COL9A3

Summary

COL9A3 (collagen type IX alpha 3 chain, HGNC:2219) is a protein-coding gene on chromosome 20q13.33, encoding Collagen alpha-3(IX) chain (Q14050). Structural component of hyaline cartilage and vitreous of the eye.

This gene encodes one of the three alpha chains of type IX collagen, the major collagen component of hyaline cartilage. Type IX collagen, a heterotrimeric molecule, is usually found in tissues containing type II collagen, a fibrillar collagen. Mutations in this gene are associated with multiple epiphyseal dysplasia type 3.

Source: NCBI Gene 1299 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Stickler syndrome (Definitive, ClinGen) — +4 more curated relationships
• Clinical variants (ClinVar): 1,755 total — 37 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 68
• MANE Select transcript: NM_001853

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2219
Approved symbol	COL9A3
Name	collagen type IX alpha 3 chain
Location	20q13.33
Locus type	gene with protein product
Status	Approved
Aliases	IDD, MED, EDM3, FLJ90759, DJ885L7.4.1
Ensembl gene	ENSG00000092758
Ensembl biotype	protein_coding
OMIM	120270
Entrez	1299

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 6 protein_coding_CDS_not_defined, 6 retained_intron, 5 protein_coding

ENST00000452372, ENST00000462700, ENST00000463487, ENST00000466192, ENST00000466532, ENST00000467819, ENST00000469802, ENST00000469852, ENST00000472880, ENST00000477612, ENST00000481800, ENST00000489045, ENST00000490398, ENST00000649368, ENST00000894732, ENST00000934235, ENST00000934236

RefSeq mRNA: 1 — MANE Select: NM_001853 NM_001853

CCDS: CCDS13505

Canonical transcript exons

ENST00000649368 — 32 exons

Exon	Start	End
ENSE00002458192	62830360	62830413
ENSE00002462733	62829628	62829681
ENSE00002529384	62829766	62829819
ENSE00002530574	62830517	62830588
ENSE00003463424	62824968	62825021
ENSE00003474805	62840542	62841159
ENSE00003479855	62828923	62828976
ENSE00003488420	62822111	62822164
ENSE00003488734	62821507	62821530
ENSE00003491188	62822591	62822632
ENSE00003493890	62819222	62819293
ENSE00003494588	62828764	62828817
ENSE00003497798	62818518	62818553
ENSE00003498943	62817567	62817635
ENSE00003509818	62826767	62826820
ENSE00003514037	62833020	62833064
ENSE00003543497	62832154	62832189
ENSE00003549526	62827923	62827976
ENSE00003553091	62836187	62836333
ENSE00003558029	62819929	62819982
ENSE00003589896	62821181	62821216
ENSE00003603727	62827241	62827294
ENSE00003604426	62837083	62837265
ENSE00003611470	62829455	62829499
ENSE00003632750	62836478	62836532
ENSE00003634520	62835921	62835953
ENSE00003653205	62826204	62826257
ENSE00003653531	62824445	62824501
ENSE00003664532	62838684	62838761
ENSE00003680949	62821757	62821810
ENSE00003789409	62825817	62825870
ENSE00003838057	62817050	62817142

Expression profiles

Bgee: expression breadth ubiquitous, 218 present calls, max score 99.94.

FANTOM5 (CAGE): breadth broad, TPM avg 5.9762 / max 300.0676, expressed in 678 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
185762	4.1278	476
185763	1.0409	188
185764	0.3186	105
185766	0.1582	33
185768	0.1380	84
185760	0.0709	43
185761	0.0576	26
185765	0.0542	21
185767	0.0101	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	99.94	gold quality
cartilage tissue	UBERON:0002418	99.84	gold quality
inferior vagus X ganglion	UBERON:0005363	98.22	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.05	gold quality
trigeminal ganglion	UBERON:0001675	97.82	gold quality
spinal cord	UBERON:0002240	97.48	gold quality
tibial nerve	UBERON:0001323	97.19	gold quality
sural nerve	UBERON:0015488	97.05	gold quality
globus pallidus	UBERON:0001875	96.11	gold quality
medial globus pallidus	UBERON:0002477	96.11	gold quality
putamen	UBERON:0001874	96.08	gold quality
subthalamic nucleus	UBERON:0001906	95.81	gold quality
lateral globus pallidus	UBERON:0002476	95.39	gold quality
parotid gland	UBERON:0001831	94.77	gold quality
medulla oblongata	UBERON:0001896	94.76	gold quality
pons	UBERON:0000988	94.72	gold quality
substantia nigra	UBERON:0002038	94.23	gold quality
amygdala	UBERON:0001876	94.20	gold quality
caudate nucleus	UBERON:0001873	94.04	gold quality
midbrain	UBERON:0001891	94.01	gold quality
superior vestibular nucleus	UBERON:0007227	93.50	gold quality
middle frontal gyrus	UBERON:0002702	93.40	gold quality
ganglionic eminence	UBERON:0004023	93.14	gold quality
inferior olivary complex	UBERON:0002127	92.98	gold quality
dorsal root ganglion	UBERON:0000044	92.94	gold quality
substantia nigra pars reticulata	UBERON:0001966	92.68	gold quality
dorsal plus ventral thalamus	UBERON:0001897	92.42	gold quality
sperm	CL:0000019	92.14	silver quality
nucleus accumbens	UBERON:0001882	91.90	gold quality
trachea	UBERON:0003126	91.81	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-MTAB-8221	yes	6667.93
E-MTAB-9435	yes	1416.28
E-MTAB-11121	yes	1039.59
E-MTAB-7008	yes	206.47
E-HCAD-11	yes	20.71
E-CURD-112	yes	7.59
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): IRX1

miRNA regulators (miRDB)

29 targeting COL9A3, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-202-3P	99.84	71.41	1290
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-105-5P	99.54	69.24	2060
HSA-MIR-7853-5P	99.54	69.30	2055
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-516A-3P	99.46	67.96	1378
HSA-MIR-516B-3P	99.46	67.96	1378
HSA-MIR-7162-5P	99.46	68.08	1368
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-1304-5P	98.90	68.58	1054
HSA-MIR-30C-1-3P	97.80	66.36	1499
HSA-MIR-30C-2-3P	97.80	66.45	1499
HSA-MIR-6788-5P	97.80	66.41	1532
HSA-MIR-6728-5P	97.79	66.33	891
HSA-MIR-4676-5P	97.54	65.29	715
HSA-MIR-575	97.54	65.18	718
HSA-MIR-27A-5P	97.01	65.63	528
HSA-MIR-3664-5P	96.74	66.56	770
HSA-MIR-4512	95.26	63.08	371
HSA-MIR-31-3P	95.17	69.82	575

Literature-anchored findings (GeneRIF, showing 20)

• Both Trp2 and Trp3 allelic products are incorporated into cross-linked fibrillar network of developing human cartilage apparently normally. Any pathological consequences are likely to be long-term and indirect rather than from overt misassembly of matrix. (PMID:12782139)
• Patients with COL9A3 in-frame deletion of three amino acid residues (G181-P183 del) and missense mutation (D617E) showed moderate progressive bilateral sensorineural hearing impairment in all frequencies. (PMID:15917166)
• a fragment of collagen type IX alpha chain is found in 34% of newborns with ureteropelvic junction obstruction, and in 100% of normals. (PMID:17701042)
• This study extends the range of gene-mutations that can cause multiple epiphyseal dysplasia-related myopathy. (PMID:20358595)
• We report an 81% mutation detection rate for pseudoachondroplasia, of which COMP+Col9A3 mutations were more prevalent (61%) than COMP mutations alone (30%). (PMID:21042783)
• Studies indicate that two SNPs that introduce tryptophan polymorphisms in COL9A2 and COL9A3 are independently linked to an increased risk of lumbar disc disease. (PMID:21311409)
• The NC2 domain of type IX collagen determines the chain composition but also the chain register of the triple helix. (PMID:23132862)
• Here, we describe the first autosomal recessive Stickler family due to loss of function mutations (c.1176_1198del, p.Gln393Cysfs*25) of COL9A3 gene. These findings extend further the role of collagen genes family in the disease pathogenesis. (PMID:24273071)
• The allelic variants in the collagen IX genes - COL9A2 and COL9A3 have been identified as genetic risk factors for intervertebral disc disease–{review} (PMID:24636772)
• A novel missense mutation was identified in a family diagnosed with multiple epiphyseal dysplasia. (PMID:25381065)
• In an Iranian population, we observed a 5.8-fold increase in the odds of degenerative disc disease in males when the Trp3 allele was present (PMID:27798555)
• rs61734651 variant in COL9A3 was not significantly associated with a predisposition to lumbar disc degeneration. (PMID:29506578)
• Study results suggest that the COL9A3 trp3 polymorphism might not be associated with intervertebral disk degeneration. [meta-analysis] (PMID:30342505)
• we report the second family with autosomal recessive Stickler syndrome due to homozygosity for a loss-of-function mutation in COL9A3 and further establish the phenotype associated with mutations in this gene (PMID:30450842)
• Homozygous type IX collagen variants, COL9A1, COL9A2, and COL9A3, causing recessive Stickler syndrome, expand the disease phenotype. (PMID:31090205)
• Multiple variants in collagen genes are associated with the susceptibility to lumbar disc herniation in the Chinese population. (PMID:32048053)
• Whole exome sequencing reveals pathogenic variants in MYO3A, MYO15A and COL9A3 and differential frequencies in ancestral alleles in hearing impairment genes among individuals from Cameroon. (PMID:33078831)
• Heterozygous COL9A3 variants cause severe peripheral vitreoretinal degeneration and retinal detachment. (PMID:33633367)
• Identification of three novel homozygous variants in COL9A3 causing autosomal recessive Stickler syndrome. (PMID:35241111)
• A novel missense COL9A3 variant in a pedigree with multiple lumbar disc herniation. (PMID:38166944)

Cross-species orthologs

0 orthologs

Paralogs (37): COL9A2 (ENSG00000049089), COL23A1 (ENSG00000050767), COL11A1 (ENSG00000060718), COL17A1 (ENSG00000065618), COL5A3 (ENSG00000080573), COL4A4 (ENSG00000081052), COL16A1 (ENSG00000084636), COL20A1 (ENSG00000101203), COL1A1 (ENSG00000108821), COL9A1 (ENSG00000112280), 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-3(IX) chain — Q14050 (reviewed: Q14050)

All UniProt accessions (2): Q14050, Q4VXW1

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 3 (EDM3) [MIM:600969] 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. Intervertebral disc disease (IDD) [MIM:603932] A common musculo-skeletal disorder caused by degeneration of intervertebral disks of the lumbar spine. It results in low-back pain and unilateral leg pain. Disease susceptibility is associated with variants affecting the gene represented in this entry. Susceptibility to intervertebral disk disease is conferred by variant p.Arg103Trp. Stickler syndrome 6 (STL6) [MIM:620022] A 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 platyspondyly 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. STL6 is an autosomal recessive form characterized by early-onset progressive hearing loss and progressive myopia, with variable manifestation of facial dysmorphism and skeletal anomalies. The disease is caused by variants affecting the gene represented in this entry.

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

RefSeq proteins (1): NP_001844* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008160	Collagen	Repeat
IPR050149	Collagen_superfamily	Family

Pfam: PF01391

UniProt features (45 total): compositionally biased region 14, sequence variant 12, region of interest 8, sequence conflict 5, short sequence motif 2, signal peptide 1, chain 1, glycosylation site 1, helix 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
5CTD	X-RAY DIFFRACTION	1.6
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-Q14050-F1	54.83	0.00

Functional residue map

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

Glycosylation sites (1): 483

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: 328 (showing top): RNGTGGGC_UNKNOWN, MODULE_52, LEE_NEURAL_CREST_STEM_CELL_DN, GOCC_COLLAGEN_TRIMER, PEREZ_TP63_TARGETS, REACTOME_NCAM_SIGNALING_FOR_NEURITE_OUT_GROWTH, MODULE_70, MODULE_66, MARTINEZ_RB1_TARGETS_DN, GOMF_EXTRACELLULAR_MATRIX_STRUCTURAL_CONSTITUENT, DELYS_THYROID_CANCER_DN, MODULE_99, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, LEE_METASTASIS_AND_ALTERNATIVE_SPLICING_DN, RICKMAN_HEAD_AND_NECK_CANCER_A

GO Biological Process (0):

GO Molecular Function (2): extracellular matrix structural constituent conferring tensile strength (GO:0030020), protein homodimerization activity (GO:0042803)

GO Cellular Component (6): extracellular region (GO:0005576), collagen type IX trimer (GO:0005594), basement membrane (GO:0005604), 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
extracellular matrix structural constituent	1
identical protein binding	1
protein dimerization activity	1
cellular anatomical structure	1
FACIT collagen trimer	1
extracellular matrix	1
endoplasmic reticulum	1
intracellular organelle lumen	1
external encapsulating structure	1
protein-containing complex	1

Protein interactions and networks

STRING

1464 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COL9A3	MATN3	O15232	919
COL9A3	SLC26A2	P50443	822
COL9A3	CILP	O75339	819
COL9A3	COMP	P49747	712
COL9A3	ASPN	Q9BXN1	684
COL9A3	MATN4	O95460	642
COL9A3	COL9A1	P20849	634
COL9A3	COL9A2	Q14055	576
COL9A3	THBS2	P35442	570
COL9A3	HAPLN1	P10915	537
COL9A3	COL11A1	P12107	497
COL9A3	MATN1	P21941	481
COL9A3	TECTA	O75443	473
COL9A3	COL2A1	P02458	466
COL9A3	COL6A1	P12109	465

IntAct

7 interactions, top by confidence:

A	B	Type	Score
EGFR	COL9A3	psi-mi:“MI:0915”(physical association)	0.550
PLOD3	PLOD2	psi-mi:“MI:0914”(association)	0.530
ERBB2	COL9A3	psi-mi:“MI:0915”(physical association)	0.370
PLOD1	PLOD2	psi-mi:“MI:0914”(association)	0.350
COLGALT2	PLOD2	psi-mi:“MI:0914”(association)	0.350

BioGRID (11): COL9A3 (Two-hybrid), COL9A3 (Affinity Capture-RNA), COL9A3 (Affinity Capture-MS), COL9A3 (Affinity Capture-MS), COL9A3 (Affinity Capture-MS), COL9A3 (Reconstituted Complex), COL9A3 (Affinity Capture-Western), USP3 (Affinity Capture-Western), COL9A3 (Affinity Capture-MS), COL9A3 (Affinity Capture-RNA), COL9A3 (PCA)

ESM2 similar proteins: A0A060WQA3, A0MSJ1, A5PN28, A6QPB3, A8WR59, B7Z0K8, C0HLN2, O35167, O76368, O88207, P08125, P12106, P12107, P12108, P13942, P20849, P20908, P20909, P25067, P25318, P25940, P32017, P70560, P83371, P98085, Q05306, Q05722, Q07092, Q07563, Q07643, Q0VF58, Q14050, Q14055, Q14993, Q28083, Q28668, Q30D77, Q32S24, Q60467, Q61245

Diamond homologs: P32017, Q14050

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
IRX1	“down-regulates quantity by repression”	COL9A3	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

1755 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	37
Likely pathogenic	15
Uncertain significance	774
Likely benign	708
Benign	106

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1322153	NM_001853.4(COL9A3):c.647dup (p.Gly217fs)	Pathogenic
1396063	NM_001853.4(COL9A3):c.1384del (p.Val462fs)	Pathogenic
1433347	NM_001853.4(COL9A3):c.1685dup (p.Gly563fs)	Pathogenic
1462627	NM_001853.4(COL9A3):c.107_116del (p.Pro36fs)	Pathogenic
1464215	NM_001853.4(COL9A3):c.181_182dup (p.Gly62fs)	Pathogenic
1467909	NM_001853.4(COL9A3):c.102dup (p.Gly35fs)	Pathogenic
1525361	NM_001853.4(COL9A3):c.469G>T (p.Gly157Ter)	Pathogenic
161450	NM_001853.4(COL9A3):c.1176_1198del (p.Gln393fs)	Pathogenic
1683454	NM_001853.4(COL9A3):c.183+2T>C	Pathogenic
1683455	NM_001853.4(COL9A3):c.268C>T (p.Arg90Ter)	Pathogenic
1703482	NM_001853.4(COL9A3):c.1204C>T (p.Arg402Ter)	Pathogenic
1703483	NM_001853.4(COL9A3):c.355del (p.Leu119fs)	Pathogenic
17138	NM_001853.4(COL9A3):c.148-2A>T	Pathogenic
17141	NM_001853.4(COL9A3):c.148-1G>A	Pathogenic
2008753	NM_001853.4(COL9A3):c.985G>T (p.Glu329Ter)	Pathogenic
2034095	NM_001853.4(COL9A3):c.9del (p.Pro4fs)	Pathogenic
2035601	NM_001853.4(COL9A3):c.558del (p.Gly187fs)	Pathogenic
2085722	NM_001853.4(COL9A3):c.1686_1693del (p.Gly563fs)	Pathogenic
2176227	NM_001853.4(COL9A3):c.395del (p.Pro132fs)	Pathogenic
2868742	NM_001853.4(COL9A3):c.1045G>T (p.Gly349Ter)	Pathogenic
2974821	NM_001853.4(COL9A3):c.754C>T (p.Arg252Ter)	Pathogenic
3009946	NM_001853.4(COL9A3):c.1267C>T (p.Arg423Ter)	Pathogenic
3031298	NM_001853.4(COL9A3):c.799C>T (p.Arg267Ter)	Pathogenic
3248329	NC_000020.10:g.(?61467253)(61467904_?)del	Pathogenic
3342250	NM_001853.4(COL9A3):c.148-2A>G	Pathogenic
3650254	NM_001853.4(COL9A3):c.577G>T (p.Gly193Ter)	Pathogenic
3660832	NM_001853.4(COL9A3):c.336dup (p.Gly113fs)	Pathogenic
3661893	NM_001853.4(COL9A3):c.1541dup (p.Val515fs)	Pathogenic
3684632	NM_001853.4(COL9A3):c.395dup (p.Gly133fs)	Pathogenic
3691420	NM_001853.4(COL9A3):c.1429A>T (p.Lys477Ter)	Pathogenic

SpliceAI

4678 predictions. Top by Δscore:

Variant	Effect	Δscore
20:62817633:GAC:G	donor_gain	1.0000
20:62817636:G:GG	donor_gain	1.0000
20:62821087:G:GT	donor_gain	1.0000
20:62822589:A:AG	acceptor_gain	1.0000
20:62822589:AG:A	acceptor_gain	1.0000
20:62822590:G:GG	acceptor_gain	1.0000
20:62822590:GG:G	acceptor_gain	1.0000
20:62822632:GGT:G	donor_loss	1.0000
20:62822634:T:A	donor_loss	1.0000
20:62825046:G:GT	donor_gain	1.0000
20:62825046:G:T	donor_gain	1.0000
20:62825047:G:GT	donor_gain	1.0000
20:62825047:G:T	donor_gain	1.0000
20:62826198:TCGCA:T	acceptor_loss	1.0000
20:62826199:CGCA:C	acceptor_loss	1.0000
20:62826200:GCA:G	acceptor_loss	1.0000
20:62826201:CA:C	acceptor_loss	1.0000
20:62826202:A:AG	acceptor_gain	1.0000
20:62826202:AG:A	acceptor_gain	1.0000
20:62826203:G:A	acceptor_loss	1.0000
20:62826203:G:GA	acceptor_gain	1.0000
20:62826203:GG:G	acceptor_gain	1.0000
20:62826203:GGGCC:G	acceptor_gain	1.0000
20:62826255:CGGGT:C	donor_loss	1.0000
20:62826256:GG:G	donor_gain	1.0000
20:62826256:GGGTA:G	donor_loss	1.0000
20:62826257:GG:G	donor_gain	1.0000
20:62826258:G:GG	donor_gain	1.0000
20:62826258:GTAA:G	donor_loss	1.0000
20:62826259:TAA:T	donor_loss	1.0000

AlphaMissense

4214 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:62824968:G:A	G193R	0.990
20:62824968:G:C	G193R	0.990
20:62840661:T:A	C662S	0.989
20:62840662:G:C	C662S	0.989
20:62824494:G:A	G190E	0.988
20:62825827:G:A	G214D	0.988
20:62828969:G:A	G334E	0.987
20:62824969:G:A	G193E	0.985
20:62826204:G:C	G229R	0.985
20:62840676:T:A	C667S	0.985
20:62840677:G:C	C667S	0.985
20:62824457:T:C	C178R	0.984
20:62824978:G:A	G196D	0.984
20:62824459:C:G	C178W	0.983
20:62826777:G:A	G250E	0.983
20:62827933:G:A	G286D	0.983
20:62840676:T:C	C667R	0.983
20:62824485:G:A	G187E	0.982
20:62825005:G:A	G205D	0.982
20:62827278:G:A	G277D	0.982
20:62830554:G:A	G418D	0.982
20:62840661:T:C	C662R	0.982
20:62840662:G:A	C662Y	0.981
20:62827286:G:C	G280R	0.980
20:62827941:G:A	G289R	0.980
20:62827941:G:C	G289R	0.980
20:62828765:G:A	G301D	0.980
20:62829456:G:A	G337D	0.980
20:62829794:G:A	G379D	0.980
20:62825014:G:A	G208D	0.979

dbSNP variants (sampled 300 via entrez): RS1000088598 (20:62836695 G>A,C), RS1000130578 (20:62833976 C>A,G,T), RS1000213171 (20:62821489 C>T), RS1000228277 (20:62817483 A>G), RS1000434731 (20:62833322 T>C), RS1000502523 (20:62825962 T>C,G), RS1000634918 (20:62839146 A>G), RS1000717848 (20:62841310 CCA>C), RS1000854254 (20:62817213 C>A,T), RS1000936456 (20:62820617 C>G,T), RS1000969299 (20:62818195 T>C), RS1001086453 (20:62841125 TAAAGA>T,TA,TAAAGAAAGA), RS1001180781 (20:62833113 G>A), RS1001235238 (20:62815428 C>G), RS1001254470 (20:62832934 G>A,C)

Disease associations

OMIM: gene MIM:120270 | disease phenotypes: MIM:600969, MIM:620022, MIM:108300, MIM:180050, MIM:312530

GenCC curated gene-disease

Disease	Classification	Inheritance
Stickler syndrome	Definitive	Autosomal recessive
epiphyseal dysplasia, multiple, 3	Definitive	Autosomal dominant
Stickler syndrome, type 6	Definitive	Autosomal recessive
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	Definitive	AR

Mondo (12): epiphyseal dysplasia, multiple, 3 (MONDO:0010964), Stickler syndrome, type 6 (MONDO:0031047), lumbar disk degenerative disorder (MONDO:0044339), hearing loss disorder (MONDO:0005365), Stickler syndrome (MONDO:0019354), connective tissue disorder (MONDO:0003900), skeletal dysplasia (MONDO:0018230), vitreoretinal degeneration (MONDO:0020248), retinal lattice degeneration (MONDO:0001455), retinal detachment (MONDO:0008375), multiple epiphyseal dysplasia due to collagen 9 anomaly (MONDO:0015627), (MONDO:0016647)

Orphanet (4): Stickler syndrome (Orphanet:828), Autosomal recessive Stickler syndrome (Orphanet:250984), Primary bone dysplasia (Orphanet:364526), OBSOLETE: Vitreoretinal degeneration (Orphanet:98670)

HPO phenotypes

68 total (30 of 68 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:0000347	Micrognathia
HP:0000407	Sensorineural hearing impairment
HP:0000483	Astigmatism
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000541	Retinal detachment
HP:0000545	Myopia
HP:0000926	Platyspondyly
HP:0001249	Intellectual disability
HP:0001324	Muscle weakness
HP:0001377	Limited elbow extension
HP:0001382	Joint hypermobility
HP:0001384	Abnormal hip joint morphology
HP:0001763	Pes planus
HP:0002515	Waddling gait
HP:0002650	Scoliosis
HP:0002655	Spondyloepiphyseal dysplasia
HP:0002656	Epiphyseal dysplasia
HP:0002663	Delayed epiphyseal ossification
HP:0002758	Osteoarthritis
HP:0002812	Coxa vara
HP:0002815	Abnormality of the knee
HP:0002829	Arthralgia
HP:0002857	Genu valgum

GWAS associations

0 associations (top):

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D003240	Connective Tissue Diseases	C17.300
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D012163	Retinal Detachment	C11.768.648
C535503	Epiphyseal dysplasia, multiple, 3 (supp.)
C535531	Intervertebral disc disease (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	increases expression, affects cotreatment	4
Air Pollutants	decreases expression, increases abundance, increases expression	3
Valproic Acid	increases methylation, affects expression, decreases expression	3
entinostat	increases expression, affects cotreatment	2
Panobinostat	increases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Estradiol	decreases expression, affects cotreatment, increases expression	2
Tobacco Smoke Pollution	decreases expression	2
Particulate Matter	increases abundance, increases expression, decreases expression	2
aristolochic acid I	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
trichostatin A	increases expression	1
sulforaphane	decreases expression	1
benzo(e)pyrene	decreases methylation, increases methylation	1
butylbenzyl phthalate	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	increases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Norethindrone Acetate	affects cotreatment, increases expression	1
Carbamazepine	affects expression	1
Dactinomycin	affects cotreatment, increases expression	1
Etoposide	affects response to substance	1
Hydrogen Peroxide	affects expression	1
Methapyrilene	decreases methylation, increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1P1	Abcam HeLa COL9A3 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00165893	PHASE4	COMPLETED	Comparison of IDD Therapy and Non-surgical Treatment for Low Back Pain Caused by Degenerative Disc Disease
NCT01502644	PHASE4	COMPLETED	Opioid Treatment for Chronic Low Back Pain and the Impact of Mood Symptoms
NCT02429908	PHASE4	COMPLETED	Post-Market Surveillance Study of the TM Ardis Interbody Fusion System
NCT03060434	PHASE4	ACTIVE_NOT_RECRUITING	Pentoxifylline and Lumbar Radiculopathy
NCT03077204	PHASE4	COMPLETED	BIO4 Clinical Case Study: Cervical Spine
NCT03223701	PHASE4	WITHDRAWN	Efficacy of Using Solum IV and BMC With GFC in TLIF
NCT03514277	PHASE4	TERMINATED	A Prospective Study to Compare Bupivacaine and Exparel Versus Bupivacaine or Exparel Alone for Postoperative Pain Relief
NCT03745040	PHASE4	SUSPENDED	Liposomal Bupivacaine in One-level Instrumented Posterior Spinal Fusion
NCT03751943	PHASE4	UNKNOWN	NanoFUSE® PL Gutter PMCF
NCT04734327	PHASE4	UNKNOWN	Orthokine Therapy in Lumbar Degenerative Disease
NCT05029726	PHASE4	RECRUITING	Regional Anesthesia in Minimally Invasive Lumbar Spine Surgery
NCT05247021	PHASE4	UNKNOWN	Erector Spinae Plane Block in Spine Surgeries
NCT05345249	PHASE4	COMPLETED	Erector Spinae Plane Block as Pain Management After Lumbar Fusion Surgery
NCT06034041	PHASE4	UNKNOWN	The Effect of Mediclore as an Anti-adhesion Agent and Safety in Full-endoscopic Spine Surgery: a Preliminary Study
NCT00215306	PHASE3	COMPLETED	CHARITÉ™ Artificial Disc Compared to Anterior Interbody Fusion for Treatment of Degenerative Disc Disease
NCT00215319	PHASE3	COMPLETED	Titanium Surgical Mesh and MOSS-Miami Screws for Lumbar Fusion.
NCT00316121	PHASE3	COMPLETED	Safety and Efficacy Study of Healos as a Bone Replacement to Treat Degenerative Disc Disease
NCT00707265	PHASE3	COMPLETED	rhBMP-2/CRM/CD HORIZON® Spinal System Pivotal Study
NCT00927238	PHASE3	COMPLETED	XL TDR® eXtreme Lateral Total Disc Replacement for the Treatment of Lumbar Degenerative Disc Disease (DDD)
NCT01011816	PHASE3	TERMINATED	Treatment of Symptomatic Lumbar Internal Disc Disruption (IDD) With the Biostat® System
NCT01941563	PHASE3	COMPLETED	A Study of SI-6603 in Patients With Lumbar Disc Herniation
NCT02412735	PHASE3	COMPLETED	Placebo-controlled Study to Evaluate Rexlemestrocel-L Alone or Combined With Hyaluronic Acid in Participants With Chronic Low Back Pain
NCT02421601	PHASE3	COMPLETED	A Study of SI-6603 in Patients With Lumbar Disc Herniation
NCT03327272	PHASE3	WITHDRAWN	Impact of Local Steroid Application in Extreme Lateral Lumbar Interbody Fusion
NCT03513445	PHASE3	WITHDRAWN	Peri-Incisional Drug Injection in Lumbar Spine Surgery
NCT04816747	PHASE3	UNKNOWN	Intradiscal and Intra-articular Injection of Autologous Platelet-Rich-Plasma (PRP) in Patients With Lumbar Degenerative Disc Disease and Facet Joint Syndrome
NCT05444751	PHASE3	ENROLLING_BY_INVITATION	GA + ESP vs. SA + ESP in Lumbar Decompression Surgeries
NCT06115512	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study of AGA111 in Patients With Degenerative Disc Disease Undergoing Lumbar Interbody Fusion
NCT06325566	PHASE3	RECRUITING	Efficacy and Safety of Rexlemestrocel-L Combined With HA* in Participants With Moderate to Severe Chronic Low Back Pain
NCT07017634	PHASE3	RECRUITING	Efficacy and Safety of Novosis Putty in Transforaminal Lumbar Interbody Fusion for Patients With Lumbar Degenerative Disc Disease
NCT07254806	PHASE3	RECRUITING	A Study to Evaluate the Effectiveness of IDCT (Intradiscal Cell Therapy) in Subjects With One Level, Symptomatic Mild to Moderate Lumbar Degenerative Disc Disease
NCT04465188	PHASE2	WITHDRAWN	Scleral Buckling for Retinal Detachment Prevention in Genetically Confirmed Stickler Syndrome
NCT00996073	PHASE2	COMPLETED	Safety and Preliminary Efficacy Study of NeoFuse in Subjects Requiring Lumbar Interbody Fusion
NCT01124006	PHASE2	COMPLETED	A Multicenter, Randomized, Double-blind, Placebo Controlled, Clinical Trial to Evaluate the Safety, Tolerability and Preliminary Effectiveness of 2 Doses of Intradiscal rhGDF-5 (Single Administration) for the Treatment of Early Stage Lumbar Disc Degeneration
NCT01290367	PHASE2	COMPLETED	Safety and Preliminary Efficacy Study of Mesenchymal Precursor Cells (MPCs) in Subjects With Lumbar Back Pain
NCT01771471	PHASE2	TERMINATED	A Study Comparing the Safety and Effectiveness of Cartilage Cell Injected Into the Lumbar Disc as Compared to a Placebo
NCT02205138	PHASE2	COMPLETED	Phase 2a Study on Allogeneic Osteoblastic Cells Implantation in Lumbar Spinal Fusion
NCT04042844	PHASE2	RECRUITING	A Single Dose of BRTX 100 for Patients With Chronic Lumbar Disc Disease (cLDD)
NCT04272606	PHASE2	COMPLETED	TXA in Spinal Fusion
NCT04294004	PHASE2	UNKNOWN	KUR-113 Bone Graft Versus Local Autograft for the Treatment of Single-level Transforaminal Lumbar Interbody Fusion