COL9A1

Summary

COL9A1 (collagen type IX alpha 1 chain, HGNC:2217) is a protein-coding gene on chromosome 6q13, encoding Collagen alpha-1(IX) chain (P20849). Structural component of hyaline cartilage and vitreous of the eye.

This gene encodes one of the three alpha chains of type IX collagen, which is a minor (5-20%) collagen component of hyaline cartilage. Type IX collagen is usually found in tissues containing type II collagen, a fibrillar collagen. Studies in knockout mice have shown that synthesis of the alpha 1 chain is essential for assembly of type IX collagen molecules, a heterotrimeric molecule, and that lack of type IX collagen is associated with early onset osteoarthritis. Mutations in this gene are associated with osteoarthritis in humans, with multiple epiphyseal dysplasia, 6, a form of chondrodysplasia, and with Stickler syndrome, a disease characterized by ophthalmic, orofacial, articular, and auditory defects. Two transcript variants that encode different isoforms have been identified for this gene.

Source: NCBI Gene 1297 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Stickler syndrome, type 4 (Definitive, ClinGen) — +3 more curated relationships
• Clinical variants (ClinVar): 1,495 total — 54 pathogenic, 39 likely-pathogenic
• Phenotypes (HPO): 71
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001851

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2217
Approved symbol	COL9A1
Name	collagen type IX alpha 1 chain
Location	6q13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000112280
Ensembl biotype	protein_coding
OMIM	120210
Entrez	1297

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 6 retained_intron, 5 protein_coding, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000320755, ENST00000357250, ENST00000360859, ENST00000370496, ENST00000447041, ENST00000470652, ENST00000486080, ENST00000489611, ENST00000489861, ENST00000493682, ENST00000644493, ENST00000682313, ENST00000683602, ENST00000683758, ENST00000683980, ENST00000684176

RefSeq mRNA: 5 — MANE Select: NM_001851 NM_001377289, NM_001377290, NM_001377291, NM_001851, NM_078485

CCDS: CCDS47447, CCDS4971, CCDS93940, CCDS93941

Canonical transcript exons

ENST00000357250 — 38 exons

Exon	Start	End
ENSE00002216771	70280812	70280874
ENSE00002232958	70302001	70302074
ENSE00002242599	70302911	70303084
ENSE00002251818	70294167	70294563
ENSE00002265178	70282898	70282918
ENSE00002269053	70281004	70281039
ENSE00002288431	70300043	70300175
ENSE00002291396	70283737	70283820
ENSE00002292122	70281390	70281464
ENSE00002310769	70270314	70270367
ENSE00002318109	70300309	70300386
ENSE00003477950	70263244	70263297
ENSE00003481146	70234539	70234593
ENSE00003499283	70274047	70274082
ENSE00003517154	70255337	70255390
ENSE00003518864	70241964	70242035
ENSE00003534459	70260657	70260710
ENSE00003545154	70253385	70253429
ENSE00003546278	70254963	70255016
ENSE00003553256	70254476	70254529
ENSE00003555708	70255150	70255203
ENSE00003565361	70271655	70271708
ENSE00003570678	70241419	70241454
ENSE00003573687	70256768	70256821
ENSE00003582485	70252262	70252315
ENSE00003586145	70242662	70242715
ENSE00003588686	70274719	70274772
ENSE00003597752	70269633	70269665
ENSE00003615132	70272065	70272088
ENSE00003619977	70268804	70268860
ENSE00003620661	70266717	70266770
ENSE00003625425	70239254	70239286
ENSE00003625468	70232583	70232771
ENSE00003627236	70225932	70226009
ENSE00003650149	70240689	70240733
ENSE00003672363	70234794	70234940
ENSE00003694376	70252120	70252173
ENSE00003920920	70216126	70217081

Expression profiles

Bgee: expression breadth ubiquitous, 149 present calls, max score 99.92.

FANTOM5 (CAGE): breadth broad, TPM avg 1.3059 / max 281.9810, expressed in 271 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
74311	0.8720	255
74313	0.1761	7
74312	0.1736	123
74310	0.0582	29
204051	0.0142	4
204052	0.0118	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	99.92	gold quality
cartilage tissue	UBERON:0002418	98.63	gold quality
ventricular zone	UBERON:0003053	91.40	gold quality
sperm	CL:0000019	86.27	gold quality
male germ cell	CL:0000015	85.84	gold quality
ganglionic eminence	UBERON:0004023	85.69	gold quality
choroid plexus epithelium	UBERON:0003911	84.77	gold quality
amygdala	UBERON:0001876	84.35	gold quality
embryo	UBERON:0000922	83.81	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.89	gold quality
endometrium epithelium	UBERON:0004811	81.78	gold quality
caudate nucleus	UBERON:0001873	81.65	gold quality
cingulate cortex	UBERON:0003027	81.47	gold quality
anterior cingulate cortex	UBERON:0009835	81.37	gold quality
putamen	UBERON:0001874	80.99	gold quality
nucleus accumbens	UBERON:0001882	80.89	gold quality
cervix squamous epithelium	UBERON:0006922	80.56	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	80.36	gold quality
substantia nigra	UBERON:0002038	80.24	gold quality
type B pancreatic cell	CL:0000169	80.11	gold quality
olfactory bulb	UBERON:0002264	80.00	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.69	gold quality
midbrain	UBERON:0001891	79.49	gold quality
spinal cord	UBERON:0002240	79.49	gold quality
Ammon’s horn	UBERON:0001954	79.28	gold quality
hypothalamus	UBERON:0001898	79.17	gold quality
right frontal lobe	UBERON:0002810	78.06	gold quality
temporal lobe	UBERON:0001871	78.05	gold quality
telencephalon	UBERON:0001893	77.25	gold quality
right atrium auricular region	UBERON:0006631	76.79	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	4118.13
E-MTAB-8221	yes	3446.52
E-MTAB-11121	yes	2361.38
E-HCAD-25	yes	20.91
E-ANND-3	yes	6.98

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SOX9

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 23)

• mutation causes multiple epiphyseal dysplasia; genetic heterogeneity (PMID:11565064)
• Data show that the proximal-promoter region of the human COL9A1 gene can drive expression of a reporter gene in chondrocytic RCS cells, but not in nonchondrocytic cell lines. (PMID:12399468)
• the amino-terminal NC4 domain of human collagen IX interacts with glycosaminoglycans and cartilage oligomeric matrix protein (PMID:15047691)
• COMP, type IX collagen and MATN3 play important roles in matrix assembly (PMID:15694129)
• A search of the microRNA database revealed a highly conserved target sequence for miR-9 immediately preceding the overlapping polyadenylation signals in the novel 3’ UTR of COL9A1, suggesting its role in posttranscriptional regulation of COL9A1. (PMID:16718610)
• COL9A1 is the fourth identified gene that can cause Stickler syndrome. (PMID:16909383)
• analysis of the crystal structure of the N-terminal NC4 domain of collagen IX (PMID:17553797)
• the matrilin-3 A-domain appears to bind exclusively to the COL3 domain of type IX collagen and this binding is abolished in the presence of a disease causing mutation in type IX collagen (PMID:17881354)
• This study extends the range of gene-mutations that can cause multiple epiphyseal dysplasia-related myopathy. (PMID:20358595)
• NC2 domain of collagen IX provides chain selection and heterotrimerization (PMID:20507993)
• A second, novel mutation was identified in COL9A1, causing autosomal recessive Stickler syndrome together with the previously described nucleotide change in two separate families. (PMID:21421862)
• COL9A1 protein is highly expressed in patients with idiopathic congenital talipes equinovarus (ICTEV) and rs1135056, which is located in the coding region of COL9A1 gene, may be associated with the pathogenesis of ICTEV. (PMID:21672422)
• Type IX collagen interacts with fibronectin providing an important molecular bridge in articular cartilage (PMID:21768108)
• The NC2 domain of type IX collagen determines the chain composition but also the chain register of the triple helix. (PMID:23132862)
• The study demonstrated that hypermethylation is associated with down-regulation of COL9A1 expression in osteoarthritic (OA) cartilage and highlights the pivotal role of epigenetics in OA. (PMID:25048791)
• We observed a significant association between rs6910140 of COL9A1 and KBD, suggesting a role of COL9A1 in the development of KBD. (PMID:25774918)
• the COL9A1 rs35470562 variant may contribute to congenital talipes equinovarus susceptibility in the Chinese population examined. (PMID:27819742)
• Whole-genome sequencing reveals possible role of deleterious mutation of COL9A1 in ossification of the posterior longitudinal ligament of the thoracic spine in the Chinese population. (PMID:30577800)
• Two tagSNPs, rs28647489 in FAT1 gene and rs550675 in COL9A1 gene, were significantly associated with the risk of oral malignancy. (PMID:30657779)
• Homozygous type IX collagen variants, COL9A1, COL9A2, and COL9A3, causing recessive Stickler syndrome, expand the disease phenotype. (PMID:31090205)
• The present study emphasizes the importance of exome-wide copy number variation analysis in molecular diagnosis and provides supporting evidence to associate COL9A1 with autosomal recessive non-syndromic HL. (PMID:31315069)
• Relationship of COL9A1 and SOX9 Genes with Genetic Susceptibility of Postmenopausal Osteoporosis. (PMID:31732751)
• Gene Environment Interactions Between the COL9A1 Gene and Maternal Drinking of Alcohol Contribute to the Risk of Congenital Talipes Equinovarus. (PMID:33372835)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	col9a1b	ENSDARG00000031483
danio_rerio	col9a1a	ENSDARG00000073699
mus_musculus	Col9a1	ENSMUSG00000026147
rattus_norvegicus	Col9a1	ENSRNOG00000012920

Paralogs (37): COL9A2 (ENSG00000049089), COL23A1 (ENSG00000050767), COL11A1 (ENSG00000060718), COL17A1 (ENSG00000065618), COL5A3 (ENSG00000080573), COL4A4 (ENSG00000081052), COL16A1 (ENSG00000084636), COL9A3 (ENSG00000092758), COL20A1 (ENSG00000101203), COL1A1 (ENSG00000108821), COL7A1 (ENSG00000114270), COL21A1 (ENSG00000124749), COL5A1 (ENSG00000130635), COL4A2 (ENSG00000134871), COL2A1 (ENSG00000139219), 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(IX) chain — P20849 (reviewed: P20849)

All UniProt accessions (5): P20849, A0A2R8YG47, A0A804HIB6, A0A804HKK1, A0A804HL06

UniProt curated annotations — full annotation on UniProt →

Function. Structural component of hyaline cartilage and vitreous of the eye.

Subunit / interactions. Heterotrimer of an alpha 1(IX), an alpha 2(IX) and an alpha 3(IX) chain.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Post-translational modifications. Covalently linked to the telopeptides of type II collagen by lysine-derived cross-links. Prolines at the third position of the tripeptide repeating unit (G-X-Y) are hydroxylated in some or all of the chains.

Disease relevance. Multiple epiphyseal dysplasia 6 (EDM6) [MIM:614135] 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. Stickler syndrome 4 (STL4) [MIM:614134] An autosomal recessive 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.

Domain organisation. Each subunit is composed of three triple-helical domains interspersed with non-collagenous domains. The globular domain at the N-terminus of type IX collagen molecules represents the NC4 domain which may participate in electrostatic interactions with polyanionic glycosaminoglycans in cartilage.

Similarity. Belongs to the fibril-associated collagens with interrupted helices (FACIT) family.

Isoforms (3)

UniProt ID	Names	Canonical?
P20849-1	1, Long	yes
P20849-2	2, Short
P20849-3	3

RefSeq proteins (5): NP_001364218, NP_001364219, NP_001364220, NP_001842, NP_511040 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008160	Collagen	Repeat
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR048287	TSPN-like_N	Domain
IPR050149	Collagen_superfamily	Family

Pfam: PF01391

UniProt features (81 total): strand 15, domain 11, compositionally biased region 10, region of interest 9, helix 9, sequence variant 8, disulfide bond 4, splice variant 4, sequence conflict 4, binding site 3, signal peptide 1, chain 1, glycosylation site 1, turn 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
5CTD	X-RAY DIFFRACTION	1.6
2UUR	X-RAY DIFFRACTION	1.8
5CTI	X-RAY DIFFRACTION	1.9
5CVA	X-RAY DIFFRACTION	2.1
5CVB	X-RAY DIFFRACTION	2.25

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P20849-F1	62.72	0.23

Functional residue map

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

Ligand- & substrate-binding residues (3): 213; 215; 253

Disulfide bonds (4): 44–242, 198–252, 411, 415

Glycosylation sites (1): 171

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-1442490	Collagen degradation
R-HSA-1650814	Collagen biosynthesis and modifying enzymes
R-HSA-186797	Signaling by PDGF
R-HSA-2022090	Assembly of collagen fibrils and other multimeric structures
R-HSA-216083	Integrin cell surface interactions
R-HSA-3000178	ECM proteoglycans
R-HSA-419037	NCAM1 interactions
R-HSA-8948216	Collagen chain trimerization

MSigDB gene sets: 286 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, GOCC_COLLAGEN_TRIMER, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, REACTOME_NCAM_SIGNALING_FOR_NEURITE_OUT_GROWTH, GGGTGGRR_PAX4_03, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, RGTTAMWNATT_HNF1_01, GOMF_EXTRACELLULAR_MATRIX_STRUCTURAL_CONSTITUENT, IRF1_Q6, MCBRYAN_PUBERTAL_BREAST_3_4WK_UP, TCF11_01, KONDO_COLON_CANCER_HCP_WITH_H3K27ME1, MODULE_88, AACTTT_UNKNOWN

GO Biological Process (1): animal organ morphogenesis (GO:0009887)

GO Molecular Function (5): extracellular matrix structural constituent conferring tensile strength (GO:0030020), carbohydrate binding (GO:0030246), protein homodimerization activity (GO:0042803), metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (5): extracellular region (GO:0005576), collagen type IX trimer (GO:0005594), endoplasmic reticulum lumen (GO:0005788), extracellular matrix (GO:0031012), collagen trimer (GO:0005581)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Collagen formation	2
Extracellular matrix organization	2
Degradation of the extracellular matrix	1
Signaling by Receptor Tyrosine Kinases	1
NCAM signaling for neurite out-growth	1
Collagen biosynthesis and modifying enzymes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
anatomical structure morphogenesis	1
animal organ development	1
extracellular matrix structural constituent	1
identical protein binding	1
protein dimerization activity	1
cation binding	1
cellular anatomical structure	1
FACIT collagen trimer	1
endoplasmic reticulum	1
intracellular organelle lumen	1
external encapsulating structure	1
protein-containing complex	1

Protein interactions and networks

STRING

1450 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COL9A1	MATN3	O15232	878
COL9A1	SLC26A2	P50443	831
COL9A1	HAPLN1	P10915	818
COL9A1	ACAN	P16112	649
COL9A1	COL9A3	Q14050	634
COL9A1	SOX9	P48436	581
COL9A1	COMP	P49747	579
COL9A1	MATN4	O95460	569
COL9A1	COL11A1	P12107	543
COL9A1	COL2A1	P02458	534
COL9A1	ASPN	Q9BXN1	505
COL9A1	SOX5	P35711	494
COL9A1	SPTBN2	O15020	491
COL9A1	CCBE1	Q6UXH8	488
COL9A1	FOXP2	O15409	480

IntAct

15 interactions, top by confidence:

A	B	Type	Score
CRYAA	COL9A1	psi-mi:“MI:0915”(physical association)	0.560
KLK6	COL9A1	psi-mi:“MI:0915”(physical association)	0.560
COL9A1	GIPC1	psi-mi:“MI:0915”(physical association)	0.560
COL9A1	COL6A1	psi-mi:“MI:0915”(physical association)	0.500
COL9A1	MATN1	psi-mi:“MI:0407”(direct interaction)	0.440
COL9A1	CFTR	psi-mi:“MI:0915”(physical association)	0.370
COL9A1	COL2A1	psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350

BioGRID (23): CTPS2 (Affinity Capture-MS), COL2A1 (Affinity Capture-MS), COL6A2 (Affinity Capture-MS), COL6A1 (Affinity Capture-MS), COL4A2 (Affinity Capture-MS), PPP1R12C (Affinity Capture-MS), VHL (Affinity Capture-MS), PPP1R12C (Affinity Capture-MS), VHL (Affinity Capture-MS), COL2A1 (Affinity Capture-MS), COL6A1 (Affinity Capture-MS), COL6A2 (Affinity Capture-MS), COL9A1 (Positive Genetic), COL2A1 (Reconstituted Complex), COL9A1 (Reconstituted Complex)

ESM2 similar proteins: A0A060WQA3, A0MSJ1, A5PN28, A6NHN0, A8WR59, C0HLN2, C7DZK3, O35167, O35348, O76368, O88207, P08122, P08572, P12106, P12107, P12108, P13942, P20849, P20850, P20908, P20909, P25067, P25940, P53420, P83371, P98085, Q01955, Q03637, Q05722, Q07092, Q07643, Q0VF58, Q14031, Q14055, Q14993, Q17RW2, Q28083, Q30D77, Q32S24, Q4ZJM7

Diamond homologs: P12106, P20849, P20850, Q05722, Q32S24, Q60847, Q641F3, Q96P44, Q99715, A0A1D5NSM8, A2AVA0, A6H584, A6NMZ7, A6QLN9, A8TX70, E1BMV3, O00339, O08746, O15232, O35701, O42401, O75578, P05099, P05555, P0C6B8, P13944, P17301, P18614, P20701, P20702, P21941, P24063, P32004, P32018, P34576, P38570, P51942, P53710, P56199, P61622

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1495 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	54
Likely pathogenic	39
Uncertain significance	530
Likely benign	630
Benign	160

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070343	NM_001851.6(COL9A1):c.1668_1671dup (p.Pro558Ter)	Pathogenic
1071983	NM_001851.6(COL9A1):c.848dup (p.Gly284fs)	Pathogenic
1072289	NM_001851.6(COL9A1):c.1933del (p.Leu645fs)	Pathogenic
1075420	NM_001851.6(COL9A1):c.1330C>T (p.Gln444Ter)	Pathogenic
1075450	NM_001851.6(COL9A1):c.59G>A (p.Trp20Ter)	Pathogenic
1075583	NM_001851.6(COL9A1):c.1817del (p.Pro606fs)	Pathogenic
1322152	NM_001851.6(COL9A1):c.1178dup (p.Gly394fs)	Pathogenic
1374860	NM_001851.6(COL9A1):c.2248C>T (p.Gln750Ter)	Pathogenic
1378976	NM_001851.6(COL9A1):c.1852C>T (p.Arg618Ter)	Pathogenic
1395500	NM_001851.6(COL9A1):c.1877del (p.Ser626fs)	Pathogenic
1453155	NC_000006.12:g.70255204dup	Pathogenic
1454270	NM_001851.6(COL9A1):c.403del (p.Asp135fs)	Pathogenic
161449	NM_001851.6(COL9A1):c.1519C>T (p.Arg507Ter)	Pathogenic
1701507	NM_001851.6(COL9A1):c.799G>T (p.Glu267Ter)	Pathogenic
17195	NM_001851.6(COL9A1):c.883C>T (p.Arg295Ter)	Pathogenic
1912945	NM_001851.6(COL9A1):c.1623dup (p.Val542fs)	Pathogenic
1913520	NM_001851.6(COL9A1):c.771dup (p.Arg258fs)	Pathogenic
1925780	NM_001851.6(COL9A1):c.611T>G (p.Leu204Ter)	Pathogenic
1936357	NM_001851.6(COL9A1):c.706C>T (p.Gln236Ter)	Pathogenic
1988476	NM_001851.6(COL9A1):c.733del (p.Leu245fs)	Pathogenic
1993223	NM_001851.6(COL9A1):c.783del (p.Ser262fs)	Pathogenic
1999289	NM_001851.6(COL9A1):c.2361_2362del (p.Ala788fs)	Pathogenic
2005843	NM_001851.6(COL9A1):c.865dup (p.Asp289fs)	Pathogenic
2026590	NM_001851.6(COL9A1):c.353_357dup (p.Thr120delinsGluTer)	Pathogenic
2103496	NM_001851.6(COL9A1):c.710G>A (p.Trp237Ter)	Pathogenic
2119491	NM_001851.6(COL9A1):c.2403dup (p.Gly802fs)	Pathogenic
2122556	NM_001851.6(COL9A1):c.415A>T (p.Lys139Ter)	Pathogenic
2424264	NC_000006.11:g.(?71011684)(71012627_?)del	Pathogenic
2707401	NM_001851.6(COL9A1):c.1889T>G (p.Leu630Ter)	Pathogenic
2784112	NM_001851.6(COL9A1):c.847_848del (p.Pro283fs)	Pathogenic

SpliceAI

5299 predictions. Top by Δscore:

Variant	Effect	Δscore
6:70232768:TGTT:T	acceptor_gain	1.0000
6:70232769:GTT:G	acceptor_gain	1.0000
6:70232772:C:CC	acceptor_gain	1.0000
6:70232772:C:T	acceptor_loss	1.0000
6:70240687:A:AC	donor_gain	1.0000
6:70240688:C:CC	donor_gain	1.0000
6:70241453:CC:C	acceptor_gain	1.0000
6:70241454:CC:C	acceptor_gain	1.0000
6:70241962:AC:A	donor_gain	1.0000
6:70241963:CC:C	donor_gain	1.0000
6:70242034:CC:C	acceptor_gain	1.0000
6:70242035:CC:C	acceptor_gain	1.0000
6:70242658:TTACC:T	donor_loss	1.0000
6:70242660:A:AC	donor_gain	1.0000
6:70242660:A:T	donor_loss	1.0000
6:70242660:AC:A	donor_gain	1.0000
6:70242661:C:CA	donor_gain	1.0000
6:70242661:CC:C	donor_gain	1.0000
6:70242661:CCA:C	donor_gain	1.0000
6:70242711:CTGCC:C	acceptor_gain	1.0000
6:70242712:TGCC:T	acceptor_gain	1.0000
6:70242714:CC:C	acceptor_gain	1.0000
6:70242714:CCCTG:C	acceptor_loss	1.0000
6:70242715:CC:C	acceptor_gain	1.0000
6:70242716:C:CA	acceptor_loss	1.0000
6:70242716:C:CC	acceptor_gain	1.0000
6:70252118:A:AC	donor_gain	1.0000
6:70252119:C:CC	donor_gain	1.0000
6:70252173:CC:C	acceptor_loss	1.0000
6:70252173:CCTGT:C	acceptor_gain	1.0000

AlphaMissense

5818 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:70294323:C:A	W180C	0.998
6:70294323:C:G	W180C	0.998
6:70294325:A:G	W180R	0.997
6:70294325:A:T	W180R	0.997
6:70294510:C:G	R118P	0.996
6:70294529:A:G	S112P	0.995
6:70283792:C:T	C242Y	0.994
6:70283813:A:G	L235P	0.993
6:70294282:A:G	L194P	0.993
6:70283792:C:G	C242S	0.992
6:70283793:A:G	C242R	0.992
6:70283793:A:T	C242S	0.992
6:70294472:A:G	W131R	0.992
6:70294472:A:T	W131R	0.992
6:70294481:A:G	W128R	0.992
6:70294481:A:T	W128R	0.992
6:70283806:C:A	W237C	0.990
6:70283806:C:G	W237C	0.990
6:70294479:C:A	W128C	0.990
6:70294479:C:G	W128C	0.990
6:70232699:C:T	G796D	0.989
6:70241998:C:T	G655E	0.989
6:70294270:C:T	C198Y	0.989
6:70300344:C:G	C44S	0.989
6:70300345:A:T	C44S	0.989
6:70232690:C:T	G799D	0.988
6:70283791:A:C	C242W	0.988
6:70283810:T:G	Q236P	0.988
6:70294271:A:G	C198R	0.988
6:70232619:C:G	G823R	0.987

dbSNP variants (sampled 300 via entrez): RS1000027163 (6:70226387 T>C), RS1000078785 (6:70295762 G>A), RS1000092686 (6:70233759 T>C), RS1000106045 (6:70299274 C>T), RS1000195974 (6:70296984 C>A), RS1000228586 (6:70220317 C>T), RS1000244184 (6:70215395 T>C), RS1000304606 (6:70294968 G>A), RS1000323555 (6:70277823 A>G), RS1000363430 (6:70274233 T>A,C), RS1000364543 (6:70289681 A>C), RS1000375667 (6:70226967 C>T), RS1000393409 (6:70245459 A>C,G), RS1000499585 (6:70261983 A>C), RS1000538500 (6:70268604 C>T)

Disease associations

OMIM: gene MIM:120210 | disease phenotypes: MIM:108300, MIM:192200, MIM:614134, MIM:614135, MIM:154700

GenCC curated gene-disease

Disease	Classification	Inheritance
Stickler syndrome, type 4	Definitive	Autosomal recessive
epiphyseal dysplasia, multiple, 6	Definitive	Autosomal dominant
multiple epiphyseal dysplasia due to collagen 9 anomaly	Supportive	Autosomal dominant
autosomal recessive Stickler syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Stickler syndrome, type 4	Definitive	AR

Mondo (14): Stickler syndrome (MONDO:0019354), congenital heart disease (MONDO:0005453), varicose disease (MONDO:0008638), Stickler syndrome, type 4 (MONDO:0013590), epiphyseal dysplasia, multiple, 6 (MONDO:0013591), hearing loss disorder (MONDO:0005365), connective tissue disorder (MONDO:0003900), optic atrophy (MONDO:0003608), inherited retinal dystrophy (MONDO:0019118), hereditary disease (MONDO:0003847), Marfan syndrome (MONDO:0007947), sensorineural hearing loss disorder (MONDO:0020678), multiple epiphyseal dysplasia due to collagen 9 anomaly (MONDO:0015627), (MONDO:0016647)

Orphanet (5): Stickler syndrome (Orphanet:828), Autosomal recessive Stickler syndrome (Orphanet:250984), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Marfan syndrome type 1 (Orphanet:284963), Marfan syndrome (Orphanet:558)

HPO phenotypes

71 total (30 of 71 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000175	Cleft palate
HP:0000218	High palate
HP:0000272	Malar flattening
HP:0000286	Epicanthus
HP:0000347	Micrognathia
HP:0000407	Sensorineural hearing impairment
HP:0000483	Astigmatism
HP:0000518	Cataract
HP:0000533	Chorioretinal atrophy
HP:0000541	Retinal detachment
HP:0000545	Myopia
HP:0000926	Platyspondyly
HP:0001324	Muscle weakness
HP:0001382	Joint hypermobility
HP:0001611	Hypernasal speech
HP:0001763	Pes planus
HP:0002515	Waddling gait
HP:0002650	Scoliosis
HP:0002654	Multiple epiphyseal dysplasia
HP:0002655	Spondyloepiphyseal dysplasia
HP:0002656	Epiphyseal dysplasia
HP:0002758	Osteoarthritis
HP:0002812	Coxa vara
HP:0002815	Abnormality of the knee
HP:0002829	Arthralgia
HP:0002857	Genu valgum
HP:0002866	Hypoplastic iliac wing
HP:0002945	Intervertebral space narrowing

GWAS associations

0 associations (top):

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D003240	Connective Tissue Diseases	C17.300
D030342	Genetic Diseases, Inborn	C16.320
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
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
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D058499	Retinal Dystrophies	C11.768.585.658
D014648	Varicose Veins	C14.907.927

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects cotreatment, decreases expression	4
entinostat	decreases expression, affects cotreatment	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1
Benzo(a)pyrene	affects methylation	1
Carbamazepine	affects expression	1
Carmustine	decreases expression	1
Cytarabine	increases expression	1
Doxorubicin	decreases expression	1
Lipopolysaccharides	increases expression, affects cotreatment	1
N-Nitrosopyrrolidine	decreases expression	1
Tretinoin	decreases expression	1
Triclosan	decreases expression	1
Aflatoxin B1	increases methylation	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT04465188	PHASE2	WITHDRAWN	Scleral Buckling for Retinal Detachment Prevention in Genetically Confirmed Stickler Syndrome
NCT00115375	PHASE2	COMPLETED	Platelet Aggregation Inhibition in Children on Clopidogrel (PICOLO)
NCT00350220	PHASE2	COMPLETED	Transfusion Strategies in Pediatric Cardiothoracic Surgery
NCT00374088	PHASE2	COMPLETED	N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT00538785	PHASE2	COMPLETED	A Study to Evaluate MEDI-524 In Children With Hemodynamically Significant Congenital Heart Disease
NCT00770705	PHASE2	WITHDRAWN	Parenteral Phenoxybenzamine During Congenital Heart Disease Surgery
NCT00919945	PHASE2	TERMINATED	Impact of Early Enteral Feeding on Splanchnic Blood Flow After Surgery for Critical Heart Disease in the Newborn
NCT01063712	PHASE2	COMPLETED	Safety and Effectiveness of the Device Nit-Occlud® PDA-R
NCT01069510	PHASE2	COMPLETED	Spironolactone in Adult Congenital Heart Disease
NCT01189981	PHASE2	COMPLETED	Effect of eHealth Encouragements to Intensive Exercise in Adolescents With Congenital Heart Disease
NCT01330433	PHASE2	COMPLETED	Effects of CoSeal on Bleeding & Adhesions in Pediatric Heart Surgery
NCT01662037	PHASE2	COMPLETED	Bosentan Therapy in Children With Functional Single Ventricle
NCT01668264	PHASE2	UNKNOWN	Imaging Assessment of Diastolic Function