COL9A2

Summary

COL9A2 (collagen type IX alpha 2 chain, HGNC:2218) is a protein-coding gene on chromosome 1p34.2, encoding Collagen alpha-2(IX) chain (Q14055). 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. This chain is unusual in that, unlike the other two type IX alpha chains, it contains a covalently attached glycosaminoglycan side chain. Mutations in this gene are associated with multiple epiphyseal dysplasia.

Source: NCBI Gene 1298 — RefSeq curated summary.

At a glance

• Gene–disease (curated): epiphyseal dysplasia, multiple, 2 (Definitive, GenCC) — +4 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 1,328 total — 35 pathogenic, 20 likely-pathogenic
• Phenotypes (HPO): 66
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001852

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2218
Approved symbol	COL9A2
Name	collagen type IX alpha 2 chain
Location	1p34.2
Locus type	gene with protein product
Status	Approved
Aliases	MED
Ensembl gene	ENSG00000049089
Ensembl biotype	protein_coding
OMIM	120260
Entrez	1298

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 9 protein_coding, 4 protein_coding_CDS_not_defined, 4 retained_intron

ENST00000372736, ENST00000372748, ENST00000417105, ENST00000427563, ENST00000461118, ENST00000466267, ENST00000482722, ENST00000488463, ENST00000490132, ENST00000495948, ENST00000496215, ENST00000642679, ENST00000869264, ENST00000869265, ENST00000869266, ENST00000869267, ENST00000869268

RefSeq mRNA: 1 — MANE Select: NM_001852 NM_001852

CCDS: CCDS450

Canonical transcript exons

ENST00000372748 — 32 exons

Exon	Start	End
ENSE00001791720	40300489	40301381
ENSE00001835600	40317123	40317286
ENSE00003460753	40310264	40310317
ENSE00003474992	40312059	40312112
ENSE00003493625	40311662	40311715
ENSE00003499173	40307703	40307756
ENSE00003499559	40309938	40309991
ENSE00003501881	40302621	40302809
ENSE00003510142	40307446	40307499
ENSE00003520514	40303928	40303972
ENSE00003532085	40311093	40311146
ENSE00003534246	40312574	40312609
ENSE00003537275	40305715	40305768
ENSE00003541814	40315590	40315664
ENSE00003543228	40311230	40311286
ENSE00003544860	40304320	40304391
ENSE00003570138	40306143	40306187
ENSE00003575596	40312456	40312479
ENSE00003601938	40304064	40304099
ENSE00003603816	40301812	40301889
ENSE00003604484	40312731	40312784
ENSE00003607602	40303530	40303676
ENSE00003620853	40310111	40310164
ENSE00003626573	40304476	40304529
ENSE00003634031	40303131	40303185
ENSE00003639494	40304794	40304847
ENSE00003647977	40314352	40314387
ENSE00003650740	40308192	40308245
ENSE00003670946	40310714	40310767
ENSE00003677535	40311500	40311547
ENSE00003678993	40303807	40303839
ENSE00003680985	40314205	40314267

Expression profiles

Bgee: expression breadth ubiquitous, 213 present calls, max score 98.07.

FANTOM5 (CAGE): breadth broad, TPM avg 4.3037 / max 229.9820, expressed in 708 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11916	1.5295	326
11910	1.1681	388
11913	0.2999	132
11915	0.2910	144
11908	0.2344	65
11917	0.2053	111
11912	0.1758	97
11909	0.1218	54
11914	0.1030	47
11918	0.0598	36

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	98.07	gold quality
tibia	UBERON:0000979	97.53	gold quality
adenohypophysis	UBERON:0002196	97.36	gold quality
cartilage tissue	UBERON:0002418	97.18	gold quality
pituitary gland	UBERON:0000007	96.63	gold quality
spinal cord	UBERON:0002240	95.78	gold quality
ganglionic eminence	UBERON:0004023	93.64	gold quality
amygdala	UBERON:0001876	92.69	gold quality
putamen	UBERON:0001874	92.62	gold quality
caudate nucleus	UBERON:0001873	91.59	gold quality
hypothalamus	UBERON:0001898	91.53	gold quality
nucleus accumbens	UBERON:0001882	90.92	gold quality
substantia nigra	UBERON:0002038	90.01	gold quality
ventricular zone	UBERON:0003053	89.84	gold quality
right frontal lobe	UBERON:0002810	89.79	gold quality
descending thoracic aorta	UBERON:0002345	89.58	gold quality
cingulate cortex	UBERON:0003027	89.38	gold quality
inferior vagus X ganglion	UBERON:0005363	89.21	gold quality
anterior cingulate cortex	UBERON:0009835	89.20	gold quality
midbrain	UBERON:0001891	88.99	gold quality
inferior olivary complex	UBERON:0002127	88.88	gold quality
right uterine tube	UBERON:0001302	88.06	gold quality
corpus callosum	UBERON:0002336	87.66	gold quality
Brodmann (1909) area 9	UBERON:0013540	87.66	gold quality
Ammon’s horn	UBERON:0001954	87.15	gold quality
forebrain	UBERON:0001890	86.57	gold quality
thoracic aorta	UBERON:0001515	86.50	gold quality
ascending aorta	UBERON:0001496	86.32	gold quality
cranial nerve II	UBERON:0000941	86.16	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	85.90	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-8221	yes	3252.94
E-HCAD-10	yes	34.96
E-GEOD-137537	yes	30.69
E-MTAB-7316	yes	26.80
E-CURD-112	yes	7.55
E-ANND-3	yes	4.60

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SOX9, TCF3

miRNA regulators (miRDB)

42 targeting COL9A2, 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-4533	100.00	69.48	2758
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-5580-5P	99.38	66.96	1139
HSA-MIR-18A-5P	99.29	71.05	806
HSA-MIR-18B-5P	99.29	71.05	806
HSA-MIR-4641	99.28	66.64	744
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-4426	99.17	66.74	1949
HSA-MIR-4735-3P	99.14	69.85	777
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-6814-5P	99.03	66.68	1273
HSA-MIR-3154	98.94	66.55	1455
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-760	98.81	66.65	1392
HSA-MIR-12126	98.09	64.82	637

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 23)

• mutations leading to skipping of exon 3 within the COL3 domain of the alpha2-chain of collagen type IX may be relatively common in patients with a special subtype of multiple epiphyseal dysplasia (PMID:12244547)
• 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)
• The collagen IX is cartilage specific, and expressed in hypertrophic chondrocytes and bone. (PMID:15625128)
• A population study using magnetic resonance imaging to define degenerative disc disease demonstrates that the TRP2 allele (Gln326Trp)of COL9A2 is a significant risk factor for development and severity of degeneration. (PMID:16371896)
• A Japanese family with an autosomal dominant multiple epiphyseal dysplasia (MED EDM2) was studied; genomic analysis for COL9A2 identified an Ex3-1A>G heterozygous mutation, which has been proved to result in skipping of exon 3. (PMID:16440132)
• Association of a COL9A2 specific haplotype with lumbar disc disease in the Japanese population. (PMID:17024315)
• Homozygosity for the Arg allele of Col9A2 seems to be more frequent in the patient group with early recurrence although the differences in the allele frequencies were statistically not significant. (PMID:18080148)
• COL9A2 polymorphisms were associated with intervertebral disc mechanics, relating genetic variations and debilitating mechanical alterations that may ultimately result in intervertebral disc degeneration. (PMID:18246003)
• This study extends the range of gene-mutations that can cause multiple epiphyseal dysplasia-related myopathy. (PMID:20358595)
• Data show that the associating G allele in COL9A2 changes a glutamine to arginine or to tryptophan and may predispose to both hip osteoarthritis and lumbar disc degeneration, making it a candidate for degenerative connective tissue diseases. (PMID:21159828)
• Data indicate that no causal SNPs in COL9A2 were significantly associated with LSS, but Haplotype Analysis showed that the “GCAGCG” haplotype (HAP2) was overrepresented in LSS patients. (PMID:21228751)
• 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)
• loss of function mutation in the COL9A2 gene causes autosomal recessive Stickler syndrome (PMID:21671392)
• The NC2 domain of type IX collagen determines the chain composition but also the chain register of the triple helix. (PMID:23132862)
• 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)
• Two novel mutations, c.143G>C in exon 2 and c.884G>A in exon 17 of the COL9A2 gene, may contribute to the development of pathological myopia. (PMID:24711017)
• Meta-analysis. Our results suggest that the COL9A2 rs12077871, rs12722877, and rs7533552 polymorphisms may not be associated with lumbar disc disease. (PMID:24983932)
• Study provides evidence that the COL9A2 Gln326Arg polymorphism contributes to the development of intervertebral disc disease in the Chinese population. (PMID:28002589)
• rs12077871, rs12722877, and rs7533552 variants in COL9A2 were not significantly associated with a predisposition to lumbar disc degeneration. (PMID:29506578)
• No significant association was found between COL9A2 polymorphism rs7533552 and the risk of lumbar disc degeneration. (PMID:30288688)
• Homozygous type IX collagen variants, COL9A1, COL9A2, and COL9A3, causing recessive Stickler syndrome, expand the disease phenotype. (PMID:31090205)
• Lack of association between COL1A1 and COL9A2 single nucleotide polymorphisms and intervertebral disc degeneration. (PMID:32419506)
• Autosomal recessive Stickler syndrome associated with homozygous mutations in the COL9A2 gene. (PMID:33356723)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	col9a2	ENSDARG00000024492
mus_musculus	Col9a2	ENSMUSG00000028626
rattus_norvegicus	Col9a2	ENSRNOG00000011502

Paralogs (37): 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), 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-2(IX) chain — Q14055 (reviewed: Q14055)

All UniProt accessions (4): A0A2R8YFT7, B1AKJ3, Q14055, H0Y409

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. The chains are linked to each other by interchain disulfide bonds. Trimers are also cross-linked via hydroxylysines.

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 2 (EDM2) [MIM:600204] 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. Stickler syndrome 5 (STL5) [MIM:614284] 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. STL5 is characterized by high myopia, vitreoretinal degeneration, retinal detachment, mild to moderate sensorineural hearing loss, short stature in childhood, and absence of cleft palate and Pierre Robin sequence. 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_001843* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008160	Collagen	Repeat
IPR050149	Collagen_superfamily	Family

Pfam: PF01391

UniProt features (34 total): region of interest 10, compositionally biased region 9, sequence variant 6, modified residue 2, glycosylation site 2, disulfide bond 2, signal peptide 1, chain 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-Q14055-F1	54.99	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.

Post-translational modifications (2): 160, 183

Disulfide bonds (2): 174, 178

Glycosylation sites (2): 169, 183

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: 278 (showing top): YAATNRNNNYNATT_UNKNOWN, BENPORATH_ES_WITH_H3K27ME3, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOCC_COLLAGEN_TRIMER, REACTOME_NCAM_SIGNALING_FOR_NEURITE_OUT_GROWTH, MODULE_66, WOO_LIVER_CANCER_RECURRENCE_UP, GOMF_EXTRACELLULAR_MATRIX_STRUCTURAL_CONSTITUENT, chr1p34, RICKMAN_HEAD_AND_NECK_CANCER_A, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, ZHAN_MULTIPLE_MYELOMA_LB_UP, AML1_01, MODULE_11, PID_AVB3_INTEGRIN_PATHWAY

GO Biological Process (1): skeletal system development (GO:0001501)

GO Molecular Function (3): extracellular matrix structural constituent conferring tensile strength (GO:0030020), protein homodimerization activity (GO:0042803), 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
system development	1
extracellular matrix structural constituent	1
identical protein binding	1
protein dimerization activity	1
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

1386 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COL9A2	MATN3	O15232	914
COL9A2	SLC26A2	P50443	871
COL9A2	CILP	O75339	803
COL9A2	HAPLN1	P10915	765
COL9A2	COMP	P49747	717
COL9A2	WDR12	Q9GZL7	680
COL9A2	ASPN	Q9BXN1	656
COL9A2	MYCL	P12524	604
COL9A2	COL9A3	Q14050	576
COL9A2	ACAN	P16112	573
COL9A2	THBS2	P35442	523
COL9A2	COL1A2	P02464	507
COL9A2	COL2A1	P02458	478
COL9A2	LAMC1	P11047	472
COL9A2	NKX3-2	P78367	463

IntAct

18 interactions, top by confidence:

A	B	Type	Score
COL9A2	UBQLN1	psi-mi:“MI:0915”(physical association)	0.560
COL9A2	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
COL9A2	UBQLN2	psi-mi:“MI:0915”(physical association)	0.560
PLOD3	PLOD2	psi-mi:“MI:0914”(association)	0.530
COL9A2	MTNR1A	psi-mi:“MI:0915”(physical association)	0.370
ERBB2	COL9A2	psi-mi:“MI:0915”(physical association)	0.370
COLGALT2	PLOD2	psi-mi:“MI:0914”(association)	0.350
COL9A2	UBQLN1	psi-mi:“MI:0915”(physical association)	0.000
COL9A2	MEOX2	psi-mi:“MI:0915”(physical association)	0.000
COL9A2	UBQLN2	psi-mi:“MI:0915”(physical association)	0.000
COL9A2	FEZ1	psi-mi:“MI:0915”(physical association)	0.000
HAP1	COL9A2	psi-mi:“MI:0915”(physical association)	0.000
COL9A2	NOA1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (15): COL9A2 (Two-hybrid), NOA1 (Two-hybrid), MEOX2 (Two-hybrid), UBQLN1 (Two-hybrid), UBQLN2 (Two-hybrid), FEZ1 (Two-hybrid), HAP1 (Two-hybrid), COL9A2 (Two-hybrid), COL9A2 (Affinity Capture-MS), COL9A2 (Affinity Capture-MS), MPPED2 (Co-fractionation), UBE2T (Co-fractionation), COL9A2 (Affinity Capture-MS), COL9A2 (Affinity Capture-MS), COL9A2 (Affinity Capture-MS)

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: C0HLN2, P12108, Q07643, Q14055

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SOX9	“up-regulates quantity by expression”	COL9A2	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

1328 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	35
Likely pathogenic	20
Uncertain significance	578
Likely benign	527
Benign	79

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1187495	NM_001852.4(COL9A2):c.723del (p.Lys243fs)	Pathogenic
1375958	NM_001852.4(COL9A2):c.557del (p.Pro186fs)	Pathogenic
1389283	NM_001852.4(COL9A2):c.1222A>T (p.Lys408Ter)	Pathogenic
1442253	NM_001852.4(COL9A2):c.1608_1614del (p.Leu537fs)	Pathogenic
1493354	NM_001852.4(COL9A2):c.1675G>T (p.Gly559Ter)	Pathogenic
1519818	NM_001852.4(COL9A2):c.908del (p.Pro303fs)	Pathogenic
17142	NM_001852.4(COL9A2):c.186+2T>C	Pathogenic
17144	NM_001852.4(COL9A2):c.186+5G>C	Pathogenic
17146	NM_001852.4(COL9A2):c.186G>C (p.Pro62=)	Pathogenic
1909440	NM_001852.4(COL9A2):c.1717dup (p.His573fs)	Pathogenic
1959013	NM_001852.4(COL9A2):c.104del (p.Pro35fs)	Pathogenic
1962137	NM_001852.4(COL9A2):c.529_532del (p.Asn177fs)	Pathogenic
1976006	NC_000001.11:g.40309992del	Pathogenic
2009390	NM_001852.4(COL9A2):c.1546G>T (p.Glu516Ter)	Pathogenic
2023401	NM_001852.4(COL9A2):c.368del (p.Pro123fs)	Pathogenic
2120546	NM_001852.4(COL9A2):c.371del (p.Pro124fs)	Pathogenic
2192619	NM_001852.4(COL9A2):c.406C>T (p.Arg136Ter)	Pathogenic
2703374	NM_001852.4(COL9A2):c.186+2T>A	Pathogenic
2711606	NM_001852.4(COL9A2):c.197del (p.Gly66fs)	Pathogenic
2856971	NM_001852.4(COL9A2):c.541G>T (p.Gly181Ter)	Pathogenic
29645	NM_001852.4(COL9A2):c.843_846+4del	Pathogenic
2967466	NM_001852.4(COL9A2):c.1577dup (p.Asp527fs)	Pathogenic
2975978	NM_001852.4(COL9A2):c.1235del (p.Gly412fs)	Pathogenic
3008335	NM_001852.4(COL9A2):c.691C>T (p.Gln231Ter)	Pathogenic
3671467	NM_001852.4(COL9A2):c.844del (p.Glu282fs)	Pathogenic
3675282	NM_001852.4(COL9A2):c.975_976delinsTT (p.Gln326Ter)	Pathogenic
3682449	NM_001852.4(COL9A2):c.823C>T (p.Arg275Ter)	Pathogenic
4532198	NM_001852.4(COL9A2):c.108_109insG (p.Pro37fs)	Pathogenic
4532281	NM_001852.4(COL9A2):c.98_99insGC (p.Gly36fs)	Pathogenic
4533341	NM_001852.4(COL9A2):c.104_105insCG (p.Pro37fs)	Pathogenic

SpliceAI

3088 predictions. Top by Δscore:

Variant	Effect	Δscore
1:40301380:TCC:T	acceptor_loss	1.0000
1:40301381:CCTG:C	acceptor_loss	1.0000
1:40301383:T:A	acceptor_loss	1.0000
1:40301806:GCTTA:G	donor_loss	1.0000
1:40301807:CTTA:C	donor_loss	1.0000
1:40301808:TTA:T	donor_loss	1.0000
1:40301809:TACCT:T	donor_loss	1.0000
1:40301810:A:C	donor_loss	1.0000
1:40301811:C:CG	donor_loss	1.0000
1:40301885:TTTTC:T	acceptor_gain	1.0000
1:40301886:TTTC:T	acceptor_gain	1.0000
1:40301887:TTC:T	acceptor_gain	1.0000
1:40301887:TTCC:T	acceptor_loss	1.0000
1:40301888:TC:T	acceptor_gain	1.0000
1:40301888:TCC:T	acceptor_loss	1.0000
1:40301889:CC:C	acceptor_gain	1.0000
1:40301889:CCTG:C	acceptor_loss	1.0000
1:40301890:C:CC	acceptor_gain	1.0000
1:40301890:CTGTA:C	acceptor_loss	1.0000
1:40301891:T:A	acceptor_loss	1.0000
1:40301892:G:GC	acceptor_gain	1.0000
1:40301897:C:CT	acceptor_gain	1.0000
1:40301898:A:T	acceptor_gain	1.0000
1:40302619:AC:A	donor_gain	1.0000
1:40302620:CC:C	donor_gain	1.0000
1:40302806:TGCT:T	acceptor_gain	1.0000
1:40302808:CT:C	acceptor_gain	1.0000
1:40302809:TC:T	acceptor_loss	1.0000
1:40302810:C:A	acceptor_loss	1.0000
1:40302810:C:CC	acceptor_gain	1.0000

AlphaMissense

4300 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:40311272:A:C	C178W	0.991
1:40311274:A:G	C178R	0.990
1:40311286:A:G	C174R	0.988
1:40311273:C:G	C178S	0.985
1:40311273:C:T	C178Y	0.985
1:40311274:A:T	C178S	0.985
1:40311285:C:G	C174S	0.984
1:40311286:A:T	C174S	0.984
1:40311284:A:C	C174W	0.982
1:40304819:C:T	G379D	0.981
1:40303645:C:T	G478D	0.980
1:40311256:C:G	G184R	0.980
1:40311546:C:T	G158D	0.980
1:40301261:C:T	C664Y	0.979
1:40311678:C:T	G152E	0.978
1:40301261:C:G	C664S	0.977
1:40301262:A:T	C664S	0.977
1:40303591:C:T	G496D	0.977
1:40303654:C:T	G475D	0.977
1:40311246:C:T	G187E	0.977
1:40301247:A:G	C669R	0.976
1:40311146:C:G	G193R	0.976
1:40311146:C:T	G193R	0.976
1:40311285:C:T	C174Y	0.976
1:40311136:C:T	G196D	0.974
1:40311145:C:T	G193E	0.974
1:40311238:C:G	G190R	0.974
1:40311238:C:T	G190R	0.974
1:40311687:C:T	G149E	0.973
1:40303829:C:T	G460D	0.972

dbSNP variants (sampled 300 via entrez): RS1000009071 (1:40313362 T>C,G), RS1000071695 (1:40314724 C>T), RS1000680596 (1:40313855 G>A,C), RS1001015047 (1:40301552 T>A,G), RS1001277237 (1:40308227 C>T), RS1001561842 (1:40302276 C>T), RS1001637084 (1:40301986 G>A,C), RS1001729863 (1:40308503 C>A), RS1001790447 (1:40318114 G>A,C), RS1001959500 (1:40318712 G>A), RS1001972451 (1:40300909 G>A), RS1002319738 (1:40318317 T>A), RS1002428610 (1:40301571 A>G), RS1002561952 (1:40310931 T>C), RS1002805746 (1:40304863 A>G)

Disease associations

OMIM: gene MIM:120260 | disease phenotypes: MIM:600204, MIM:614284, MIM:108300, MIM:156000

GenCC curated gene-disease

Disease	Classification	Inheritance
Stickler syndrome, type 5	Definitive	Autosomal recessive
epiphyseal dysplasia, multiple, 2	Definitive	Autosomal dominant
multiple epiphyseal dysplasia due to collagen 9 anomaly	Supportive	Autosomal dominant
autosomal recessive Stickler syndrome	Supportive	Autosomal recessive
Stickler syndrome	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Stickler syndrome	Limited	AR

Mondo (9): epiphyseal dysplasia, multiple, 2 (MONDO:0010844), Stickler syndrome, type 5 (MONDO:0013666), Stickler syndrome (MONDO:0019354), connective tissue disorder (MONDO:0003900), Meniere disease (MONDO:0007972), lumbar disk degenerative disorder (MONDO:0044339), intellectual disability (MONDO:0001071), multiple epiphyseal dysplasia due to collagen 9 anomaly (MONDO:0015627), (MONDO:0016647)

Orphanet (4): Autosomal recessive Stickler syndrome (Orphanet:250984), Stickler syndrome (Orphanet:828), NON RARE IN EUROPE: Menière disease (Orphanet:45360), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

66 total (30 of 66 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000175	Cleft palate
HP:0000201	Pierre-Robin sequence
HP:0000218	High palate
HP:0000272	Malar flattening
HP:0000331	Short chin
HP:0000347	Micrognathia
HP:0000407	Sensorineural hearing impairment
HP:0000518	Cataract
HP:0000541	Retinal detachment
HP:0000545	Myopia
HP:0000926	Platyspondyly
HP:0001324	Muscle weakness
HP:0001382	Joint hypermobility
HP:0001385	Hip dysplasia
HP:0002007	Frontal bossing
HP:0002136	Broad-based gait
HP:0002515	Waddling gait
HP:0002650	Scoliosis
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:0002970	Genu varum
HP:0003028	Abnormality of the ankle
HP:0003045	Abnormal patella morphology

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST90000025_917	Appendicular lean mass	2.000000e-09
GCST90020028_526	Hip circumference adjusted for BMI	4.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004980	appendicular lean mass
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D003240	Connective Tissue Diseases	C17.300
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008575	Meniere Disease	C09.218.568.217.500
C535502	Epiphyseal dysplasia, multiple, 2 (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

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects cotreatment, increases expression	6
sodium arsenite	increases expression	3
bisphenol A	decreases methylation, increases expression	2
Vorinostat	affects cotreatment, increases expression	2
Cisplatin	affects cotreatment, increases expression	2
aristolochic acid I	decreases expression	1
sotorasib	increases expression, affects cotreatment	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
arsenite	increases methylation	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline	increases expression	1
pentanal	increases expression	1
di-n-butylphosphoric acid	affects expression	1
entinostat	increases 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	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	decreases methylation	1
jinfukang	affects cotreatment, increases expression	1
trametinib	increases expression, affects cotreatment	1
NVP-BKM120	affects cotreatment, increases expression	1
Zoledronic Acid	increases expression	1
Arsenic	increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Camptothecin	increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Estradiol	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04197050	PHASE4	UNKNOWN	Effect of Sacubitril/Valsartan on Reduced Right Ventricular Ejection Fraction in Patients With CTD
NCT04928586	PHASE4	UNKNOWN	Immunosuppressant Combined With Pirfenidone in CTD-ILD
NCT05440240	PHASE4	RECRUITING	Percutaneous Needle Fasciotomy +/- Corticosteroid Injection for Dupuytren’s Contracture
NCT05505409	PHASE4	UNKNOWN	Efficacy and Safety of Pirfenidone in CTD-ILD
NCT06499233	PHASE4	RECRUITING	Efficacy and Safety of Prophylactic Treatment for Pneumocystis Jirovecii Pneumonia in Patients With Autoimmune Inflammatory Rheumatic Disease
NCT01574313	PHASE4	COMPLETED	Effect of Stellate Ganglion Block on Meniere’s Disease
NCT02529475	PHASE4	TERMINATED	Evaluation of Inner Ear and Brain Structures With Contrast-enhanced MRI in Healthy Subjects (HYDROPS)
NCT04815187	PHASE4	ACTIVE_NOT_RECRUITING	Repurposed Use of Allergic Rhinitis and Allergic Asthma Drug to Reduce Vertigo and Hearing Loss in Meniere’s Disease
NCT00864201	PHASE3	UNKNOWN	A Study to Evaluate the Use of Bosentan in Patients With Exercise Induced Pulmonary Arterial Hypertension Associated With Connective Tissue Disease
NCT01196091	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01205438	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01488708	PHASE3	TERMINATED	On Open-Label Study in Participants With Systemic Lupus Erythematosus
NCT03626688	PHASE3	COMPLETED	A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients
NCT03683186	PHASE3	ENROLLING_BY_INVITATION	A Study Evaluating the Long-Term Efficacy and Safety of Ralinepag in Subjects With PAH Via an Open-Label Extension
NCT04084678	PHASE3	TERMINATED	A Study of Ralinepag to Evaluate Effects on Exercise Capacity by CPET in Subjects With WHO Group 1 PH
NCT06716606	PHASE3	RECRUITING	A Study to Investigate the Long-term Safety and Efficacy of Belimumab in Adults With Interstitial Lung Disease (ILD) Associated With Systemic Sclerosis (SSc) and Other Connective Tissue Diseases (CTD) (BLISSconneCTD-OLE)
NCT06917690	PHASE3	RECRUITING	A Study to Learn About the Safety and Efficacy of the Drug Oleogel-S10 in Japanese Patients With Epidermolysis Bullosa
NCT03664674	PHASE3	COMPLETED	Phase 3 Study of OTO-104 in Subjects With Unilateral Meniere’s Disease
NCT04677972	PHASE3	COMPLETED	SPI-1005 for the Treatment of Meniere’s Disease
NCT05851508	PHASE3	RECRUITING	The Effecttiveness of Intratympanic Methylprednisolon Injections Compared to Placebo in the Treatment of Vertigo Attacks in Meniere’s Disease
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)
NCT05420350	PHASE2	UNKNOWN	Lamotrigine and Bupropion for Meniere’s Disease
NCT06544434	PHASE2	RECRUITING	Laser Acupuncture for Meniere Disease
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)
NCT04674735	PHASE1	WITHDRAWN	Safety of APSLXR in Patients Presenting Vertigo of Vestibular Origin or Meniere’s Disease