Vascular brain injury

Summary

Vascular brain injury (MONDO:0005621) is a disease with 5 cohort genes (25 GWAS associations across 4 studies) and 7 clinical trials.

At a glance

• Cohort genes: 5
• GWAS associations: 25
• Clinical trials: 7

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	vascular brain injury
Mondo ID	MONDO:0005621
EFO	EFO:0006791
MeSH	D020214
Is cancer (heuristic)	no

Also known as: Brain injury, Vascular · Brain Vascular injury · Brain Vascular trauma · injury, Brain Vascular · injury, Vascular Brain · injury, Vascular, Brain · trauma, Brain Vascular · trauma, cerebrovascular · Vascular Brain Injuries · Vascular injury, Brain · Vascular trauma, Brain · Vascular Traumas, Brain

Data availability: 25 GWAS associations (4 studies).

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › cerebrovascular disorder › vascular brain injury

Related subtypes (23): cerebral arteritis, intracranial thrombosis, occlusion precerebral artery, vascular dementia, stroke disorder, internal carotid artery stenosis, carotid artery disorder, brain ischemia, brain infarction, cerebral amyloid angiopathy, basal ganglia cerebrovascular disorder, intracranial arterial disease, intracranial vasospasm, subclavian steal syndrome, pseudotumor cerebri, cerebral sinovenous thrombosis, HTRA1-related autosomal dominant cerebral small vessel disease, familial porencephaly, microangiopathy and leukoencephalopathy, pontine, autosomal dominant, cathepsin a-related arteriopathy-strokes-leukoencephalopathy, precerebral artery stenosis, cerebral artery stenosis, APP-related brain and vascular amyloidosis

Genetics & variants

GWAS landscape

25 GWAS associations across 4 studies. Top hits map to 9 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs954846345	2e-09	RNF213	G	1.54
rs187517362	3e-09	RBFOX1	A	1.94
rs7090595	3e-08	PGAM1, EXOSC1	T	1.42
rs148200633	8e-08	NPTX1 - RPL32P31	T	1.34
rs7048146	6e-07	PALM2AKAP2	T	0.29
rs11769293	1e-06	CREB5 - TRIL	T	1.05
chr3:66952276	2e-06		C	1.28
rs11144781	2e-06	PCSK5	T	0.8
chr10:106180121	3e-06		G	2.54
rs34660913	3e-06	RASSF10 - BMAL1	T	0.63
rs7596264	5e-06	ARHGAP15	G	0.44
chr7:134674232	6e-06		A	1.04
rs6041428	6e-06	PA2G4P2 - LINC01722	G	1.26
rs9685722	6e-06		T	0.48
rs11602337	8e-06	LUZP2 - RPL36AP40	T	0.29
rs2018293	8e-06	SEZ6L	T	0.31
rs62174474	8e-06	CALCRL-AS1	C	0.71
chr8:80222312	9e-06		T	0.35

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90473331	UK Biobank Whole-Genome Sequencing Consortium	2025	282	458,158	Whole-genome sequencing of 490,640 UK Biobank participants.
GCST90104138	Choe EK	2022	0	0	Leveraging deep phenotyping from health check-up cohort with 10,000 Korean individuals for phenome-wide association study of 136 traits.
GCST90104139	Choe EK	2022	0	0	Leveraging deep phenotyping from health check-up cohort with 10,000 Korean individuals for phenome-wide association study of 136 traits.
GCST002590	Beecham GW	2014	0	0	Genome-wide association meta-analysis of neuropathologic features of Alzheimer’s disease and related dementias.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	18

MAF distribution

Bucket	Variants
common (>=0.05)	8
low_freq (0.01-0.05)	8
rare (<0.01)	2
unknown	0

Functional consequences

Consequence	Count
intron_variant	10
unknown	5
intergenic_variant	3

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs954846345	17	80294030	C>A,G,T	0.009	intron_variant	RNF213	2e-09	Tier 4: intronic/intergenic
rs187517362	16	7555082	G>A	0.009	intron_variant	RBFOX1	3e-09	Tier 4: intronic/intergenic
rs7090595	10	97429204	C>A,T	0.018	intron_variant	PGAM1, EXOSC1	3e-08	Tier 4: intronic/intergenic
rs148200633	17	80526970	C>T	0.01	intron_variant	NPTX1 - RPL32P31	8e-08	Tier 4: intronic/intergenic
rs7048146	9	109537042	C>T	0.389	intron_variant	PALM2AKAP2	6e-07	Tier 4: intronic/intergenic
rs11769293	7	28872190	C>T	0.029	intergenic_variant	CREB5 - TRIL	1e-06	Tier 4: intronic/intergenic
chr3:66952276				0.016			2e-06	Tier 4: intronic/intergenic
rs11144781	9	76178505	G>T	0.032	intron_variant	PCSK5	2e-06	Tier 4: intronic/intergenic
chr10:106180121				0.011			3e-06	Tier 4: intronic/intergenic
rs34660913	11	13136463	C>T	0.093	intergenic_variant	RASSF10 - BMAL1	3e-06	Tier 4: intronic/intergenic
rs7596264	2	143411066	A>G	0.13	intron_variant	ARHGAP15	5e-06	Tier 4: intronic/intergenic
chr7:134674232				0.022			6e-06	Tier 4: intronic/intergenic
rs6041428	20	12525698	A>G	0.016	intron_variant	PA2G4P2 - LINC01722	6e-06	Tier 4: intronic/intergenic
rs9685722				0.121			6e-06	Tier 4: intronic/intergenic
rs11602337	11	25092235	C>T	0.292	intergenic_variant	LUZP2 - RPL36AP40	8e-06	Tier 4: intronic/intergenic
rs2018293	22	26308595	C>A,T	0.185	intron_variant	SEZ6L	8e-06	Tier 4: intronic/intergenic
rs62174474	2	187315682	T>A,C	0.056	intron_variant	CALCRL-AS1	8e-06	Tier 4: intronic/intergenic
chr8:80222312				0.161			9e-06	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SEZ6L	HGNC:10763	ENSG00000100095	Q9BYH1	Seizure 6-like protein	gwas
ARHGAP15	HGNC:21030	ENSG00000075884	Q53QZ3	Rho GTPase-activating protein 15	gwas
CFAP58	HGNC:26676	ENSG00000120051	Q5T655	Cilia- and flagella-associated protein 58	gwas
AGBL3	HGNC:27981	ENSG00000146856	Q8NEM8	Cytosolic carboxypeptidase 3	gwas
PCSK5	HGNC:8747	ENSG00000099139	Q92824	Proprotein convertase subtilisin/kexin type 5	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SEZ6L	Seizure 6-like protein	May contribute to specialized endoplasmic reticulum functions in neurons.
ARHGAP15	Rho GTPase-activating protein 15	GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state.
CFAP58	Cilia- and flagella-associated protein 58	Has an essential role in the assembly and organization of the sperm flagellar axoneme.
AGBL3	Cytosolic carboxypeptidase 3	Metallocarboxypeptidase that mediates deglutamylation of tubulin and non-tubulin target proteins.
PCSK5	Proprotein convertase subtilisin/kexin type 5	Serine endoprotease that processes various proproteins by cleavage at paired basic amino acids, recognizing the RXXX[KR]R consensus motif.

Protein-family classification

Druggable: 3 · Difficult: 1 · Unknown: 1 · 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
Protease	2	14.7×	0.028
Complement	1	53.6×	0.037
Scaffold/PPI	1	3.5×	0.344
Other/Unknown	1	0.4×	0.983

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SEZ6L	Complement	yes		Sushi_SCR_CCP_dom, CUB_dom, Sperma_CUB_dom_sf
ARHGAP15	Scaffold/PPI	no		RhoGAP_dom, PH_domain, Rho_GTPase_activation_prot
CFAP58	Other/Unknown	no		CFAP58_CC
AGBL3	Protease	yes		Peptidase_M14, Pepdidase_M14_N, Cytosolic_carboxypeptidase
PCSK5	Protease	yes	3.4.21.B26	Peptidase_S8/S53_dom, EGF, P_dom

Expression context

Cohort genes with no expression data: 0.

5 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
buccal mucosa cell	2
endothelial cell	1
ganglionic eminence	1
lateral nuclear group of thalamus	1
blood	1
bone marrow cell	1
granulocyte	1
bronchial epithelial cell	1
oocyte	1
secondary oocyte	1
calcaneal tendon	1
left ovary	1
saphenous vein	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SEZ6L	167	broad	marker	ganglionic eminence, endothelial cell, lateral nuclear group of thalamus
ARHGAP15	207	broad	marker	blood, bone marrow cell, granulocyte
CFAP58	156	tissue_specific	marker	oocyte, secondary oocyte, bronchial epithelial cell
AGBL3	192	ubiquitous	marker	buccal mucosa cell, calcaneal tendon, left ovary
PCSK5	264	ubiquitous	marker	buccal mucosa cell, saphenous vein, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SEZ6L	2,443
PCSK5	2,359
ARHGAP15	1,627
CFAP58	573
AGBL3	413

Structural data

PDB: 3 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SEZ6L	Q9BYH1	1
ARHGAP15	Q53QZ3	1
CFAP58	Q5T655	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PCSK5	Q92824	76.31
AGBL3	Q8NEM8	64.26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 5 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
NGF processing	1	951.7×	0.007	PCSK5
Assembly of active LPL and LIPC lipase complexes	1	200.3×	0.017	PCSK5
Carboxyterminal post-translational modifications of tubulin	1	79.3×	0.029	AGBL3
RAC3 GTPase cycle	1	39.6×	0.044	ARHGAP15
RAC1 GTPase cycle	1	20.4×	0.068	ARHGAP15
Post-translational protein modification	1	6.4×	0.173	AGBL3
Metabolism of proteins	1	4.1×	0.223	AGBL3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of low-density lipoprotein particle receptor catabolic process	1	1123.5×	0.006	PCSK5
renin secretion into blood stream	1	842.6×	0.006	PCSK5
viral life cycle	1	842.6×	0.006	PCSK5
plasma lipoprotein particle remodeling	1	842.6×	0.006	PCSK5
peptide biosynthetic process	1	842.6×	0.006	PCSK5
respiratory tube development	1	674.1×	0.006	PCSK5
protein localization to motile cilium	1	674.1×	0.006	CFAP58
cytokine precursor processing	1	674.1×	0.006	PCSK5
protein side chain deglutamylation	1	561.7×	0.007	AGBL3
sperm mitochondrial sheath assembly	1	421.3×	0.008	CFAP58
cerebellar Purkinje cell layer development	1	306.4×	0.010	SEZ6L
limb morphogenesis	1	210.7×	0.012	PCSK5
embryonic digestive tract development	1	198.3×	0.012	PCSK5
peptide hormone processing	1	187.2×	0.012	PCSK5
synapse maturation	1	187.2×	0.012	SEZ6L
sperm flagellum assembly	1	134.8×	0.015	CFAP58
sperm axoneme assembly	1	93.6×	0.021	CFAP58
embryonic skeletal system development	1	78.4×	0.023	PCSK5
embryo implantation	1	70.2×	0.025	PCSK5
adult locomotory behavior	1	60.2×	0.027	SEZ6L
small GTPase-mediated signal transduction	1	36.6×	0.041	ARHGAP15
anterior/posterior pattern specification	1	36.2×	0.041	PCSK5
protein processing	1	34.0×	0.042	PCSK5
cholesterol homeostasis	1	31.2×	0.043	PCSK5
regulation of small GTPase mediated signal transduction	1	28.8×	0.043	ARHGAP15
Notch signaling pathway	1	28.3×	0.043	CFAP58
kidney development	1	28.1×	0.043	PCSK5
regulation of cell shape	1	24.6×	0.047	ARHGAP15
flagellated sperm motility	1	23.4×	0.048	CFAP58
heart development	1	15.8×	0.068	PCSK5

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 1 of 5 evidence-associated genes (20%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SEZ6L	0	0
ARHGAP15	0	0
CFAP58	0	0
AGBL3	0	0
PCSK5	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PCSK5	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PCSK5	3.4.21.B26

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	SEZ6L
D	Druggable family + AlphaFold only, no drug	2	AGBL3, PCSK5
E	Difficult family or no structure, no drug	2	ARHGAP15, CFAP58

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SEZ6L	0	—
ARHGAP15	0	—
CFAP58	0	—
AGBL3	0	—
PCSK5	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 7.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	7

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06898242	Not specified	ACTIVE_NOT_RECRUITING	Early Myofascial Manual Treatment in Subjects With Spasticity Following Acquired Brain Injury
NCT03886675	Not specified	UNKNOWN	Intervention With Cerebral Embolic Protection in TEVAR: Gaseous Protection
NCT03975985	Not specified	TERMINATED	The Effectiveness of Core Stability Exercises
NCT04242602	Not specified	COMPLETED	Multimodal Monitoring of Cerebral Autoregulation After Pediatric Brain Injury
NCT05146037	Not specified	UNKNOWN	INTERvention With Cerebral Embolic Protection in Transcatheter Aortic Valve Implantation (INTERCEPTavi)
NCT05656638	Not specified	COMPLETED	Treatment of Grammatical Time Marking in Post-Stroke Aphasia
NCT06016374	Not specified	UNKNOWN	Development and Validation of a Structured Tele-rehabilitation Programme of Brain Injured Patients