Stickler syndrome type 1

Summary

Stickler syndrome type 1 (MONDO:0007160) is a disease caused by COL2A1 (GenCC Definitive), with 2 cohort genes and 3 clinical trials.

At a glance

• Causal gene: COL2A1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 322
• Phenotypes (HPO): 21
• Clinical trials: 3

Clinical features

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0000327	Hypoplasia of the maxilla	Very frequent (80-99%)
HP:0000343	Long philtrum	Very frequent (80-99%)
HP:0000518	Cataract	Very frequent (80-99%)
HP:0000541	Retinal detachment	Very frequent (80-99%)
HP:0000545	Myopia	Very frequent (80-99%)
HP:0002652	Skeletal dysplasia	Very frequent (80-99%)
HP:0003196	Short nose	Very frequent (80-99%)
HP:0004327	Abnormal vitreous humor morphology	Very frequent (80-99%)
HP:0000175	Cleft palate	Frequent (30-79%)
HP:0000407	Sensorineural hearing impairment	Frequent (30-79%)
HP:0000520	Proptosis	Frequent (30-79%)
HP:0000926	Platyspondyly	Frequent (30-79%)
HP:0001634	Mitral valve prolapse	Frequent (30-79%)
HP:0002758	Osteoarthritis	Frequent (30-79%)
HP:0002829	Arthralgia	Frequent (30-79%)
HP:0005930	Abnormality of epiphysis morphology	Frequent (30-79%)
HP:0100734	Abnormality of vertebral epiphysis morphology	Frequent (30-79%)
HP:6000015	Tympanic membrane hypermobility	Frequent (30-79%)
HP:0001382	Joint hypermobility	Frequent (30-79%)
HP:0000572	Visual loss	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Stickler syndrome type 1
Mondo ID	MONDO:0007160
MeSH	C537492
OMIM	108300
Orphanet	90653
DOID	DOID:0080676
ICD-11	203625278
NCIT	C168733
UMLS	C2020284
MedGen	810955
GARD	0005018
Is cancer (heuristic)	no

Also known as: Stickler syndrome type 1 · Stickler syndrome, type I · STL1

Data availability: 322 ClinVar variants · 4 GenCC gene-disease records · 3 cell lines.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › syndromic disease › Stickler syndrome › Stickler syndrome type 1

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

Subtypes (1): Stickler syndrome, type I, nonsyndromic ocular

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

322 retrieved; paginated sample, class counts are floors:

81 conflicting classifications of pathogenicity, 78 pathogenic, 39 uncertain significance, 38 likely pathogenic, 27 benign/likely benign, 27 benign, 25 pathogenic/likely pathogenic, 7 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1067210	NM_001844.5(COL2A1):c.1996-9G>A	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070315	NM_001844.5(COL2A1):c.3490G>A (p.Gly1164Ser)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1072940	NM_001844.5(COL2A1):c.2094+1G>C	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1074468	NM_001844.5(COL2A1):c.1A>G (p.Met1Val)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1172708	NM_001844.5(COL2A1):c.3270_3273delinsCAGCAAGGAGACAAGGAGACAGAG (p.Glu1090fs)	COL2A1	Pathogenic	criteria provided, single submitter
1185019	NM_001844.5(COL2A1):c.610-17_617del	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1185064	NM_001844.5(COL2A1):c.2748CCCTGGTCC[1] (p.914PGP[2])	COL2A1	Pathogenic	criteria provided, single submitter
1199413	NM_001844.5(COL2A1):c.2464G>A (p.Gly822Ser)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1213981	NM_001844.5(COL2A1):c.3896G>A (p.Trp1299Ter)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1224342	NM_001844.5(COL2A1):c.3121G>A (p.Gly1041Ser)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1300141	NM_001844.5(COL2A1):c.1887+1G>A	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1326887	NM_001844.5(COL2A1):c.4317+1G>T	COL2A1	Pathogenic	criteria provided, single submitter
1326889	NM_001844.5(COL2A1):c.4074+1G>A	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1334674	NM_001844.5(COL2A1):c.3280C>T (p.Gln1094Ter)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1454288	NM_001844.5(COL2A1):c.2219del (p.Pro740fs)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1455692	NM_001844.5(COL2A1):c.2858del (p.Pro953fs)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1483186	NM_001844.5(COL2A1):c.2609G>A (p.Gly870Glu)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1486498	NM_001844.5(COL2A1):c.1365+1G>A	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1512633	NM_001844.5(COL2A1):c.3436-1G>A	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1685276	NM_001844.5(COL2A1):c.1484G>A (p.Gly495Glu)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685650	NM_001844.5(COL2A1):c.4171T>C (p.Tyr1391His)	COL2A1	Pathogenic	criteria provided, single submitter
1685652	NM_001844.5(COL2A1):c.1492G>C (p.Gly498Arg)	COL2A1	Pathogenic	criteria provided, single submitter
1685653	NM_001844.5(COL2A1):c.737G>T (p.Gly246Val)	COL2A1	Pathogenic	criteria provided, single submitter
1699396	NM_001844.5(COL2A1):c.569del (p.Lys190fs)	COL2A1	Pathogenic	criteria provided, single submitter
1707475	NM_001844.5(COL2A1):c.4085del (p.Gly1362fs)	COL2A1	Pathogenic	criteria provided, single submitter
1707640	NM_001844.5(COL2A1):c.2895+1G>C	COL2A1	Pathogenic	criteria provided, single submitter
1709832	NM_001844.5(COL2A1):c.1966C>T (p.Gln656Ter)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1709946	NM_001844.5(COL2A1):c.388G>T (p.Glu130Ter)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17355	NM_001844.5(COL2A1):c.2794C>T (p.Arg932Ter)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
17358	NM_001844.5(COL2A1):c.2751del (p.Gly918fs)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 46 · Orphanet: 19 · 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
COL2A1	Definitive	Autosomal dominant	Stickler syndrome type 1	46

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
LOXL3	Orphanet:250984	Autosomal recessive Stickler syndrome

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
COL2A1	HGNC:2200	ENSG00000139219	P02458	Collagen alpha-1(II) chain	gencc,clinvar
LOXL3	HGNC:13869	ENSG00000115318	P58215	Lysyl oxidase homolog 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL2A1	Collagen alpha-1(II) chain	Type II collagen is specific for cartilaginous tissues.
LOXL3	Lysyl oxidase homolog 3	Protein-lysine 6-oxidase that mediates the oxidation of peptidyl lysine residues to allysine in target proteins.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL2A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen
LOXL3	Enzyme (other)	yes	1.4.3.13	SRCR, Lysyl_oxidase, Lysyl_oxidase_CS

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
corpus epididymis	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL2A1	145	broad	marker	tibia, cartilage tissue, corpus epididymis
LOXL3	198	ubiquitous	marker	tibia, cartilage tissue, tendon of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL2A1	2,491
LOXL3	1,130

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL2A1	P02458	11

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LOXL3	P58215	84.11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. 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
Assembly of collagen fibrils and other multimeric structures	2	200.3×	4e-04	COL2A1, LOXL3
Fibronectin matrix formation	1	285.5×	0.015	COL2A1
Crosslinking of collagen fibrils	1	285.5×	0.015	LOXL3
Collagen formation	1	228.4×	0.015	LOXL3
MET activates PTK2 signaling	1	190.3×	0.015	COL2A1
Elastic fibre formation	1	167.9×	0.015	LOXL3
Collagen chain trimerization	1	129.8×	0.015	COL2A1
Signaling by PDGF	1	126.9×	0.015	COL2A1
NCAM1 interactions	1	124.1×	0.015	COL2A1
Developmental Lineage of Pancreatic Ductal Cells	1	114.2×	0.015	COL2A1
Collagen degradation	1	87.8×	0.016	COL2A1
Collagen biosynthesis and modifying enzymes	1	85.2×	0.016	COL2A1
Non-integrin membrane-ECM interactions	1	77.2×	0.016	COL2A1
ECM proteoglycans	1	75.1×	0.016	COL2A1
Integrin cell surface interactions	1	67.2×	0.017	COL2A1
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	43.6×	0.024	COL2A1
Extracellular matrix organization	1	31.6×	0.031	LOXL3

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
roof of mouth development	2	247.8×	3e-04	COL2A1, LOXL3
collagen fibril organization	2	224.7×	3e-04	COL2A1, LOXL3
fibronectin fibril organization	1	4213.0×	0.003	LOXL3
peptidyl-lysine oxidation	1	2808.7×	0.003	LOXL3
otic vesicle development	1	1404.3×	0.004	COL2A1
anterior head development	1	1404.3×	0.004	COL2A1
cartilage development involved in endochondral bone morphogenesis	1	1203.7×	0.004	COL2A1
negative regulation of T-helper 17 cell lineage commitment	1	1203.7×	0.004	LOXL3
proteoglycan metabolic process	1	936.2×	0.004	COL2A1
notochord development	1	842.6×	0.004	COL2A1
limb bud formation	1	766.0×	0.004	COL2A1
embryonic skeletal joint morphogenesis	1	766.0×	0.004	COL2A1
positive regulation of integrin-mediated signaling pathway	1	648.1×	0.004	LOXL3
somite development	1	561.7×	0.004	LOXL3
cartilage condensation	1	383.0×	0.006	COL2A1
tissue homeostasis	1	280.9×	0.007	COL2A1
cellular response to BMP stimulus	1	280.9×	0.007	COL2A1
endochondral ossification	1	271.8×	0.007	COL2A1
spinal cord development	1	255.3×	0.007	LOXL3
extrinsic apoptotic signaling pathway in absence of ligand	1	234.1×	0.007	COL2A1
negative regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	205.5×	0.008	COL2A1
heart morphogenesis	1	187.2×	0.008	COL2A1
epithelial to mesenchymal transition	1	156.0×	0.009	LOXL3
chondrocyte differentiation	1	150.5×	0.009	COL2A1
inner ear morphogenesis	1	150.5×	0.009	COL2A1
cartilage development	1	125.8×	0.010	COL2A1
lung development	1	99.1×	0.013	LOXL3
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×	0.022	COL2A1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
LOXL3	PYRITHIONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LOXL3	3	4
COL2A1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PYRITHIONE	4	LOXL3
DISULFIRAM	4	LOXL3
THIRAM	2	LOXL3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
LOXL3	6	Binding:6
COL2A1	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
LOXL3	1.4.3.13	protein-lysine 6-oxidase

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

3 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.

Compound	Max phase	Cohort target (bioactivity)
PYRITHIONE	4	LOXL3
DISULFIRAM	4	LOXL3
THIRAM	2	LOXL3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	LOXL3
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	1	COL2A1

Undrugged target profiles

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

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

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT07146516	Not specified	RECRUITING	Retinal Detachment Prevention (Laser Prophylaxis) in Stickler Syndrome (SS)