Knobloch syndrome 1

Summary

Knobloch syndrome 1 (MONDO:0800167) is a disease caused by COL18A1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: COL18A1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 71
• Phenotypes (HPO): 26

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		119	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0000541	Retinal detachment	Very frequent (80-99%)
HP:0000545	Myopia	Very frequent (80-99%)
HP:0000608	Macular degeneration	Very frequent (80-99%)
HP:0001362	Skull defect	Very frequent (80-99%)
HP:0002085	Occipital encephalocele	Very frequent (80-99%)
HP:0000238	Hydrocephalus	Frequent (30-79%)
HP:0000529	Progressive visual loss	Frequent (30-79%)
HP:0000572	Visual loss	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0004327	Abnormal vitreous humor morphology	Frequent (30-79%)
HP:0007773	Vitreoretinopathy	Frequent (30-79%)
HP:0001382	Joint hypermobility	Occasional (5-29%)
HP:0000076	Vesicoureteral reflux	Occasional (5-29%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0001083	Ectopia lentis	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001595	Abnormality of the hair	Occasional (5-29%)
HP:0001643	Patent ductus arteriosus	Occasional (5-29%)
HP:0001651	Dextrocardia	Occasional (5-29%)
HP:0002021	Pyloric stenosis	Occasional (5-29%)
HP:0005280	Depressed nasal bridge	Occasional (5-29%)
HP:0011800	Midface retrusion	Occasional (5-29%)
HP:0030037	Bifid ureter	Occasional (5-29%)
HP:0100764	Lymphangioma	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Knobloch syndrome 1
Mondo ID	MONDO:0800167
MeSH	C537209
OMIM	267750
Orphanet	1571
SNOMED CT	703542000
UMLS	C4551775
MedGen	1642123
GARD	0000380
Is cancer (heuristic)	no

Also known as: KNO1 · KNOBLOCH syndrome 1 · Knobloch syndrome type 1 · Knobloch syndrome, type 1 · Knobloch-Layer syndrome · myopia retinal detachment encephalocele · retinal detachment-occipital encephalocele syndrome

Data availability: 71 ClinVar variants · 2 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › vitreous body disorder › vitreous disorder › vitreous syneresis › vitreoretinal degeneration › Knobloch syndrome › Knobloch syndrome 1

Related subtypes (1): Knobloch syndrome 2

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

71 retrieved; paginated sample, class counts are floors:

23 uncertain significance, 13 likely pathogenic, 9 pathogenic, 8 conflicting classifications of pathogenicity, 6 benign/likely benign, 6 likely benign, 3 benign, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3779131	NC_000008.11:g.46018383_46018384del		Pathogenic	criteria provided, single submitter
1366287	NM_001379500.1(COL18A1):c.1187_1200dup (p.Pro401fs)	COL18A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1381645	NM_001379500.1(COL18A1):c.1459C>T (p.Arg487Ter)	COL18A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1417839	NM_001379500.1(COL18A1):c.3044_3062del (p.Pro1015fs)	COL18A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1457175	NM_001379500.1(COL18A1):c.1274_1283del (p.Pro425fs)	COL18A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1924745	NM_001379500.1(COL18A1):c.2577+1G>A	COL18A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3768373	NM_001379500.1(COL18A1):c.1002del (p.Glu335fs)	COL18A1	Pathogenic	criteria provided, single submitter
403722	NM_001379500.1(COL18A1):c.2673dup (p.Gly892fs)	COL18A1	Pathogenic	criteria provided, multiple submitters, no conflicts
65410	NM_001379500.1(COL18A1):c.3523_3524del (p.Leu1175fs)	COL18A1	Pathogenic	criteria provided, multiple submitters, no conflicts
866461	NM_001379500.1(COL18A1):c.688dup (p.Gln230fs)	COL18A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
191317	NM_001379500.1(COL18A1):c.2743C>T (p.Arg915Ter)	SLC19A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280186	NM_001379500.1(COL18A1):c.2979_2980delinsC (p.Pro996fs)	SLC19A1	Pathogenic	criteria provided, multiple submitters, no conflicts
3779126	NC_000008.11:g.45977025_45977031dup		Likely pathogenic	criteria provided, single submitter
3779127	NC_000008.11:g.46000826_46000827del		Likely pathogenic	criteria provided, single submitter
3779130	NC_000008.11:g.46013517_46013544del		Likely pathogenic	criteria provided, single submitter
17119	NM_001379500.1(COL18A1):c.3013+3A>C	COL18A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2431924	NM_001379500.1(COL18A1):c.2032-1G>A	COL18A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2824556	NM_001379500.1(COL18A1):c.798+1G>T	COL18A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3767339	NM_001379500.1(COL18A1):c.597_603dup (p.Gly202fs)	COL18A1	Likely pathogenic	criteria provided, single submitter
4086148	NM_001379500.1(COL18A1):c.3465del (p.Ala1156fs)	COL18A1	Likely pathogenic	criteria provided, single submitter
4755450	NM_001379500.1(COL18A1):c.3054_3063del (p.Gly1019fs)	COL18A1	Likely pathogenic	criteria provided, single submitter
4814145	NM_001379500.1(COL18A1):c.3217-1G>T	COL18A1	Likely pathogenic	criteria provided, single submitter
4847238	NM_001379500.1(COL18A1):c.1453-2A>C	COL18A1	Likely pathogenic	criteria provided, single submitter
3383350	NM_001379500.1(COL18A1):c.1222-2A>G	MIR6815	Likely pathogenic	criteria provided, single submitter
3024164	NM_001379500.1(COL18A1):c.3083C>A (p.Ser1028Ter)	SLC19A1	Likely pathogenic	criteria provided, single submitter
1046232	NM_001379500.1(COL18A1):c.1221G>A (p.Pro407=)	COL18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1119343	NM_001379500.1(COL18A1):c.3316C>T (p.Arg1106Trp)	COL18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1483949	NM_001379500.1(COL18A1):c.797C>T (p.Thr266Met)	COL18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1505525	NM_001379500.1(COL18A1):c.2728G>A (p.Gly910Arg)	COL18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1519449	NM_001379500.1(COL18A1):c.107-12513C>T	COL18A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
COL18A1	Definitive	Autosomal recessive	Knobloch syndrome 1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COL18A1	Orphanet:1571	Knobloch syndrome

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
COL18A1	HGNC:2195	ENSG00000182871	P39060	Collagen alpha-1(XVIII) chain	gencc,clinvar
SLC19A1	HGNC:10937	ENSG00000173638	P41440	Reduced folate transporter	clinvar
MIR6815	HGNC:50225	ENSG00000275167		microRNA 6815	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL18A1	Collagen alpha-1(XVIII) chain	Probably plays a major role in determining the retinal structure as well as in the closure of the neural tube.
SLC19A1	Reduced folate transporter	Antiporter that mediates the import of reduced folates or a subset of cyclic dinucleotides, driven by the export of organic anions.

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
Transporter	1	25.9×	0.076
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL18A1	Other/Unknown	no		Collagen, DUF959_COL18_N, Collagenase_NC10/endostatin
SLC19A1	Transporter	yes		Folate_carrier, SLC19A1, MFS_trans_sf
MIR6815	Other/Unknown	no

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	2
popliteal artery	1
right coronary artery	1
tibial artery	1
endothelial cell	1
jejunal mucosa	1
body of stomach	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL18A1	266	ubiquitous	marker	right coronary artery, popliteal artery, tibial artery
SLC19A1	238	ubiquitous	marker	jejunal mucosa, blood, endothelial cell
MIR6815	77		yes	sural nerve, blood, body of stomach

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL18A1	2,316
SLC19A1	1,161
MIR6815	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC19A1	P41440	19
COL18A1	P39060	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 3 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
Metabolism of folate and pterines	1	317.2×	0.016	SLC19A1
Laminin interactions	1	190.3×	0.016	COL18A1
Activation of Matrix Metalloproteinases	1	154.3×	0.016	COL18A1
Collagen chain trimerization	1	129.8×	0.016	COL18A1
Assembly of collagen fibrils and other multimeric structures	1	100.2×	0.016	COL18A1
Metabolism of water-soluble vitamins and cofactors	1	90.6×	0.016	SLC19A1
Collagen degradation	1	87.8×	0.016	COL18A1
Collagen biosynthesis and modifying enzymes	1	85.2×	0.016	COL18A1
Integrin cell surface interactions	1	67.2×	0.018	COL18A1
Metabolism of vitamins and cofactors	1	58.3×	0.019	SLC19A1
Metabolism	1	5.8×	0.165	SLC19A1

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
methotrexate transport	1	4213.0×	0.002	SLC19A1
response to hydrostatic pressure	1	2106.5×	0.002	COL18A1
folate transmembrane transport	1	2106.5×	0.002	SLC19A1
folate import across plasma membrane	1	2106.5×	0.002	SLC19A1
response to xenobiotic stimulus	2	69.1×	0.002	COL18A1, SLC19A1
folic acid transport	1	1404.3×	0.002	SLC19A1
cyclic-GMP-AMP transmembrane import across plasma membrane	1	1053.2×	0.002	SLC19A1
positive regulation of cGAS/STING signaling pathway	1	1053.2×	0.002	SLC19A1
folic acid metabolic process	1	561.7×	0.004	SLC19A1
endothelial cell morphogenesis	1	526.6×	0.004	COL18A1
xenobiotic transmembrane transport	1	468.1×	0.004	SLC19A1
obsolete organic anion transport	1	401.2×	0.004	SLC19A1
female pregnancy	1	105.3×	0.014	SLC19A1
response to toxic substance	1	105.3×	0.014	SLC19A1
animal organ morphogenesis	1	95.8×	0.015	COL18A1
transport across blood-brain barrier	1	89.6×	0.015	SLC19A1
skeletal system development	1	62.9×	0.020	COL18A1
visual perception	1	39.8×	0.029	COL18A1
angiogenesis	1	31.2×	0.035	COL18A1
negative regulation of cell population proliferation	1	21.1×	0.049	COL18A1
cell adhesion	1	18.7×	0.053	COL18A1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
SLC19A1	PRALATREXATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC19A1	4	4
COL18A1	0	0
MIR6815	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PRALATREXATE	4	SLC19A1
RALTITREXED	4	SLC19A1
PEMETREXED	4	SLC19A1
METHOTREXATE	4	SLC19A1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC19A1	18	Binding:18

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

4 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)
PRALATREXATE	4	SLC19A1
RALTITREXED	4	SLC19A1
PEMETREXED	4	SLC19A1
METHOTREXATE	4	SLC19A1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SLC19A1
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	COL18A1, MIR6815

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)
COL18A1	0	—
MIR6815	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.