Stickler syndrome type 2

Summary

Stickler syndrome type 2 (MONDO:0011493) is a disease caused by COL11A1 (GenCC Definitive), with 3 cohort genes and 3 clinical trials.

At a glance

• Causal gene: COL11A1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 291
• Phenotypes (HPO): 9
• Clinical trials: 3

Clinical features

Signs & symptoms

Clinical features (HPO)

9 HPO clinical features (Orphanet curated; top 9 by frequency):

HPO ID	Term	Frequency
HP:0000407	Sensorineural hearing impairment	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:0004327	Abnormal vitreous humor morphology	Very frequent (80-99%)
HP:0007957	Corneal opacity	Very frequent (80-99%)
HP:0000175	Cleft palate	Frequent (30-79%)
HP:0000488	Retinopathy	Frequent (30-79%)
HP:6000015	Tympanic membrane hypermobility	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Stickler syndrome type 2
Mondo ID	MONDO:0011493
MeSH	C537493
OMIM	604841
Orphanet	90654
DOID	DOID:0080675
ICD-11	1652024415
NCIT	C74985
UMLS	C1858084
MedGen	347615
GARD	0005020
Is cancer (heuristic)	no

Also known as: COL11A1 Stickler syndrome · Stickler syndrome caused by mutation in COL11A1 · Stickler syndrome type II · Stickler syndrome, type 2 · STICKLER syndrome, type II · STL 2 · STL2

Data availability: 291 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Stickler syndrome › Stickler syndrome type 2

Related subtypes (4): Stickler syndrome type 1, Stickler syndrome, type 4, 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

291 retrieved; paginated sample, class counts are floors:

94 conflicting classifications of pathogenicity, 84 uncertain significance, 31 likely pathogenic, 28 benign, 23 benign/likely benign, 16 pathogenic, 10 pathogenic/likely pathogenic, 4 likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1032776	NM_001854.4(COL11A1):c.3816+2dup	COL11A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1175708	NM_001854.4(COL11A1):c.4519-2del	COL11A1	Pathogenic	criteria provided, single submitter
1184490	NM_001854.4(COL11A1):c.2755-2A>G	COL11A1	Pathogenic	criteria provided, single submitter
1216773	NM_001854.4(COL11A1):c.2513G>A (p.Gly838Glu)	COL11A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1236179	NM_001854.4(COL11A1):c.3655-2del	COL11A1	Pathogenic	criteria provided, single submitter
1304338	NM_001854.4(COL11A1):c.2241+5G>T	COL11A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324096	NM_001854.4(COL11A1):c.1245+1G>A	COL11A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1687305	NM_001854.4(COL11A1):c.2916+1G>A	COL11A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17131	NM_001854.4(COL11A1):c.1874G>T (p.Gly625Val)	COL11A1	Pathogenic	no assertion criteria provided
2202829	NM_001854.4(COL11A1):c.1191del (p.Asn398fs)	COL11A1	Pathogenic	criteria provided, multiple submitters, no conflicts
2683754	NM_001854.4(COL11A1):c.3762+2T>C	COL11A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
289715	NM_001854.4(COL11A1):c.4554+1G>C	COL11A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3236626	NM_001854.4(COL11A1):c.1951C>T (p.Arg651Ter)	COL11A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3366880	NM_001854.4(COL11A1):c.4353_4356+4del	COL11A1	Pathogenic	no assertion criteria provided
3366893	NM_001854.4(COL11A1):c.4459_4464+1del	COL11A1	Pathogenic	no assertion criteria provided
3366894	NM_001854.4(COL11A1):c.4537G>T (p.Gly1513Cys)	COL11A1	Pathogenic	no assertion criteria provided
372792	NM_001854.4(COL11A1):c.1630-2del	COL11A1	Pathogenic	criteria provided, multiple submitters, no conflicts
39776	NM_001854.4(COL11A1):c.3816+1G>A	COL11A1	Pathogenic	criteria provided, multiple submitters, no conflicts
4082350	NM_001854.4(COL11A1):c.807T>A (p.Tyr269Ter)	COL11A1	Pathogenic	criteria provided, single submitter
4277508	NM_001854.4(COL11A1):c.3908G>A (p.Gly1303Asp)	COL11A1	Pathogenic	criteria provided, single submitter
498797	NM_001854.4(COL11A1):c.4547G>T (p.Gly1516Val)	COL11A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
504339	NM_001854.4(COL11A1):c.2808+1G>A	COL11A1	Pathogenic	criteria provided, multiple submitters, no conflicts
560981	NM_001854.4(COL11A1):c.4396G>T (p.Glu1466Ter)	COL11A1	Pathogenic	criteria provided, single submitter
619967	NM_001854.4(COL11A1):c.3438+2_3438+3del	COL11A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
620141	NM_001854.4(COL11A1):c.4084C>T (p.Arg1362Ter)	COL11A1	Pathogenic	criteria provided, multiple submitters, no conflicts
425637	NM_000088.4(COL1A1):c.658C>T (p.Arg220Ter)	COL1A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1029385	NM_001854.4(COL11A1):c.1684-1G>C	COL11A1	Likely pathogenic	criteria provided, single submitter
1174529	NC_000001.10:g.(103388956_103400026)(104094395?)del	COL11A1	Likely pathogenic	criteria provided, single submitter
1179083	NM_001854.4(COL11A1):c.4186G>T (p.Gly1396Cys)	COL11A1	Likely pathogenic	criteria provided, single submitter
1698769	NM_001854.4(COL11A1):c.3276+1G>C	COL11A1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 15 · 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
COL11A1	Definitive	Autosomal dominant	Stickler syndrome type 2	17

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COL11A1	Orphanet:2021	Fibrochondrogenesis
COL11A1	Orphanet:440354	Autosomal dominant myopia-midfacial retrusion-sensorineural hearing loss-rhizomelic dysplasia syndrome
COL11A1	Orphanet:560	Marshall syndrome
COL11A1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
COL11A1	Orphanet:90654	Stickler syndrome type 2
COL1A1	Orphanet:1310	Caffey disease
COL1A1	Orphanet:1899	Arthrochalasia Ehlers-Danlos syndrome
COL1A1	Orphanet:216796	Osteogenesis imperfecta type 1
COL1A1	Orphanet:216804	Osteogenesis imperfecta type 2
COL1A1	Orphanet:216812	Osteogenesis imperfecta type 3
COL1A1	Orphanet:216820	Osteogenesis imperfecta type 4
COL1A1	Orphanet:230857	Ehlers-Danlos/osteogenesis imperfecta syndrome
COL1A1	Orphanet:287	Classical Ehlers-Danlos syndrome
COL1A1	Orphanet:31112	Dermatofibrosarcoma protuberans
COL1A1	Orphanet:314029	High bone mass osteogenesis imperfecta

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
COL11A1	HGNC:2186	ENSG00000060718	P12107	Collagen alpha-1(XI) chain	gencc,clinvar
COL1A1	HGNC:2197	ENSG00000108821	P02452	Collagen alpha-1(I) chain	clinvar
AMY2A	HGNC:477	ENSG00000243480	P04746	Pancreatic alpha-amylase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL11A1	Collagen alpha-1(XI) chain	May play an important role in fibrillogenesis by controlling lateral growth of collagen II fibrils.
COL1A1	Collagen alpha-1(I) chain	Type I collagen is a member of group I collagen (fibrillar forming collagen).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL11A1	Other/Unknown	no		Fib_collagen_C, Laminin_G, Collagen
COL1A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen
AMY2A	Enzyme (other)	yes	3.2.1.1	Alpha_amylase, GH13_cat_dom, A-amylase/branching_C

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
periodontal ligament	2
cartilage tissue	1
tibia	1
skin of hip	1
stromal cell of endometrium	1
body of pancreas	1
islet of Langerhans	1
pancreas	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL11A1	209	broad	marker	tibia, cartilage tissue, periodontal ligament
COL1A1	298	ubiquitous	marker	stromal cell of endometrium, skin of hip, periodontal ligament
AMY2A	125	tissue_specific	marker	body of pancreas, pancreas, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL1A1	5,341
COL11A1	2,433
AMY2A	1,844

Intra-cohort edges

A	B	Sources
COL11A1	COL1A1	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AMY2A	P04746	51
COL1A1	P02452	14

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
COL11A1	P12107	53.06

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 32. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
MET activates PTK2 signaling	2	253.8×	5e-04	COL11A1, COL1A1
Collagen chain trimerization	2	173.0×	5e-04	COL11A1, COL1A1
Developmental Lineage of Pancreatic Ductal Cells	2	152.3×	5e-04	COL11A1, COL1A1
Assembly of collagen fibrils and other multimeric structures	2	133.6×	5e-04	COL11A1, COL1A1
Collagen degradation	2	117.1×	5e-04	COL11A1, COL1A1
Collagen biosynthesis and modifying enzymes	2	113.6×	5e-04	COL11A1, COL1A1
Non-integrin membrane-ECM interactions	2	102.9×	6e-04	COL11A1, COL1A1
Defective VWF binding to collagen type I	1	1268.9×	0.003	COL1A1
Enhanced cleavage of VWF variant by ADAMTS13	1	951.7×	0.003	COL1A1
Defective VWF cleavage by ADAMTS13 variant	1	951.7×	0.003	COL1A1
Enhanced binding of GP1BA variant to VWF multimer:collagen	1	543.8×	0.005	COL1A1
Defective binding of VWF variant to GPIb:IX:V	1	543.8×	0.005	COL1A1
Digestion of dietary carbohydrate	1	317.2×	0.007	AMY2A
GP1b-IX-V activation signalling	1	317.2×	0.007	COL1A1
Anchoring fibril formation	1	253.8×	0.008	COL1A1
Digestion and absorption	1	253.8×	0.008	AMY2A
Platelet Adhesion to exposed collagen	1	223.9×	0.008	COL1A1
Scavenging by Class A Receptors	1	200.3×	0.008	COL1A1
Fibronectin matrix formation	1	190.3×	0.008	COL1A1
Crosslinking of collagen fibrils	1	190.3×	0.008	COL1A1
Digestion	1	190.3×	0.008	AMY2A
RUNX2 regulates osteoblast differentiation	1	152.3×	0.009	COL1A1
Platelet Aggregation (Plug Formation)	1	146.4×	0.009	COL1A1
Syndecan interactions	1	141.0×	0.009	COL1A1
GPVI-mediated activation cascade	1	102.9×	0.012	COL1A1
Developmental Lineage of Pancreatic Acinar Cells	1	100.2×	0.012	AMY2A
Developmental Cell Lineages	1	74.6×	0.016	AMY2A
ECM proteoglycans	1	50.1×	0.023	COL1A1
Integrin cell surface interactions	1	44.8×	0.024	COL1A1
Cell surface interactions at the vascular wall	1	31.7×	0.033	COL1A1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
collagen fibril organization	2	149.8×	0.003	COL11A1, COL1A1
cellular response to vitamin E	1	5617.3×	0.005	COL1A1
cellular response to fluoride	1	2808.7×	0.005	COL1A1
tooth mineralization	1	1872.4×	0.005	COL1A1
tendon development	1	1404.3×	0.005	COL11A1
polysaccharide digestion	1	1404.3×	0.005	AMY2A
carbohydrate catabolic process	1	1123.5×	0.005	AMY2A
cellular response to acetaldehyde	1	1123.5×	0.005	COL1A1
sensory perception of sound	2	67.3×	0.005	COL11A1, COL1A1
visual perception	2	53.0×	0.005	COL11A1, COL1A1
intramembranous ossification	1	936.2×	0.005	COL1A1
cartilage development involved in endochondral bone morphogenesis	1	802.5×	0.006	COL1A1
bone trabecula formation	1	702.2×	0.006	COL1A1
proteoglycan metabolic process	1	624.1×	0.006	COL11A1
skin morphogenesis	1	468.1×	0.008	COL1A1
collagen-activated tyrosine kinase receptor signaling pathway	1	432.1×	0.008	COL1A1
response to hyperoxia	1	374.5×	0.008	COL1A1
negative regulation of cell-substrate adhesion	1	351.1×	0.008	COL1A1
collagen biosynthetic process	1	351.1×	0.008	COL1A1
chondrocyte development	1	312.1×	0.008	COL11A1
detection of mechanical stimulus involved in sensory perception of sound	1	312.1×	0.008	COL11A1
response to steroid hormone	1	280.9×	0.009	COL1A1
cartilage condensation	1	255.3×	0.009	COL11A1
ventricular cardiac muscle tissue morphogenesis	1	234.1×	0.009	COL11A1
endochondral ossification	1	181.2×	0.011	COL1A1
cellular response to fibroblast growth factor stimulus	1	181.2×	0.011	COL1A1
response to cAMP	1	170.2×	0.011	COL1A1
endodermal cell differentiation	1	165.2×	0.011	COL11A1
face morphogenesis	1	165.2×	0.011	COL1A1
response to hydrogen peroxide	1	156.0×	0.011	COL1A1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 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
AMY2A	ACARBOSE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AMY2A	1	4
COL11A1	0	0
COL1A1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ACARBOSE	4	AMY2A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
AMY2A	20	Binding:15, Functional:5
COL1A1	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AMY2A	3.2.1.1	alpha-amylase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
ACARBOSE	4	AMY2A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	AMY2A
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	COL11A1, COL1A1

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)
COL11A1	0	—
COL1A1	8	—

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)