Stickler syndrome, type 4

Summary

Stickler syndrome, type 4 (MONDO:0013590) is a disease caused by COL9A1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: COL9A1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 38

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Stickler syndrome, type 4
Mondo ID	MONDO:0013590
OMIM	614134
UMLS	C3279941
MedGen	481571
GARD	0018358
Is cancer (heuristic)	no

Also known as: autosomal recessive Stickler syndrome caused by mutation in COL9A1 · COL9A1 autosomal recessive Stickler syndrome · STICKLER syndrome, type IV · STL4

Data availability: 38 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Stickler syndrome › Stickler syndrome, type 4

Related subtypes (4): Stickler syndrome type 1, Stickler syndrome type 2, Stickler syndrome, type 5, Stickler syndrome, type 6

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

38 retrieved; paginated sample, class counts are floors:

24 uncertain significance, 6 conflicting classifications of pathogenicity, 2 benign/likely benign, 2 pathogenic, 2 likely pathogenic, 1 likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1388848	NM_001851.6(COL9A1):c.14G>A (p.Trp5Ter)	COL9A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
161449	NM_001851.6(COL9A1):c.1519C>T (p.Arg507Ter)	COL9A1	Pathogenic	criteria provided, multiple submitters, no conflicts
17195	NM_001851.6(COL9A1):c.883C>T (p.Arg295Ter)	COL9A1	Pathogenic	criteria provided, single submitter
2664714	NM_001851.6(COL9A1):c.1450-1G>T	COL9A1	Likely pathogenic	criteria provided, single submitter
597109	NM_001851.6(COL9A1):c.1052C>A (p.Ser351Ter)	COL9A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
282983	NM_001851.6(COL9A1):c.1634G>A (p.Arg545His)	COL9A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
357811	NM_001851.6(COL9A1):c.902C>T (p.Pro301Leu)	COL9A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
374336	NM_001851.6(COL9A1):c.876+2T>A	COL9A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
449774	NM_001851.6(COL9A1):c.353G>A (p.Arg118Gln)	COL9A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
833926	NM_001851.6(COL9A1):c.460G>C (p.Val154Leu)	COL9A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
930660	NM_001851.6(COL9A1):c.352C>T (p.Arg118Ter)	COL9A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
547841	NM_001844.5(COL2A1):c.2618G>T (p.Gly873Val)	COL2A1	Uncertain significance	criteria provided, single submitter
1054519	NM_001851.6(COL9A1):c.680C>T (p.Pro227Leu)	COL9A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1064099	NM_001851.6(COL9A1):c.2404G>A (p.Gly802Ser)	COL9A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1318479	NM_001851.6(COL9A1):c.2228C>T (p.Ala743Val)	COL9A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1354895	NM_001851.6(COL9A1):c.73G>C (p.Val25Leu)	COL9A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1381175	NM_001851.6(COL9A1):c.2270C>T (p.Pro757Leu)	COL9A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1386321	NM_001851.6(COL9A1):c.1561G>C (p.Ala521Pro)	COL9A1	Uncertain significance	criteria provided, single submitter
1420675	NM_001851.6(COL9A1):c.2333C>T (p.Ala778Val)	COL9A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1464634	NM_001851.6(COL9A1):c.2158C>T (p.Arg720Trp)	COL9A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1493374	NM_001851.6(COL9A1):c.2552A>G (p.Asn851Ser)	COL9A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1699500	NM_001851.6(COL9A1):c.2284A>G (p.Ile762Val)	COL9A1	Uncertain significance	criteria provided, single submitter
17194	NM_001851.6(COL9A1):c.876+2dup	COL9A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1805759	NM_001851.6(COL9A1):c.2260G>C (p.Gly754Arg)	COL9A1	Uncertain significance	criteria provided, single submitter
2664842	NM_001851.6(COL9A1):c.1864G>A (p.Gly622Arg)	COL9A1	Uncertain significance	criteria provided, single submitter
2664923	NM_001851.6(COL9A1):c.443G>A (p.Gly148Asp)	COL9A1	Uncertain significance	criteria provided, single submitter
3393168	NM_001851.6(COL9A1):c.1558-10C>T	COL9A1	Uncertain significance	criteria provided, single submitter
357800	NM_001851.6(COL9A1):c.2617C>G (p.Arg873Gly)	COL9A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3594101	NM_001851.6(COL9A1):c.2708C>A (p.Pro903Gln)	COL9A1	Uncertain significance	criteria provided, single submitter
393272	NM_001851.6(COL9A1):c.1553A>T (p.Asp518Val)	COL9A1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 20 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
COL9A1	Definitive	Autosomal recessive	Stickler syndrome, type 4	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COL9A1	Orphanet:166002	Multiple epiphyseal dysplasia due to collagen 9 anomaly
COL9A1	Orphanet:250984	Autosomal recessive Stickler syndrome
COL2A1	Orphanet:137678	Spondyloepiphyseal dysplasia with metatarsal shortening
COL2A1	Orphanet:166100	Autosomal dominant otospondylomegaepiphyseal dysplasia
COL2A1	Orphanet:1856	Spondyloperipheral dysplasia-short ulna syndrome
COL2A1	Orphanet:209867	Autosomal dominant rhegmatogenous retinal detachment
COL2A1	Orphanet:2380	Legg-Calvé-Perthes disease
COL2A1	Orphanet:459051	Spondyloepiphyseal dysplasia, Stanescu type
COL2A1	Orphanet:485	Kniest dysplasia
COL2A1	Orphanet:85166	Platyspondylic dysplasia, Torrance type
COL2A1	Orphanet:85198	Dysspondyloenchondromatosis
COL2A1	Orphanet:86820	Familial avascular necrosis of femoral head
COL2A1	Orphanet:90653	Stickler syndrome type 1
COL2A1	Orphanet:93279	Mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis
COL2A1	Orphanet:93296	Achondrogenesis type 2
COL2A1	Orphanet:93297	Hypochondrogenesis
COL2A1	Orphanet:93315	Spondylometaphyseal dysplasia, ‘corner fracture’ type
COL2A1	Orphanet:93316	Spondylometaphyseal dysplasia, Schmidt type
COL2A1	Orphanet:93346	Spondyloepimetaphyseal dysplasia congenita, Strudwick type
COL2A1	Orphanet:94068	Spondyloepiphyseal dysplasia congenita

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
COL9A1	HGNC:2217	ENSG00000112280	P20849	Collagen alpha-1(IX) chain	gencc,clinvar
COL2A1	HGNC:2200	ENSG00000139219	P02458	Collagen alpha-1(II) chain	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL9A1	Collagen alpha-1(IX) chain	Structural component of hyaline cartilage and vitreous of the eye.
COL2A1	Collagen alpha-1(II) chain	Type II collagen is specific for cartilaginous tissues.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL9A1	Other/Unknown	no		Collagen, ConA-like_dom_sf, TSPN-like_N
COL2A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cartilage tissue	2
tibia	2
ventricular zone	1
corpus epididymis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL9A1	149	broad	marker	tibia, cartilage tissue, ventricular zone
COL2A1	145	broad	marker	tibia, cartilage tissue, corpus epididymis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL2A1	2,491
COL9A1	1,488

Intra-cohort edges

A	B	Sources
COL2A1	COL9A1	biogrid_interaction, intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL2A1	P02458	11
COL9A1	P20849	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Collagen chain trimerization	2	259.6×	7e-05	COL9A1, COL2A1
Signaling by PDGF	2	253.8×	7e-05	COL9A1, COL2A1
NCAM1 interactions	2	248.3×	7e-05	COL9A1, COL2A1
Assembly of collagen fibrils and other multimeric structures	2	200.3×	7e-05	COL9A1, COL2A1
Collagen degradation	2	175.7×	7e-05	COL9A1, COL2A1
Collagen biosynthesis and modifying enzymes	2	170.4×	7e-05	COL9A1, COL2A1
ECM proteoglycans	2	150.3×	8e-05	COL9A1, COL2A1
Integrin cell surface interactions	2	134.3×	9e-05	COL9A1, COL2A1
Fibronectin matrix formation	1	285.5×	0.005	COL2A1
MET activates PTK2 signaling	1	190.3×	0.007	COL2A1
Developmental Lineage of Pancreatic Ductal Cells	1	114.2×	0.010	COL2A1
Non-integrin membrane-ECM interactions	1	77.2×	0.014	COL2A1
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	43.6×	0.023	COL2A1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
otic vesicle development	1	1404.3×	0.005	COL2A1
anterior head development	1	1404.3×	0.005	COL2A1
cartilage development involved in endochondral bone morphogenesis	1	1203.7×	0.005	COL2A1
proteoglycan metabolic process	1	936.2×	0.005	COL2A1
notochord development	1	842.6×	0.005	COL2A1
limb bud formation	1	766.0×	0.005	COL2A1
embryonic skeletal joint morphogenesis	1	766.0×	0.005	COL2A1
cartilage condensation	1	383.0×	0.008	COL2A1
tissue homeostasis	1	280.9×	0.008	COL2A1
cellular response to BMP stimulus	1	280.9×	0.008	COL2A1
endochondral ossification	1	271.8×	0.008	COL2A1
extrinsic apoptotic signaling pathway in absence of ligand	1	234.1×	0.009	COL2A1
negative regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	205.5×	0.009	COL2A1
heart morphogenesis	1	187.2×	0.010	COL2A1
chondrocyte differentiation	1	150.5×	0.010	COL2A1
inner ear morphogenesis	1	150.5×	0.010	COL2A1
cartilage development	1	125.8×	0.011	COL2A1
roof of mouth development	1	123.9×	0.011	COL2A1
collagen fibril organization	1	112.3×	0.012	COL2A1
animal organ morphogenesis	1	95.8×	0.013	COL9A1
skeletal system development	1	62.9×	0.019	COL2A1
central nervous system development	1	57.7×	0.020	COL2A1
sensory perception of sound	1	50.5×	0.021	COL2A1
regulation of gene expression	1	41.7×	0.025	COL2A1
visual perception	1	39.8×	0.025	COL2A1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COL9A1	0	0
COL2A1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
COL2A1	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	COL9A1, COL2A1

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
COL9A1	0	—
COL2A1	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.