Knobloch syndrome 2

Summary

Knobloch syndrome 2 (MONDO:0100119) is a disease caused by PAK2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: PAK2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Knobloch syndrome 2
Mondo ID	MONDO:0100119
OMIM	618458
UMLS	C5676897
MedGen	1812153
GARD	0026052
Is cancer (heuristic)	no

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

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 2

Related subtypes (1): 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

4 retrieved; paginated sample, class counts are floors:

2 likely pathogenic, 2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
2921281	NM_002577.4(PAK2):c.1273G>A (p.Asp425Asn)	PAK2	Likely pathogenic	criteria provided, single submitter
3362907	NM_002577.4(PAK2):c.836A>C (p.Gln279Pro)	PAK2	Likely pathogenic	criteria provided, single submitter
3390951	NM_002577.4(PAK2):c.1476A>C (p.Lys492Asn)	PAK2	Uncertain significance	criteria provided, single submitter
3589117	NM_002577.4(PAK2):c.1309G>A (p.Val437Ile)	PAK2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
PAK2	Strong	Autosomal dominant	Knobloch syndrome 2	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PAK2	Orphanet:1571	Knobloch syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PAK2	HGNC:8591	ENSG00000180370	Q13177	Serine/threonine-protein kinase PAK 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
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.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
corpus callosum	1
cortical plate	1
ganglionic eminence	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
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

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PAK2	Q13177	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 27. Enrichment computed across 1 evidence-associated genes (1 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 1 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	5710.0×	0.002	PAK2
Stimulation of the cell death response by PAK-2p34	1	5710.0×	0.002	PAK2
Nef and signal transduction	1	1268.9×	0.006	PAK2
CD28 dependent Vav1 pathway	1	878.5×	0.006	PAK2
Activation of RAC1	1	815.7×	0.006	PAK2
Sema3A PAK dependent Axon repulsion	1	671.8×	0.006	PAK2
Ephrin signaling	1	571.0×	0.006	PAK2
RHO GTPases activate PAKs	1	543.8×	0.006	PAK2
CD209 (DC-SIGN) signaling	1	519.1×	0.006	PAK2
VEGFR2 mediated vascular permeability	1	407.9×	0.006	PAK2
Generation of second messenger molecules	1	346.1×	0.006	PAK2
FCERI mediated MAPK activation	1	346.1×	0.006	PAK2
RHOH GTPase cycle	1	308.6×	0.006	PAK2
Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation	1	300.5×	0.006	PAK2
RHOV GTPase cycle	1	285.5×	0.006	PAK2
Regulation of activated PAK-2p34 by proteasome mediated degradation	1	278.5×	0.006	PAK2
RHOU GTPase cycle	1	278.5×	0.006	PAK2
Smooth Muscle Contraction	1	265.6×	0.006	PAK2
RHOJ GTPase cycle	1	200.3×	0.007	PAK2
RHOQ GTPase cycle	1	181.3×	0.007	PAK2
RHOG GTPase cycle	1	148.3×	0.009	PAK2
VEGFA-VEGFR2 Pathway	1	139.3×	0.009	PAK2
MAPK6/MAPK4 signaling	1	135.9×	0.009	PAK2
RAC2 GTPase cycle	1	126.9×	0.009	PAK2
RAC3 GTPase cycle	1	119.0×	0.009	PAK2
CDC42 GTPase cycle	1	72.3×	0.014	PAK2
RAC1 GTPase cycle	1	61.1×	0.016	PAK2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein localization to cell-cell junction	1	1872.4×	0.004	PAK2
cardiac muscle hypertrophy	1	1685.2×	0.004	PAK2
adherens junction assembly	1	1296.3×	0.004	PAK2
dendritic spine development	1	1203.7×	0.004	PAK2
regulation of axonogenesis	1	887.0×	0.004	PAK2
negative regulation of protein kinase activity	1	842.6×	0.004	PAK2
stimulatory C-type lectin receptor signaling pathway	1	732.7×	0.004	PAK2
regulation of cytoskeleton organization	1	648.1×	0.004	PAK2
negative regulation of stress fiber assembly	1	581.1×	0.004	PAK2
vascular endothelial growth factor receptor signaling pathway	1	481.5×	0.004	PAK2
regulation of MAPK cascade	1	455.5×	0.004	PAK2
positive regulation of extrinsic apoptotic signaling pathway	1	455.5×	0.004	PAK2
bicellular tight junction assembly	1	330.4×	0.005	PAK2
cellular response to transforming growth factor beta stimulus	1	276.3×	0.006	PAK2
cellular response to starvation	1	193.7×	0.008	PAK2
protein autophosphorylation	1	145.3×	0.009	PAK2
protein phosphorylation	1	68.0×	0.019	PAK2
cell migration	1	61.5×	0.020	PAK2
intracellular signal transduction	1	38.1×	0.030	PAK2
negative regulation of apoptotic process	1	34.8×	0.032	PAK2
apoptotic process	1	28.7×	0.036	PAK2
signal transduction	1	16.1×	0.062	PAK2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
PAK2	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PAK2	11	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
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

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: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

11 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)
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)	1	PAK2
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.