

Isoforms (3)

UniProt ID	Names	Canonical?
P02458-2	2	yes
P02458-1	1
P02458-3	3

RefSeq proteins (2): NP_001835, NP_149162 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000885	Fib_collagen_C	Domain
IPR001007	VWF_dom	Domain
IPR008160	Collagen	Repeat
IPR050149	Collagen_superfamily	Family

Pfam: PF00093, PF01391, PF01410

UniProt features (194 total): sequence variant 84, modified residue 29, compositionally biased region 22, sequence conflict 20, glycosylation site 9, strand 5, binding site 5, disulfide bond 5, region of interest 3, chain 2, site 2, domain 2, splice variant 2, signal peptide 1, propeptide 1, turn 1, helix 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
6HG7	X-RAY DIFFRACTION	1
5NIR	X-RAY DIFFRACTION	1.74
5OCX	X-RAY DIFFRACTION	1.75
7NZE	X-RAY DIFFRACTION	2.05
6NIX	X-RAY DIFFRACTION	2.1
2SEB	X-RAY DIFFRACTION	2.5
6BIN	X-RAY DIFFRACTION	2.5
5OCY	X-RAY DIFFRACTION	2.6
5MV4	X-RAY DIFFRACTION	2.9
2FSE	X-RAY DIFFRACTION	3.1
1U5M	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P02458-F1	53.56	0.16

Antibody-complex structures (SAbDab): 3 — 5MV4, 5OCX, 5OCY

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 (2): 181–182 (cleavage; by procollagen n-endopeptidase); 1241–1242 (cleavage; by procollagen c-endopeptidase)

Ligand- & substrate-binding residues (5): 1301; 1303; 1304; 1306; 1309

Post-translational modifications (29): 190, 287, 299, 308, 374, 608, 620, 659, 668, 670, 671, 674, 907, 908, 914, 920, 1130, 1144, 1181, 1186 …

Disulfide bonds (5): 1283–1315, 1289, 1306, 1323–1485, 1393–1438

Glycosylation sites (9): 190, 287, 299, 308, 374, 608, 620, 1130, 1388

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-1442490	Collagen degradation
R-HSA-1566977	Fibronectin matrix formation
R-HSA-1650814	Collagen biosynthesis and modifying enzymes
R-HSA-186797	Signaling by PDGF
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell
R-HSA-2022090	Assembly of collagen fibrils and other multimeric structures
R-HSA-216083	Integrin cell surface interactions
R-HSA-3000171	Non-integrin membrane-ECM interactions
R-HSA-3000178	ECM proteoglycans
R-HSA-419037	NCAM1 interactions
R-HSA-8874081	MET activates PTK2 signaling
R-HSA-8948216	Collagen chain trimerization
R-HSA-9925563	Developmental Lineage of Pancreatic Ductal Cells

MSigDB gene sets: 881 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GSE45365_NK_CELL_VS_CD11B_DC_UP, TGGTGCT_MIR29A_MIR29B_MIR29C, MODULE_52, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, MYOGENIN_Q6, GOBP_COLLAGEN_FIBRIL_ORGANIZATION, GOBP_CARTILAGE_DEVELOPMENT, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOCC_COLLAGEN_TRIMER

GO Biological Process (31): skeletal system development (GO:0001501), cartilage condensation (GO:0001502), tissue homeostasis (GO:0001894), endochondral ossification (GO:0001958), chondrocyte differentiation (GO:0002062), heart morphogenesis (GO:0003007), proteoglycan metabolic process (GO:0006029), central nervous system development (GO:0007417), visual perception (GO:0007601), sensory perception of sound (GO:0007605), regulation of gene expression (GO:0010468), collagen fibril organization (GO:0030199), notochord development (GO:0030903), inner ear morphogenesis (GO:0042472), cartilage development (GO:0051216), roof of mouth development (GO:0060021), limb bud formation (GO:0060174), embryonic skeletal joint morphogenesis (GO:0060272), cartilage development involved in endochondral bone morphogenesis (GO:0060351), otic vesicle development (GO:0071599), cellular response to BMP stimulus (GO:0071773), anterior head development (GO:0097065), extrinsic apoptotic signaling pathway in absence of ligand (GO:0097192), negative regulation of extrinsic apoptotic signaling pathway in absence of ligand (GO:2001240), ossification (GO:0001503), limb morphogenesis (GO:0035108), animal organ development (GO:0048513), skeletal system morphogenesis (GO:0048705), system development (GO:0048731), inner ear development (GO:0048839), bone development (GO:0060348)

GO Molecular Function (9): extracellular matrix structural constituent (GO:0005201), extracellular matrix structural constituent conferring tensile strength (GO:0030020), MHC class II protein binding (GO:0042289), protein homodimerization activity (GO:0042803), proteoglycan binding (GO:0043394), metal ion binding (GO:0046872), platelet-derived growth factor binding (GO:0048407), protein binding (GO:0005515), identical protein binding (GO:0042802)

GO Cellular Component (10): extracellular region (GO:0005576), collagen type II trimer (GO:0005585), collagen type XI trimer (GO:0005592), basement membrane (GO:0005604), obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788), extracellular matrix (GO:0031012), collagen trimer (GO:0005581), fibrillar collagen trimer (GO:0005583), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Extracellular matrix organization	4
Collagen formation	2
Degradation of the extracellular matrix	1
Signaling by Receptor Tyrosine Kinases	1
Adaptive Immune System	1
NCAM signaling for neurite out-growth	1
MET promotes cell motility	1
Collagen biosynthesis and modifying enzymes	1
Developmental Cell Lineages of the Exocrine Pancreas	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cartilage development	3
system development	2
endochondral bone morphogenesis	2
inner ear development	2
extracellular matrix	2
protein binding	2
cellular anatomical structure	2
fibrillar collagen trimer	2
skeletal system morphogenesis	1
cell aggregation	1
multicellular organismal-level homeostasis	1
anatomical structure homeostasis	1
replacement ossification	1
cell differentiation	1
heart development	1
animal organ morphogenesis	1
glycoprotein metabolic process	1
nervous system development	1
sensory perception of light stimulus	1
sensory perception of mechanical stimulus	1
gene expression	1
regulation of macromolecule biosynthetic process	1
extracellular matrix organization	1
embryonic organ development	1
ear morphogenesis	1
embryonic morphogenesis	1
skeletal system development	1
animal organ development	1
connective tissue development	1
anatomical structure development	1
limb morphogenesis	1
anatomical structure formation involved in morphogenesis	1
embryonic skeletal system morphogenesis	1
embryonic skeletal joint development	1
sensory organ development	1
tube development	1
epithelium development	1
structural molecule activity	1
extracellular matrix structural constituent	1
MHC protein binding	1

Protein interactions and networks

STRING

2402 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COL2A1	SOX9	P48436	945
COL2A1	COL11A1	P12107	900
COL2A1	MMP13	P45452	856
COL2A1	SOX5	P35711	845
COL2A1	COL11A2	P13942	840
COL2A1	SOX6	P35712	827
COL2A1	ADAMTS5	Q9UNA0	805
COL2A1	BMP2	P12643	792
COL2A1	TGFB1	P01137	785
COL2A1	RUNX2	Q13950	778
COL2A1	FGFR3	P22607	758
COL2A1	PTHLH	P12272	745
COL2A1	ADAMTS4	O75173	719
COL2A1	HAPLN1	P10915	717
COL2A1	MATN1	P21941	705

IntAct

27 interactions, top by confidence:

A	B	Type	Score
C1QTNF9	C1QTNF9B	psi-mi:“MI:0914”(association)	0.780
MMP9	TIMP1	psi-mi:“MI:0914”(association)	0.640
FKBP9	CASC3	psi-mi:“MI:0914”(association)	0.530
C1QTNF9B	PLOD3	psi-mi:“MI:0914”(association)	0.530
COLGALT2	COL1A1	psi-mi:“MI:0914”(association)	0.530
COL1A1	GOLIM4	psi-mi:“MI:0914”(association)	0.500
COL2A1	COCH	psi-mi:“MI:0407”(direct interaction)	0.440
COL2A1		psi-mi:“MI:0915”(physical association)	0.370
HYAL1	COL2A1	psi-mi:“MI:0915”(physical association)	0.370
COL2A1	RELA	psi-mi:“MI:0915”(physical association)	0.370
M		psi-mi:“MI:0914”(association)	0.350
COL8A1	CCDC85C	psi-mi:“MI:0914”(association)	0.350
C1QTNF1	PLOD2	psi-mi:“MI:0914”(association)	0.350
COL8A2	P4HA2	psi-mi:“MI:0914”(association)	0.350
CHODL	RAD51C	psi-mi:“MI:0914”(association)	0.350
LAIR2	PLOD3	psi-mi:“MI:0914”(association)	0.350
MMP2	PLOD3	psi-mi:“MI:0914”(association)	0.350
C1QC	C1QL1	psi-mi:“MI:0914”(association)	0.350
CNPY2	COL2A1	psi-mi:“MI:0914”(association)	0.350
C1QTNF2	COL2A1	psi-mi:“MI:0914”(association)	0.350
COL9A1	COL2A1	psi-mi:“MI:0914”(association)	0.350
OSCAR	COL2A1	psi-mi:“MI:0914”(association)	0.350
COL2A1	P4HA1	psi-mi:“MI:0914”(association)	0.350
NXPH2	VGF	psi-mi:“MI:0914”(association)	0.350
PLOD1	PLK4	psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350

BioGRID (62): COL2A1 (Affinity Capture-MS), COL2A1 (Affinity Capture-MS), COL2A1 (Affinity Capture-MS), COL2A1 (Affinity Capture-MS), PLOD1 (Affinity Capture-MS), COL2A1 (Affinity Capture-MS), COL2A1 (Affinity Capture-MS), COL2A1 (Affinity Capture-MS), COL2A1 (Affinity Capture-MS), COL2A1 (Affinity Capture-MS), COL2A1 (Affinity Capture-MS), COL2A1 (Affinity Capture-MS), COL2A1 (Affinity Capture-MS), COL2A1 (Affinity Capture-MS), COL2A1 (Proximity Label-MS)

ESM2 similar proteins: C0HJN3, C0HJN5, C0HJN7, C0HJN9, C0HJP3, C0HJP5, C0HJP7, C0HLG7, C0HLG9, C0HLH1, C0HLH3, C0HLH5, C0HLH9, C0HLI1, C0HLI3, C0HLI4, C0HLI5, C0HLI7, C0HLI8, C0HLI9, C0HLJ1, C0HLJ3, C0HLJ5, C0HLJ7, C0HLJ9, C0HM84, C0HM86, C0HM93, C0HM95, O46392, P02452, P02453, P02454, P02457, P02458, P02459, P02461, P02465, P02466, P02467

Diamond homologs: A0MSJ1, C7DZK3, O42350, O88207, P02452, P02457, P02458, P02459, P02460, P02461, P02466, P05997, P08121, P12105, P12107, P13941, P13942, P20908, P20909, Q17RW2, Q30D77, Q32S24, Q3U962, Q5QNQ9, Q60467, Q61245, Q64739, Q6P4Z2, Q80ZF0, Q8IZC6, Q91717, Q9JI03, Q9YIB4, B8V7R6, O46392, O93484, P02453, P02454, P02465, P02467

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
RUNX2	“up-regulates quantity by expression”	COL2A1	“transcriptional regulation”
SOX9	“up-regulates quantity by expression”	COL2A1	“transcriptional regulation”
SOX5	“up-regulates quantity by expression”	COL2A1	“transcriptional regulation”
SOX6	“up-regulates quantity by expression”	COL2A1	“transcriptional regulation”
COL2A1	“up-regulates activity”	“A10/b1 integrin”	binding
MMP13	“down-regulates quantity by destabilization”	COL2A1	cleavage
MMP1	“down-regulates quantity by destabilization”	COL2A1	cleavage
COL2A1	up-regulates	“A2/b1 integrin”	binding
COL2A1	up-regulates	“A10/b1 integrin”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 37 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Collagen biosynthesis and modifying enzymes	10	68.2×	1e-14
Collagen degradation	6	42.2×	4e-07
Assembly of collagen fibrils and other multimeric structures	5	40.1×	8e-06

GO biological processes:

GO term	Partners	Fold	FDR
collagen fibril organization	6	43.5×	8e-07

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — WDTC.

Clinical variants and AI predictions

ClinVar

3518 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	625
Likely pathogenic	406
Uncertain significance	839
Likely benign	1048
Benign	192

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1039265	NM_001844.5(COL2A1):c.1735G>A (p.Gly579Arg)	Pathogenic
1048782	NM_001844.5(COL2A1):c.1023+1G>C	Pathogenic
1067287	NM_001844.5(COL2A1):c.2356-1G>A	Pathogenic
1067359	NM_001844.5(COL2A1):c.1007G>A (p.Gly336Asp)	Pathogenic
1067521	NM_001844.5(COL2A1):c.2726G>C (p.Gly909Ala)	Pathogenic
1069407	NM_001844.5(COL2A1):c.3966_3967del (p.Cys1323fs)	Pathogenic
1069618	NM_001844.5(COL2A1):c.3122_3125dup (p.Asp1043fs)	Pathogenic
1069981	NM_001844.5(COL2A1):c.1385del (p.Gly462fs)	Pathogenic
1070294	NM_001844.5(COL2A1):c.2150del (p.Gly717fs)	Pathogenic
1070315	NM_001844.5(COL2A1):c.3490G>A (p.Gly1164Ser)	Pathogenic
1070686	NM_001844.5(COL2A1):c.4323_4324del (p.Thr1442fs)	Pathogenic
1070703	NM_001844.5(COL2A1):c.2942dup (p.Ile982fs)	Pathogenic
1070922	NM_001844.5(COL2A1):c.2491G>C (p.Gly831Arg)	Pathogenic
1071652	NM_001844.5(COL2A1):c.3996del (p.Lys1333fs)	Pathogenic
1072582	NM_001844.5(COL2A1):c.1214G>A (p.Gly405Asp)	Pathogenic
1072583	NM_001844.5(COL2A1):c.1142G>A (p.Gly381Asp)	Pathogenic
1072584	NM_001844.5(COL2A1):c.709-1G>C	Pathogenic
1072940	NM_001844.5(COL2A1):c.2094+1G>C	Pathogenic
1074308	NM_001844.5(COL2A1):c.1259G>A (p.Gly420Glu)	Pathogenic
1074466	NM_001844.5(COL2A1):c.510del (p.Gly171fs)	Pathogenic
1074468	NM_001844.5(COL2A1):c.1A>G (p.Met1Val)	Pathogenic
1074613	NM_001844.5(COL2A1):c.1409del (p.Lys470fs)	Pathogenic
1074747	NC_000012.12:g.47976568del	Pathogenic
1074778	NM_001844.5(COL2A1):c.1043del (p.Gly348fs)	Pathogenic
1075160	NM_001844.5(COL2A1):c.4159C>T (p.Gln1387Ter)	Pathogenic
1075253	NM_001844.5(COL2A1):c.4293C>A (p.Tyr1431Ter)	Pathogenic
1075846	NM_001844.5(COL2A1):c.509del (p.Pro170fs)	Pathogenic
1076164	NM_001844.5(COL2A1):c.4405G>T (p.Asp1469Tyr)	Pathogenic
1076165	NM_001844.5(COL2A1):c.3623del (p.Pro1208fs)	Pathogenic
1076166	NM_001844.5(COL2A1):c.2478_2479del (p.Glu826fs)	Pathogenic

SpliceAI

4771 predictions. Top by Δscore:

Variant	Effect	Δscore
12:47973549:TGTTT:T	acceptor_gain	1.0000
12:47973554:C:CC	acceptor_gain	1.0000
12:47974084:CTCA:C	donor_loss	1.0000
12:47974085:T:TA	donor_loss	1.0000
12:47974086:C:CG	donor_loss	1.0000
12:47974087:A:AC	donor_gain	1.0000
12:47974087:ACCG:A	donor_loss	1.0000
12:47974088:C:CC	donor_gain	1.0000
12:47974088:C:CT	donor_loss	1.0000
12:47974327:CTGAA:C	acceptor_gain	1.0000
12:47974328:TGAA:T	acceptor_gain	1.0000
12:47974329:GAA:G	acceptor_gain	1.0000
12:47974330:AA:A	acceptor_gain	1.0000
12:47974332:C:CC	acceptor_gain	1.0000
12:47974671:TCAC:T	donor_loss	1.0000
12:47974672:CACAT:C	donor_loss	1.0000
12:47974673:A:AC	donor_gain	1.0000
12:47974673:AC:A	donor_loss	1.0000
12:47974674:C:CA	donor_gain	1.0000
12:47974674:CA:C	donor_gain	1.0000
12:47974674:CAT:C	donor_gain	1.0000
12:47974674:CATG:C	donor_gain	1.0000
12:47974674:CATGG:C	donor_gain	1.0000
12:47974858:GTCTC:G	acceptor_gain	1.0000
12:47974860:CTC:C	acceptor_gain	1.0000
12:47974861:TC:T	acceptor_gain	1.0000
12:47974862:CC:C	acceptor_gain	1.0000
12:47974862:CCT:C	acceptor_loss	1.0000
12:47974863:C:CC	acceptor_gain	1.0000
12:47974866:C:CT	acceptor_gain	1.0000

AlphaMissense

9353 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:47973492:A:G	L1460P	1.000
12:47974093:C:G	C1438S	1.000
12:47974094:A:G	C1438R	1.000
12:47974094:A:T	C1438S	1.000
12:47974227:G:C	C1393W	1.000
12:47974228:C:G	C1393S	1.000
12:47974228:C:T	C1393Y	1.000
12:47974229:A:G	C1393R	1.000
12:47974229:A:T	C1393S	1.000
12:47974235:A:C	Y1391D	1.000
12:47974267:A:G	L1380P	1.000
12:47974804:G:C	C1315W	1.000
12:47974805:C:G	C1315S	1.000
12:47974805:C:T	C1315Y	1.000
12:47974806:A:G	C1315R	1.000
12:47974806:A:T	C1315S	1.000
12:47975354:G:C	C1283W	1.000
12:47975355:C:T	C1283Y	1.000
12:47975356:A:G	C1283R	1.000
12:47975997:C:T	G1188D	1.000
12:47976006:C:T	G1185E	1.000
12:47979554:C:T	G897E	1.000
12:47985011:C:T	G606D	1.000
12:47985021:C:G	G603R	1.000
12:47987148:C:T	G432D	1.000
12:47994028:C:T	G279E	1.000
12:47994037:C:T	G276D	1.000
12:48000070:C:A	W47C	1.000
12:48000070:C:G	W47C	1.000
12:47973416:G:C	C1485W	0.999

dbSNP variants (sampled 300 via entrez): RS1000135028 (12:47978188 A>G), RS1000173907 (12:48006568 GAAA>G,GAA,GAAAA), RS1000264739 (12:47988882 G>A,C), RS1000339376 (12:48005325 C>G,T), RS1000437820 (12:48005555 C>T), RS1000466404 (12:47993807 A>C,T), RS1000553710 (12:47999851 A>G), RS1000775108 (12:47987441 T>C), RS1000802118 (12:48000403 C>A,T), RS1000815520 (12:47987588 G>A), RS1000839040 (12:47975908 A>G), RS1000890754 (12:47981704 G>A,T), RS1000922088 (12:47981914 T>C), RS1000930744 (12:47981657 C>T), RS1001097580 (12:47976350 C>G,T)

Disease associations

OMIM: gene MIM:120140 | disease phenotypes: MIM:200610, MIM:108300, MIM:132450, MIM:150600, MIM:151210, MIM:156550, MIM:183900, MIM:184250, MIM:184255, MIM:271700, MIM:604864, MIM:609162, MIM:609508, MIM:616583, MIM:619248, MIM:608805, MIM:604308, MIM:614569, MIM:154700, MIM:160700, MIM:184253, MIM:119530, MIM:268000, MIM:607086, MIM:142700, MIM:132400, MIM:148050, MIM:614134, MIM:614135, MIM:215150, MIM:184840, MIM:277610, MIM:180050, MIM:312530, MIM:248200

GenCC curated gene-disease

Disease	Classification	Inheritance
achondrogenesis type II	Definitive	Autosomal dominant
spondyloepiphyseal dysplasia with metatarsal shortening	Definitive	Autosomal dominant
Stickler syndrome type 1	Definitive	Autosomal dominant
platyspondylic dysplasia, Torrance type	Definitive	Autosomal dominant
Kniest dysplasia	Definitive	Autosomal dominant
spondyloperipheral dysplasia	Definitive	Autosomal dominant
dysplasia of the proximal femoral epiphyses	Definitive	Autosomal dominant
spondyloepiphyseal dysplasia congenita	Definitive	Autosomal dominant
Stickler syndrome, type I, nonsyndromic ocular	Definitive	Autosomal dominant
spondyloepimetaphyseal dysplasia, Strudwick type	Definitive	Autosomal dominant
Legg-Calve-Perthes disease	Strong	Autosomal dominant
otospondylomegaepiphyseal dysplasia, autosomal recessive	Strong	Autosomal recessive
mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis	Strong	Autosomal dominant
avascular necrosis of femoral head, primary, 1	Strong	Autosomal dominant
spondyloepiphyseal dysplasia, Stanescu type	Moderate	Unknown
multiple epiphyseal dysplasia, Beighton type	Supportive	Autosomal dominant
autosomal dominant rhegmatogenous retinal detachment	Supportive	Autosomal dominant
dysspondyloenchondromatosis	Supportive	Autosomal dominant
familial avascular necrosis of femoral head	Supportive	Autosomal dominant
hypochondrogenesis	Supportive	Autosomal dominant
spondylometaphyseal dysplasia, Schmidt type	Supportive	Autosomal dominant
otospondylomegaepiphyseal dysplasia	Limited	Autosomal recessive
vitreoretinopathy with phalangeal epiphyseal dysplasia	Limited	Unknown

ClinGen Gene-Disease Validity (8)

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

Disease	Classification	Inheritance
achondrogenesis type II	Definitive	AD
Kniest dysplasia	Definitive	AD
Stickler syndrome type 1	Definitive	AD
dysplasia of the proximal femoral epiphyses	Definitive	AD
platyspondylic dysplasia, Torrance type	Definitive	AD
COL2A1-related spondyloepiphyseal dysplasia	Definitive	AD
spondyloepiphyseal dysplasia, Stanescu type	Moderate	AD
spondyloperipheral dysplasia	Definitive	AD

Mondo (51): achondrogenesis type II (MONDO:0008702), Stickler syndrome type 1 (MONDO:0007160), multiple epiphyseal dysplasia, Beighton type (MONDO:0007562), Legg-Calve-Perthes disease (MONDO:0007885), platyspondylic dysplasia, Torrance type (MONDO:0007895), Kniest dysplasia (MONDO:0007987), spondyloepiphyseal dysplasia congenita (MONDO:0008471), spondyloepimetaphyseal dysplasia, Strudwick type (MONDO:0008476), spondylometaphyseal dysplasia, ‘corner fracture’ type (MONDO:0008479), spondyloperipheral dysplasia (MONDO:0010078), mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis (MONDO:0011496), spondyloepiphyseal dysplasia with metatarsal shortening (MONDO:0012206), Stickler syndrome, type I, nonsyndromic ocular (MONDO:0012287), spondyloepiphyseal dysplasia, Stanescu type (MONDO:0014701), vitreoretinopathy with phalangeal epiphyseal dysplasia (MONDO:0031001)

Orphanet (39): Achondrogenesis (Orphanet:932), Achondrogenesis type 2 (Orphanet:93296), Spondyloepiphyseal dysplasia with metatarsal shortening (Orphanet:137678), Multiple epiphyseal dysplasia, Beighton type (Orphanet:166011), Spondyloperipheral dysplasia-short ulna syndrome (Orphanet:1856), Legg-Calvé-Perthes disease (Orphanet:2380), Spondyloepiphyseal dysplasia, Stanescu type (Orphanet:459051), Kniest dysplasia (Orphanet:485), Stickler syndrome (Orphanet:828), Platyspondylic dysplasia, Torrance type (Orphanet:85166), Familial avascular necrosis of femoral head (Orphanet:86820), Stickler syndrome type 1 (Orphanet:90653), Mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis (Orphanet:93279), Spondylometaphyseal dysplasia, ‘corner fracture’ type (Orphanet:93315), Spondyloepimetaphyseal dysplasia congenita, Strudwick type (Orphanet:93346)

HPO phenotypes

360 total (30 of 360 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000160	Narrow mouth
HP:0000162	Glossoptosis
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000176	Submucous cleft hard palate
HP:0000185	Cleft soft palate
HP:0000193	Bifid uvula
HP:0000201	Pierre-Robin sequence
HP:0000211	Trismus
HP:0000218	High palate
HP:0000248	Brachycephaly
HP:0000256	Macrocephaly
HP:0000272	Malar flattening
HP:0000280	Coarse facial features
HP:0000307	Pointed chin
HP:0000308	Microretrognathia
HP:0000311	Round face
HP:0000316	Hypertelorism
HP:0000324	Facial asymmetry
HP:0000327	Hypoplasia of the maxilla
HP:0000339	Pugilistic facies
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000384	Preauricular skin tag
HP:0000385	Small earlobe

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST006976_65	Macular thickness	5.000000e-10
GCST007843_21	Rheumatoid arthritis	3.000000e-12
GCST009959_10	Retinal detachment or retinal break	1.000000e-06
GCST011693_10	Triglyceride levels	6.000000e-07
GCST90002388_430	Lymphocyte count	3.000000e-10
GCST90002399_336	Neutrophil percentage of white cells	9.000000e-11

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0010698	retinal break
EFO:0004530	triglyceride measurement
EFO:0004587	lymphocyte count
EFO:0007990	neutrophil percentage of leukocytes

MeSH disease descriptors (37)

Descriptor	Name	Tree numbers
D003240	Connective Tissue Diseases	C17.300
D000082602	Developmental Dysplasia of the Hip	C05.550.518.384.500; C05.660.297; C16.131.621.297
D005271	Femur Head Necrosis	C05.116.852.175; C23.550.717.732.368
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D007873	Legg-Calve-Perthes Disease	C05.116.852.175.570
D008382	Marfan Syndrome	C05.116.099.674; C14.240.400.725; C14.280.400.725; C16.131.077.550; C16.131.240.400.720; C16.320.540; C17.300.500
D009216	Myopia	C11.744.636
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D010003	Osteoarthritis	C05.550.114.606; C05.799.613
D012163	Retinal Detachment	C11.768.648
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
D012600	Scoliosis	C05.116.900.800.875
D000080362	Stargardt Disease	C11.270.872; C11.768.585.439.339; C16.320.290.724
C536017	Achondrogenesis type 2 (supp.)
C562834	Aortic Aneurysm, Familial Thoracic 1 (supp.)
C535964	Collagenopathy, type 2 alpha 1 (supp.)
C535766	Czech dysplasia, metatarsal type (supp.)
C565046	Epiphyseal Dysplasia, Multiple, with Myopia and Conductive Deafness (supp.)
C563007	Hypochondrogenesis (supp.)
C537015	KBG syndrome (supp.)
C537207	Kniest dysplasia (supp.)
C536030	MASS syndrome (supp.)
C566121	Orofacial Cleft 1 (supp.)
C565740	Osteoarthritis with Mild Chondrodysplasia (supp.)
C535776	Pierre Robin syndrome with fetal chondrodysplasia (supp.)
C563627	Platyspondylic Lethal Skeletal Dysplasia, Torrance Type (supp.)
C535788	Spondyloepiphyseal dysplasia, congenita (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2364188 (PROTEIN COMPLEX GROUP), CHEMBL5169108 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3809324	COL2A1		0.00	0

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.08	IC50	8.3	nM	CHEMBL4081997

PubChem BioAssay actives

1 with measured affinity, of 16 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-(2-aminoethyl)-4-[4-[(4-oxo-3,5,6,7-tetrahydrocyclopenta[d]pyrimidin-2-yl)sulfanylmethyl]phenyl]benzenesulfonamide	1917789: Inhibition of Collagen-II-alpha 1 (unknown origin) incubated for 22 hrs by Coomassie blue staining based SDS-PAGE analysis	ic50	0.0083	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	6
Resveratrol	affects cotreatment, decreases expression, increases expression, decreases reaction	4
Valproic Acid	decreases expression, decreases methylation, increases expression	4
Dexamethasone	decreases reaction, increases expression, decreases expression, affects cotreatment	3
Glucosamine	decreases reaction, affects expression, affects reaction, decreases expression, increases expression	3
Rotenone	decreases expression, increases expression	3
Tetrachlorodibenzodioxin	affects expression, decreases expression	3
Cyclosporine	decreases expression	3
bisphenol A	affects expression, decreases expression	2
entinostat	decreases expression, affects cotreatment	2
Curcumin	increases expression, affects cotreatment	2
Lipopolysaccharides	decreases expression, decreases reaction, affects cotreatment, increases expression	2
N-((3,5-difluorophenyl)acetyl)alanyl-2-phenylglycine-1,1-dimethylethyl ester	increases expression	1
2,4,6-tribromophenol	decreases expression	1
cobaltiprotoporphyrin	decreases reaction, increases expression, increases reaction	1
decabromobiphenyl ether	increases expression	1
HT-2 toxin	decreases expression	1
trichostatin A	increases expression	1
arsenite	increases methylation	1
tetrabromobisphenol A	decreases expression	1
benzo(k)fluoranthene	decreases expression	1
diacerein	decreases expression, decreases reaction, increases expression	1
benzo(e)pyrene	affects methylation	1
benz(a)anthracene	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression	1
indeno(1,2,3-cd)pyrene	decreases expression	1
glucosamine 3-O-sulfate	increases expression	1
alpinetin	decreases expression, decreases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment, decreases expression	1
irigenin	decreases expression, decreases reaction	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5217288	Binding	Inhibition of Collagen-II-alpha 1 (unknown origin) at 20 uM incubated for 22 hrs by Coomassie blue staining based SDS-PAGE analysis	Development of a putative Zn2+-chelating but highly selective MMP-13 inhibitor. — Bioorg Med Chem Lett

Cellosaurus cell lines

24 cell lines: 19 induced pluripotent stem cell, 3 finite cell line, 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A1QP	MCRIi019-A-7	Induced pluripotent stem cell	Female
CVCL_A5QB	JLUEYEi001-A	Induced pluripotent stem cell	Female
CVCL_A9XZ	MCRIi019-A-2	Induced pluripotent stem cell	Female
CVCL_BV08	GM22828	Transformed cell line	Male
CVCL_BV09	GM22829	Finite cell line	Male
CVCL_D0D5	CMGANTi006-A	Induced pluripotent stem cell	Male
CVCL_D0D6	CMGANTi007-A	Induced pluripotent stem cell	Male
CVCL_D0HR	MCRIi019-A-6	Induced pluripotent stem cell	Female
CVCL_D9C7	Ubigene HEK293 COL2A1 KO	Transformed cell line	Female
CVCL_GR12	GM07892	Finite cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03639532	PHASE4	COMPLETED	Ceramic-on-Ceramic Versus Ceramic-on-HXLPE THA
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
NCT00208468	PHASE3	TERMINATED	A Randomised Multi-centre Study to Compare the Long-term Performance of the Future Hip to 3 Other Implants in Primary Total Hip Replacement
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
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT02065167	PHASE2	COMPLETED	Evaluation of Mesenchymal Stem Cells to Treat Avascular Necrosis of the Hip
NCT04465188	PHASE2	WITHDRAWN	Scleral Buckling for Retinal Detachment Prevention in Genetically Confirmed Stickler Syndrome
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)
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
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)
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects