Knobloch syndrome

Summary

Knobloch syndrome (MONDO:0800166) is a disease with 5 cohort genes.

At a glance

• Cohort genes: 5
• ClinVar variants: 241

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Knobloch syndrome
Mondo ID	MONDO:0800166
OMIM	267750
ICD-11	1664056510
UMLS	C1849409
MedGen	336594
GARD	0026470
Is cancer (heuristic)	no

Data availability: 241 ClinVar variants · 1 cell line.

Disease family

An umbrella term covering 2 Mondo subtypes.

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

Related subtypes (8): Wagner disease, snowflake vitreoretinal degeneration, X-linked retinoschisis, Stickler syndrome, exudative vitreoretinopathy, enhanced S-cone syndrome, CAPN5-related vitreoretinopathy, BEST1-related vitreoretinochoroidopathy

Subtypes (2): Knobloch syndrome 2, Knobloch syndrome 1

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

241 retrieved; paginated sample, class counts are floors:

80 uncertain significance, 54 benign, 53 conflicting classifications of pathogenicity, 22 pathogenic, 19 benign/likely benign, 7 likely pathogenic, 5 likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
17115	NM_001379500.1(COL18A1):c.12-2A>T	BNAT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1366287	NM_001379500.1(COL18A1):c.1187_1200dup (p.Pro401fs)	COL18A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1685646	NM_001379500.1(COL18A1):c.2666_2667insT (p.Gly892fs)	COL18A1	Pathogenic	criteria provided, multiple submitters, no conflicts
17117	NM_001379500.1(COL18A1):c.2823dup (p.Gly942fs)	COL18A1	Pathogenic	criteria provided, single submitter
2504107	NM_001379500.1(COL18A1):c.3329_3336del (p.His1110fs)	COL18A1	Pathogenic	criteria provided, single submitter
29652	COL18A1, 2-BP DEL, 3617CT	COL18A1	Pathogenic	no assertion criteria provided
29653	COL18A1, 2-BP DEL	COL18A1	Pathogenic	no assertion criteria provided
403722	NM_001379500.1(COL18A1):c.2673dup (p.Gly892fs)	COL18A1	Pathogenic	criteria provided, multiple submitters, no conflicts
438061	NM_001379500.1(COL18A1):c.2368C>T (p.Arg790Ter)	COL18A1	Pathogenic	criteria provided, multiple submitters, no conflicts
548656	NM_001379500.1(COL18A1):c.1070dup (p.Gly358fs)	COL18A1	Pathogenic	no assertion criteria provided
623178	NM_001379500.1(COL18A1):c.3809+2T>C	COL18A1	Pathogenic	criteria provided, multiple submitters, no conflicts
623349	NM_001379500.1(COL18A1):c.2978_2987del (p.Pro993fs)	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
65411	NM_001379500.1(COL18A1):c.2118dup (p.Gly707fs)	COL18A1	Pathogenic	criteria provided, multiple submitters, no conflicts
684620	NM_001379500.1(COL18A1):c.3522_3523del (p.Leu1175fs)	COL18A1	Pathogenic	no assertion criteria provided
812292	NM_001379500.1(COL18A1):c.429dup (p.Ala144fs)	COL18A1	Pathogenic	no assertion criteria provided
872909	NM_001379500.1(COL18A1):c.268del (p.Arg90fs)	COL18A1	Pathogenic	criteria provided, single submitter
872910	NM_001379500.1(COL18A1):c.589del (p.Leu197fs)	COL18A1	Pathogenic	no assertion criteria provided
915433	NM_001379500.1(COL18A1):c.1158del (p.Gly387fs)	COL18A1	Pathogenic	criteria provided, multiple submitters, no conflicts
976335	NM_001379500.1(COL18A1):c.3532_3533del (p.Gly1178fs)	COL18A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1697333	NM_002577.4(PAK2):c.1303G>A (p.Glu435Lys)	PAK2	Pathogenic	no assertion criteria provided
548657	NM_001379500.1(COL18A1):c.3959_3960insTGCC (p.Cys1321fs)	SLC19A1	Pathogenic	no assertion criteria provided
666965	NM_001379500.1(COL18A1):c.3241C>T (p.Arg1081Ter)	SLC19A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1098639	NM_001379500.1(COL18A1):c.107-11987C>A	COL18A1	Likely pathogenic	criteria provided, single submitter
1120116	NM_001379500.1(COL18A1):c.1335_1336dup (p.Gly446fs)	COL18A1	Likely pathogenic	criteria provided, single submitter
17119	NM_001379500.1(COL18A1):c.3013+3A>C	COL18A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3384068	NM_001379500.1(COL18A1):c.1733_1742del (p.Ala578fs)	COL18A1	Likely pathogenic	criteria provided, single submitter
427899	NM_001379500.1(COL18A1):c.1613G>T (p.Gly538Val)	COL18A1	Likely pathogenic	criteria provided, single submitter
800861	NM_001379500.1(COL18A1):c.3826_3827del (p.Trp1276fs)	COL18A1	Likely pathogenic	no assertion criteria provided
915432	NM_001379500.1(COL18A1):c.1876C>T (p.Arg626Ter)	COL18A1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ADAMTS18	Orphanet:369970	Microcornea-myopic chorioretinal atrophy-telecanthus syndrome
COL18A1	Orphanet:1571	Knobloch syndrome
PAK2	Orphanet:1571	Knobloch syndrome

Cohort genes → proteins

5 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC19A1	HGNC:10937	ENSG00000173638	P41440	Reduced folate transporter	clinvar
ADAMTS18	HGNC:17110	ENSG00000140873	Q8TE60	A disintegrin and metalloproteinase with thrombospondin motifs 18	clinvar
COL18A1	HGNC:2195	ENSG00000182871	P39060	Collagen alpha-1(XVIII) chain	clinvar
BNAT1	HGNC:56666	ENSG00000273796		breast cancer associated ESR1 regulating natural antisense transcript 1	clinvar
PAK2	HGNC:8591	ENSG00000180370	Q13177	Serine/threonine-protein kinase PAK 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
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.
PAK2	Serine/threonine-protein kinase PAK 2	Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell motility, cell cycle progression, apoptosis or proliferation.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.6

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	15.6×	0.224
Protease	1	7.3×	0.224
Kinase	1	5.5×	0.224
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC19A1	Transporter	yes		Folate_carrier, SLC19A1, MFS_trans_sf
ADAMTS18	Protease	yes		TSP1_rpt, Peptidase_M12B, Peptidase_M12B_N
COL18A1	Other/Unknown	no		Collagen, DUF959_COL18_N, Collagenase_NC10/endostatin
BNAT1	Other/Unknown	no
PAK2	Kinase	yes	2.7.11.1	CRIB_dom, Prot_kinase_dom, Ser/Thr_kinase_AS

Expression context

Cohort genes with no expression data: 0.

4 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
tibial artery	2
blood	1
endothelial cell	1
jejunal mucosa	1
cerebellar vermis	1
male germ line stem cell (sensu Vertebrata) in testis	1
secondary oocyte	1
popliteal artery	1
right coronary artery	1
left ovary	1
metanephros cortex	1
corpus callosum	1
cortical plate	1
ganglionic eminence	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC19A1	238	ubiquitous	marker	jejunal mucosa, blood, endothelial cell
ADAMTS18	152	broad	marker	cerebellar vermis, secondary oocyte, male germ line stem cell (sensu Vertebrata) in testis
COL18A1	266	ubiquitous	marker	right coronary artery, popliteal artery, tibial artery
BNAT1	126		yes	left ovary, metanephros cortex, tibial artery
PAK2	291	ubiquitous	marker	ganglionic eminence, cortical plate, corpus callosum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PAK2	3,195
COL18A1	2,316
SLC19A1	1,161
ADAMTS18	1,040
BNAT1	0

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC19A1	P41440	19
COL18A1	P39060	9
PAK2	Q13177	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ADAMTS18	Q8TE60	73.83

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 49. Enrichment computed across 5 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of PAK-2p34 activity by PS-GAP/RHG10	1	1427.5×	0.017	PAK2
Stimulation of the cell death response by PAK-2p34	1	1427.5×	0.017	PAK2
Nef and signal transduction	1	317.2×	0.031	PAK2
CD28 dependent Vav1 pathway	1	219.6×	0.031	PAK2
Activation of RAC1	1	203.9×	0.031	PAK2
Sema3A PAK dependent Axon repulsion	1	167.9×	0.031	PAK2
Metabolism of folate and pterines	1	158.6×	0.031	SLC19A1
Ephrin signaling	1	142.8×	0.031	PAK2
RHO GTPases activate PAKs	1	135.9×	0.031	PAK2
CD209 (DC-SIGN) signaling	1	129.8×	0.031	PAK2
VEGFR2 mediated vascular permeability	1	102.0×	0.031	PAK2
Laminin interactions	1	95.2×	0.031	COL18A1
Generation of second messenger molecules	1	86.5×	0.031	PAK2
FCERI mediated MAPK activation	1	86.5×	0.031	PAK2
Activation of Matrix Metalloproteinases	1	77.2×	0.031	COL18A1
Defective B3GALTL causes PpS	1	77.2×	0.031	ADAMTS18
RHOH GTPase cycle	1	77.2×	0.031	PAK2
O-glycosylation of TSR domain-containing proteins	1	75.1×	0.031	ADAMTS18
Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation	1	75.1×	0.031	PAK2
RHOV GTPase cycle	1	71.4×	0.031	PAK2
Regulation of activated PAK-2p34 by proteasome mediated degradation	1	69.6×	0.031	PAK2
RHOU GTPase cycle	1	69.6×	0.031	PAK2
Smooth Muscle Contraction	1	66.4×	0.031	PAK2
Collagen chain trimerization	1	64.9×	0.031	COL18A1
Diseases associated with O-glycosylation of proteins	1	53.9×	0.036	ADAMTS18
Assembly of collagen fibrils and other multimeric structures	1	50.1×	0.036	COL18A1
RHOJ GTPase cycle	1	50.1×	0.036	PAK2
Metabolism of water-soluble vitamins and cofactors	1	45.3×	0.037	SLC19A1
RHOQ GTPase cycle	1	45.3×	0.037	PAK2
Collagen degradation	1	43.9×	0.037	COL18A1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 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	2106.5×	0.011	SLC19A1
response to hydrostatic pressure	1	1053.2×	0.011	COL18A1
folate transmembrane transport	1	1053.2×	0.011	SLC19A1
folate import across plasma membrane	1	1053.2×	0.011	SLC19A1
folic acid transport	1	702.2×	0.011	SLC19A1
cyclic-GMP-AMP transmembrane import across plasma membrane	1	526.6×	0.011	SLC19A1
positive regulation of cGAS/STING signaling pathway	1	526.6×	0.011	SLC19A1
protein localization to cell-cell junction	1	468.1×	0.011	PAK2
cardiac muscle hypertrophy	1	421.3×	0.011	PAK2
response to xenobiotic stimulus	2	34.5×	0.011	SLC19A1, COL18A1
negative regulation of platelet aggregation	1	351.1×	0.012	ADAMTS18
adherens junction assembly	1	324.1×	0.012	PAK2
dendritic spine development	1	300.9×	0.012	PAK2
folic acid metabolic process	1	280.9×	0.012	SLC19A1
endothelial cell morphogenesis	1	263.3×	0.012	COL18A1
xenobiotic transmembrane transport	1	234.1×	0.012	SLC19A1
regulation of axonogenesis	1	221.7×	0.012	PAK2
negative regulation of protein kinase activity	1	210.7×	0.012	PAK2
obsolete organic anion transport	1	200.6×	0.012	SLC19A1
stimulatory C-type lectin receptor signaling pathway	1	183.2×	0.013	PAK2
regulation of cytoskeleton organization	1	162.0×	0.014	PAK2
negative regulation of stress fiber assembly	1	145.3×	0.015	PAK2
vascular endothelial growth factor receptor signaling pathway	1	120.4×	0.016	PAK2
regulation of MAPK cascade	1	113.9×	0.016	PAK2
positive regulation of extrinsic apoptotic signaling pathway	1	113.9×	0.016	PAK2
eye development	1	87.8×	0.021	ADAMTS18
bicellular tight junction assembly	1	82.6×	0.021	PAK2
cellular response to transforming growth factor beta stimulus	1	69.1×	0.024	PAK2
female pregnancy	1	52.7×	0.030	SLC19A1
response to toxic substance	1	52.7×	0.030	SLC19A1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 5 evidence-associated genes (60%) 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
PAK2	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PAK2	11	4
SLC19A1	4	4
ADAMTS18	0	0
COL18A1	0	0
BNAT1	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
FEDRATINIB	4	PAK2
NERATINIB	4	PAK2
BOSUTINIB	4	PAK2
NINTEDANIB	4	PAK2
MIDOSTAURIN	4	PAK2
LESTAURTINIB	3	PAK2
R-406	2	PAK2
TOZASERTIB	2	PAK2
KW-2449	1	PAK2
PF-03758309	1	PAK2
GSK-690693	1	PAK2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PAK2	376	Binding:373, ADMET:3
SLC19A1	18	Binding:18

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PAK2	2.7.11.1	non-specific serine/threonine protein kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PAK2	376

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

15 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
FEDRATINIB	4	PAK2
NERATINIB	4	PAK2
BOSUTINIB	4	PAK2
NINTEDANIB	4	PAK2
MIDOSTAURIN	4	PAK2
LESTAURTINIB	3	PAK2
R-406	2	PAK2
TOZASERTIB	2	PAK2
KW-2449	1	PAK2
PF-03758309	1	PAK2
GSK-690693	1	PAK2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	SLC19A1, PAK2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ADAMTS18
E	Difficult family or no structure, no drug	2	COL18A1, BNAT1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ADAMTS18	0	—
COL18A1	0	—
BNAT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.