COL9A1

protein-coding

collagen type IX alpha 1 chain, the group of Collagen proteoglycans|Collagens

Gene summary

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. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001851.6

Inheritance

AR, AD

ClinVar variants

P:110U:513B:305

Top phenotype

Stickler syndrome, type IV

gnomAD constraint

pLI —, LoF o/e 0.63

Max pathogenic AF

—

Genomic locus

chr6:70,216,040-70,303,084

External References & Databases

Ensembl (ENSG00000112280)

Transcript & Mutation Effects

hg38 • Region Span ~87.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive Stickler syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016647

Submitter: Orphanet

Stickler syndrome, type 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013590

Submitter: ClinGen

COL9A1 was first reported in relation to autosomal recessive Stickler Syndrome in 2006 (Van Camp et al., PMID: 16909383). This condition is characterized by moderate-to-severe hearing loss, which may be progressive and accompanied by ocular phenotypes (including vision issues, retinal degeneration, vitreous anomalies) and skeletal features (including epiphyseal dysplasia). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found clear differences in inheritance pattern and phenotypes. Therefore, the following disease entities have been split into two disease entities, Stickler Syndrome (OMIM: 614134) and multiple epiphyseal dysplasia (OMIM: 614135). The split curation for multiple epiphyseal dysplasia will be evaluated separately. 8 variants (missense, nonsense, frameshift) that have been reported in at least 8 probands in 6 publications (PMIDs: 16909383, 21421862, 31315069, 33951325, 36597107, 39406934) are included in this curation. The maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by experimental evidence (mouse models, expression-level data; PMIDs: 8197187, 8464901, 15802199; gEAR expression database). Mouse models indicate that mutants have hearing loss, cochlear structural anomalies, and skeletal anomalies. Expression-level evidence in mice shows strong expression throughout the cochlea. In summary, there is definitive evidence supporting the relationship between COL9A1 and autosomal recessive Stickler Syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Of note, there is no evidence to support an association with heritable thoracic aortic aneurysm and dissection. This classification was approved by the ClinGen Hearing Loss GCEP on the meeting date 10/8/2025 (SOP Version 11).

Stickler syndrome, type 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013590

Submitter: Labcorp Genetics (formerly Invitae)

Stickler syndrome, type 4DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013590

Submitter: G2P

epiphyseal dysplasia, multiple, 6DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013591

Submitter: G2P

Stickler syndrome, type 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013590

Submitter: Genomics England PanelApp

Stickler syndrome, type 4MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013590

Submitter: Ambry Genetics

epiphyseal dysplasia, multiple, 6LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0013591

Submitter: Labcorp Genetics (formerly Invitae)

epiphyseal dysplasia, multiple, 6LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013591

Submitter: Ambry Genetics

multiple epiphyseal dysplasia due to collagen 9 anomalySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015627

Submitter: Orphanet

Clinical Genomic Database (CGD)

Stickler syndrome, type IVAR

Manifestation: Audiologic/Otolaryngologic; Craniofacial;Musculoskeletal; Ophthalmologic

Intervention: Audiologic/Otolaryngologic; Ophthalmologic

Rationale: Though the condition may be recognizable, early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; Avoidance of risk factors related to ocular manifestations (eg, contact sports) is indicated

Refs: 11565064; 16909383; 20301479

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COL9A1 variants in ClinVar

19 Conditions Cataloged

not providedTotal: 1291

not specifiedTotal: 245

COL9A1-related disorderTotal: 126

Inborn genetic diseasesTotal: 118

Stickler syndrome, type 4Total: 39

Epiphyseal dysplasia, multiple, 6Total: 28

Connective tissue disorderTotal: 15

Stickler syndromeTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001851.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			12 clinvar	265 clinvar	2 clinvar	279
missense			487 clinvar	38 clinvar		525
nonsense	16 clinvar	11 clinvar	2 clinvar			29
start loss						0
frameshift	31 clinvar	17 clinvar	4 clinvar			52
splice donor/acceptor (+/-2bp)	1 clinvar	34 clinvar	8 clinvar			43
Total	48	62	513	303	2	928

Highest pathogenic variant AF is 0.00017008069

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001851.6	RefSeq	NP_001842.3	38	MANE Select
ENST00000357250.11	Ensembl	ENSP00000349790.6	38	MANE Select
NM_001377289.1	RefSeq	NP_001364218.1	33	Standard
NM_001377290.1	RefSeq	NP_001364219.1	31	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
ECM-receptor interaction - Homo sapiens (human)
Focal adhesion - Homo sapiens (human)
Protein digestion and absorption - Homo sapiens (human)
Human papillomavirus infection - Homo sapiens (human)

Biological Process

animal organ morphogenesis
extracellular matrix organization

Molecular Function

extracellular matrix structural constituent
extracellular matrix structural constituent conferring tensile strength
metal ion binding

Cellular Component

extracellular region
collagen type IX trimer
extracellular space
endoplasmic reticulum lumen
extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000357250
Coding exons: 38
Length: 88023
Individuals with no LoFs: 125646
Homozygous LoFs: 0
Heterozygous LoFs: 102
Defined: 125748
p: 0.000406

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.186	514	526	0.977	0.0000283	5773
Missense (PolyPhen)		189	231.24	0.81734		2307
Synonymous	-2.58	221	177	1.25	0.00000962	1946
Loss of Function	2.78	40	64.0	0.625	0.00000340	749

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00051	0.00049	rare
Latino/Admixed American	0.00032	0.00032	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00044	0.00044	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00054	0.00054	rare
South Asian	0.00033	0.00033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Structural component of hyaline cartilage and vitreous of the eye.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:11565064}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:16909383}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.175

Intolerance Scores

LoFtool: 0.0671
RVIS EVS: -0.86
RVIS percentile EVS: 10.96

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.598

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High