Vascular dementia

Summary

Vascular dementia (MONDO:0004648) is a disease with 34 cohort genes (120 GWAS associations across 15 studies) and 88 clinical trials. The dominant Reactome pathway is Scavenging by Class A Receptors (3 cohort genes). Top therapeutic interventions include rivastigmine, donepezil, and galantamine.

At a glance

• Cohort genes: 34
• GWAS associations: 120
• ClinVar variants: 38
• Clinical trials: 88

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	vascular dementia
Mondo ID	MONDO:0004648
EFO	EFO:0004718
MeSH	D015140
DOID	DOID:8725
ICD-10-CM	F01, F01.5
ICD-11	1365258270
NCIT	C34525
SNOMED CT	429998004
UMLS	C0011269
MedGen	41447
Anatomy (UBERON)	UBERON:0003499
Is cancer (heuristic)	no

Also known as: multi infarct dementia · vascular dementia

Data availability: 38 ClinVar variants · 120 GWAS associations (15 studies).

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by developmental or physiological process › psychiatric disorder › cognitive disorder › dementia › vascular dementia

Related subtypes (8): Alzheimer disease, Lewy body dementia, hereditary dementia, dementia pugilistica, parkinsonism with dementia of Guadeloupe, AIDS dementia complex, progressive dementia with neuroserpin inclusion bodies, childhood-onset dementia

Subtypes (1): multi-infarct dementia

Genetics & variants

GWAS landscape

120 GWAS associations across 15 studies. Top hits map to 34 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs429358	3e-196	APOE	C	0.88
rs10119	1e-17	TOMM40	G	0.33
rs290227	7e-11	SYK	G	2.2
rs4380108	1e-08	MARCHF10-DT	C	0.17
rs117834366	2e-08	CNTNAP2	A	6.03
rs55747619	8e-08	ITSN2	C	0.38
rs9379092	1e-07	CAGE1, SSR1	G	0.34
rs3757193	1e-07	RPS6KA2	C	2.15
rs17315346	3e-07	BRINP2 - LINC01645	C	2.41
rs1738249	3e-07	DNAH8	C	0.05
rs3871399	3e-07	CMTM7	C	0.55
rs12095469	4e-07	OSBPL9	G	3.65
rs4820650	4e-07	CRYBB2P1, GRK3-AS1	T	0.05
rs61859886	4e-07	MGMT	T	0.27
rs9857196	5e-07	RYK	T	3.44
rs115331896	7e-07	CRBN	T	3.14
rs35810115	7e-07	ZNF675	C	1.17
rs4401880	7e-07	LPL - RPL30P9	C	0.02
rs637924	7e-07	LINC02497 - LINC02501	T	0.06
rs17335455	8e-07	NXPH1 - GAPDHP68	T	0.1
rs4823298	8e-07	FBLN1	T	0.03
rs12814413	9e-07	RBMS2	T	0.05
rs4665372	9e-07	CGREF1	T	0.1
rs517484	9e-07	RAB9BP1 - RNA5SP189	T	0.12
rs17239230	1e-06	RPL6P14 - RNU6-351P	G	3.03
rs7992701	1e-06	LINC00448 - LINC00376	G	0.17
rs9358063	1e-06	DTNBP1	T	0.06
rs9390947	1e-06	GRIK2 - R3HDM2P2	A	3.01
rs57721847	1e-06	NKX2-6 - STC1	C	2.63
chr16:35951515	1e-06		?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90476502	Verma A	2024	4,533	443,622	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90449025	Fongang B	2024	3,892	466,606	A genome-wide association meta-analysis of all-cause and vascular dementia.
GCST90473240	UK Biobank Whole-Genome Sequencing Consortium	2025	2,074	456,366	Whole-genome sequencing of 490,640 UK Biobank participants.
GCST90652220	Liu TY	2025	1,866	225,176	Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population.
GCST90476501	Verma A	2024	1,530	119,510	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90480733	Verma A	2024	1,530	119,510	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST009025	Moreno-Grau S	2019	1,168	3,289	Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer’s disease and three causality networks: The GR@ACE project.
GCST90481678	Verma A	2024	536	59,026	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST009026	Moreno-Grau S	2019	373	3,289	Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer’s disease and three causality networks: The GR@ACE project.
GCST90435838	Zhou W	2018	189	402,383	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	1
Tier 2: splice/UTR	2
Tier 3: regulatory	1
Tier 4: intronic/intergenic	46

MAF distribution

Bucket	Variants
common (>=0.05)	39
low_freq (0.01-0.05)	9
rare (<0.01)	1
unknown	1

Functional consequences

Consequence	Count
intron_variant	34
intergenic_variant	10
3_prime_UTR_variant	2
missense_variant	1
non_coding_transcript_exon_variant	1
unknown	1
regulatory_region_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs429358	19	44908684	T>C	0.155	missense_variant	APOE	3e-196	Tier 1: coding
rs10119	19	44903416	G>A	0.248	3_prime_UTR_variant	TOMM40	1e-17	Tier 2: splice/UTR
rs290227	9	90874382	G>A,C,T	0.4	intron_variant	SYK	7e-11	Tier 4: intronic/intergenic
rs4380108	17	62816124	C>A,T	0.313	intron_variant	MARCHF10-DT	1e-08	Tier 4: intronic/intergenic
rs117834366	7	147937799	G>A	0.011	intron_variant	CNTNAP2	2e-08	Tier 4: intronic/intergenic
rs55747619	2	24307578	C>G	0.087	intron_variant	ITSN2	8e-08	Tier 4: intronic/intergenic
rs9379092	6	7344298	G>A	0.117	intron_variant	CAGE1, SSR1	1e-07	Tier 4: intronic/intergenic
rs3757193	6	166509975	C>A,T	0.083	intron_variant	RPS6KA2	1e-07	Tier 4: intronic/intergenic
rs17315346	1	177313099	C>A,T	0.015	intergenic_variant	BRINP2 - LINC01645	3e-07	Tier 4: intronic/intergenic
rs1738249	6	38786184	C>G,T	0.301	intron_variant	DNAH8	3e-07	Tier 4: intronic/intergenic
rs3871399	3	32454921	C>A,G	0.124	3_prime_UTR_variant	CMTM7	3e-07	Tier 2: splice/UTR
rs12095469	1	51740410	G>A	0.053	intron_variant	OSBPL9	4e-07	Tier 4: intronic/intergenic
rs4820650	22	25529391	T>A,C	0.247	intron_variant	CRYBB2P1, GRK3-AS1	4e-07	Tier 4: intronic/intergenic
rs61859886	10	129554928	T>A,G	0.153	intron_variant	MGMT	4e-07	Tier 4: intronic/intergenic
rs9857196	3	134111816	T>A,C	0.02	intron_variant	RYK	5e-07	Tier 4: intronic/intergenic
rs115331896	3	3163258	T>C,G	0.012	intron_variant	CRBN	7e-07	Tier 4: intronic/intergenic
rs35810115	19	23597961	C>A,T	0.05	non_coding_transcript_exon_variant	ZNF675	7e-07	Tier 4: intronic/intergenic
rs4401880	8	20088555	C>T	0.325	intron_variant	LPL - RPL30P9	7e-07	Tier 4: intronic/intergenic
rs637924	4	31463988	T>C	0.256	intergenic_variant	LINC02497 - LINC02501	7e-07	Tier 4: intronic/intergenic
rs17335455	7	8814316	T>A,G	0.163	intergenic_variant	NXPH1 - GAPDHP68	8e-07	Tier 4: intronic/intergenic
rs4823298	22	45520107	T>A,C	0.458	intron_variant	FBLN1	8e-07	Tier 4: intronic/intergenic
rs12814413	12	56522830	T>A,C,G	0.351	intron_variant	RBMS2	9e-07	Tier 4: intronic/intergenic
rs4665372	2	27102969	T>A,C	0.395	intron_variant	CGREF1	9e-07	Tier 4: intronic/intergenic
rs517484	5	105154429	T>A,C	0.197	intron_variant	RAB9BP1 - RNA5SP189	9e-07	Tier 4: intronic/intergenic
rs17239230	4	104910430	G>A,T	0.052	intron_variant	RPL6P14 - RNU6-351P	1e-06	Tier 4: intronic/intergenic
rs7992701	13	62905005	G>A,C,T	0.44	intergenic_variant	LINC00448 - LINC00376	1e-06	Tier 4: intronic/intergenic
rs9358063	6	15564800	T>C,G	0.419	intron_variant	DTNBP1	1e-06	Tier 4: intronic/intergenic
rs9390947	6	103115326	A>C	0.062	intergenic_variant	GRIK2 - R3HDM2P2	1e-06	Tier 4: intronic/intergenic
rs57721847	8	23837432	C>A,G,T	0.116	intergenic_variant	NKX2-6 - STC1	1e-06	Tier 4: intronic/intergenic
chr16:35951515							1e-06	Tier 4: intronic/intergenic

ClinVar germline variants

38 retrieved; paginated sample, class counts are floors:

31 uncertain significance, 3 conflicting classifications of pathogenicity, 2 benign/likely benign, 1 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1184940	NM_002775.5(HTRA1):c.847G>A (p.Gly283Arg)	HTRA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
872948	NM_000435.3(NOTCH3):c.323G>A (p.Cys108Tyr)	NOTCH3	Pathogenic	criteria provided, single submitter
625897	NM_001733.7(C1R):c.336G>C (p.Met112Ile)	C1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
804628	NM_000435.3(NOTCH3):c.2149C>T (p.Arg717Cys)	NOTCH3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
535987	NM_000548.5(TSC2):c.4432G>A (p.Asp1478Asn)	TSC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
624024	NM_033629.6(TREX1):c.914A>G (p.Tyr305Cys)	ATRIP	Uncertain significance	criteria provided, multiple submitters, no conflicts
1301535	NM_001733.7(C1R):c.674G>A (p.Arg225Gln)	C1R	Uncertain significance	no assertion criteria provided
434559	NM_001127222.2(CACNA1A):c.1348T>C (p.Ser450Pro)	CACNA1A	Uncertain significance	criteria provided, single submitter
650820	NM_031443.4(CCM2):c.328G>A (p.Asp110Asn)	CCM2	Uncertain significance	criteria provided, single submitter
872944	NM_031443.4(CCM2):c.1283T>G (p.Ile428Ser)	CCM2	Uncertain significance	no assertion criteria provided
1301523	NM_014043.4(CHMP2B):c.157G>C (p.Gly53Arg)	CHMP2B	Uncertain significance	no assertion criteria provided
1301522	NM_001845.6(COL4A1):c.*36T>A	COL4A1	Uncertain significance	no assertion criteria provided
872945	NM_001845.6(COL4A1):c.2440G>A (p.Gly814Arg)	COL4A1	Uncertain significance	no assertion criteria provided
71669	NM_001846.4(COL4A2):c.4291C>T (p.Arg1431Cys)	COL4A2	Uncertain significance	no assertion criteria provided
1301533	NM_024656.4(COLGALT1):c.1411C>T (p.Arg471Trp)	COLGALT1	Uncertain significance	no assertion criteria provided
1301525	NM_005219.5(DIAPH1):c.1093T>C (p.Phe365Leu)	DIAPH1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1301529	NM_015268.4(DNAJC13):c.1036C>G (p.Leu346Val)	DNAJC13	Uncertain significance	no assertion criteria provided
1301524	NM_001134407.3(GRIN2A):c.937A>G (p.Ile313Val)	GRIN2A	Uncertain significance	no assertion criteria provided
180746	NM_002775.5(HTRA1):c.961G>A (p.Ala321Thr)	HTRA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
872947	NM_021999.5(ITM2B):c.193C>T (p.Leu65Phe)	ITM2B	Uncertain significance	no assertion criteria provided
872943	NM_194454.3(KRIT1):c.1565T>C (p.Ile522Thr)	KRIT1	Uncertain significance	criteria provided, single submitter
872949	NM_006172.4(NPPA):c.377G>A (p.Arg126Gln)	LOC114827827	Uncertain significance	criteria provided, multiple submitters, no conflicts
1301526	NM_005957.5(MTHFR):c.938G>C (p.Gly313Ala)	MTHFR	Uncertain significance	no assertion criteria provided
1301532	NM_015039.4(NMNAT2):c.427G>A (p.Val143Met)	NMNAT2	Uncertain significance	no assertion criteria provided
1301537	NM_006031.6(PCNT):c.2179C>G (p.His727Asp)	PCNT	Uncertain significance	no assertion criteria provided
206519	NM_002693.3(POLG):c.2218A>G (p.Asn740Asp)	POLG	Uncertain significance	criteria provided, multiple submitters, no conflicts
1301536	NM_000311.5(PRNP):c.713C>T (p.Pro238Leu)	PRNP	Uncertain significance	no assertion criteria provided
872950	NM_000447.3(PSEN2):c.53C>T (p.Thr18Met)	PSEN2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1301531	NM_001257180.2(SLC20A2):c.1858C>T (p.Arg620Trp)	SLC20A2	Uncertain significance	no assertion criteria provided
943552	NM_005359.6(SMAD4):c.1060G>A (p.Val354Met)	SMAD4	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 101 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC20A2	Orphanet:1980	Bilateral striopallidodentate calcinosis
SNCA	Orphanet:171695	Parkinsonian-pyramidal syndrome
SNCA	Orphanet:2828	Young-onset Parkinson disease
SNCA	Orphanet:411602	Hereditary late-onset Parkinson disease
SYK	Orphanet:695807	Immunodeficiency-systemic inflammation-lymphoma predisposition syndrome
TSC2	Orphanet:210159	Adult hepatocellular carcinoma
TSC2	Orphanet:269001	Isolated focal cortical dysplasia type IIa
TSC2	Orphanet:269008	Isolated focal cortical dysplasia type IIb
TSC2	Orphanet:538	Lymphangioleiomyomatosis
TSC2	Orphanet:805	Tuberous sclerosis complex
TSC2	Orphanet:88924	Autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis
C1R	Orphanet:169147	Immunodeficiency due to a classical component pathway complement deficiency
C1R	Orphanet:300345	Autosomal systemic lupus erythematosus
C1R	Orphanet:75392	Periodontal Ehlers-Danlos syndrome
UBQLN2	Orphanet:803	Amyotrophic lateral sclerosis
CNTNAP2	Orphanet:163681	CNTNAP2-related developmental and epileptic encephalopathy
CACNA1A	Orphanet:2131	Alternating hemiplegia of childhood
CACNA1A	Orphanet:2382	Lennox-Gastaut syndrome
CACNA1A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
CACNA1A	Orphanet:569	Familial or sporadic hemiplegic migraine
CACNA1A	Orphanet:71518	Benign paroxysmal torticollis of infancy
CACNA1A	Orphanet:97	Familial paroxysmal ataxia
CACNA1A	Orphanet:98758	Spinocerebellar ataxia type 6
KRIT1	Orphanet:221061	Familial cerebral cavernous malformation
PCNT	Orphanet:2637	Microcephalic osteodysplastic primordial dwarfism type II
PCNT	Orphanet:808	Seckel syndrome
THSD1	Orphanet:231160	Familial cerebral saccular aneurysm
THSD1	Orphanet:363999	Non-immune hydrops fetalis
VPS13A	Orphanet:2388	Choreoacanthocytosis
CCM2	Orphanet:221061	Familial cerebral cavernous malformation
COL4A1	Orphanet:36383	COL4A1/2-related familial vascular leukoencephalopathy
COL4A1	Orphanet:477749	Pontine autosomal dominant microangiopathy with leukoencephalopathy
COL4A1	Orphanet:481986	Familial schizencephaly
COL4A1	Orphanet:73229	HANAC syndrome
COL4A1	Orphanet:75326	Familial isolated retinal arteriolar tortuosity
COL4A1	Orphanet:899	Walker-Warburg syndrome
COL4A1	Orphanet:99810	Familial porencephaly
COL4A2	Orphanet:36383	COL4A1/2-related familial vascular leukoencephalopathy
COL4A2	Orphanet:99810	Familial porencephaly
TMEM106B	Orphanet:100069	Semantic dementia
TMEM106B	Orphanet:100070	Progressive non-fluent aphasia
TMEM106B	Orphanet:275864	Behavioral variant of frontotemporal dementia
CHMP2B	Orphanet:100069	Semantic dementia
CHMP2B	Orphanet:100070	Progressive non-fluent aphasia
CHMP2B	Orphanet:275864	Behavioral variant of frontotemporal dementia
CHMP2B	Orphanet:803	Amyotrophic lateral sclerosis
COLGALT1	Orphanet:99810	Familial porencephaly
DIAPH1	Orphanet:2573	Moyamoya disease
DIAPH1	Orphanet:477814	Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome
DIAPH1	Orphanet:494444	DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome

Cohort genes → proteins

34 cohort genes, 34 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	3
multi_evidence	31

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC20A2	HGNC:10947	ENSG00000168575	Q08357	Sodium-dependent phosphate transporter 2	clinvar
SNCA	HGNC:11138	ENSG00000145335	P37840	Alpha-synuclein	clinvar
SYK	HGNC:11491	ENSG00000165025	P43405	Tyrosine-protein kinase SYK	gwas
TSC2	HGNC:12363	ENSG00000103197	P49815	Tuberin	clinvar
TUBB2A	HGNC:12412	ENSG00000137267	Q13885	Tubulin beta-2A chain	clinvar
C1R	HGNC:1246	ENSG00000159403	P00736	Complement C1r subcomponent	clinvar
UBQLN2	HGNC:12509	ENSG00000188021	Q9UHD9	Ubiquilin-2	clinvar
CNTNAP2	HGNC:13830	ENSG00000174469	Q9UHC6	Contactin-associated protein-like 2	gwas
CACNA1A	HGNC:1388	ENSG00000141837	O00555	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	clinvar
KRIT1	HGNC:1573	ENSG00000001631	O00522	Krev interaction trapped protein 1	clinvar
PCNT	HGNC:16068	ENSG00000160299	O95613	Pericentrin	clinvar
NMNAT2	HGNC:16789	ENSG00000157064	Q9BZQ4	Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 2	clinvar
THSD1	HGNC:17754	ENSG00000136114	Q9NS62	Thrombospondin type-1 domain-containing protein 1	clinvar
VPS13A	HGNC:1908	ENSG00000197969	Q96RL7	Intermembrane lipid transfer protein VPS13A	clinvar
CCM2	HGNC:21708	ENSG00000136280	Q9BSQ5	Cerebral cavernous malformations 2 protein	clinvar
COL4A1	HGNC:2202	ENSG00000187498	P02462	Collagen alpha-1(IV) chain	clinvar
COL4A2	HGNC:2203	ENSG00000134871	P08572	Collagen alpha-2(IV) chain	clinvar
TMEM106B	HGNC:22407	ENSG00000106460	Q9NUM4	Transmembrane protein 106B	clinvar
CHMP2B	HGNC:24537	ENSG00000083937	Q9UQN3	Charged multivesicular body protein 2b	clinvar
COLGALT1	HGNC:26182	ENSG00000130309	Q8NBJ5	Procollagen galactosyltransferase 1	clinvar
DIAPH1	HGNC:2876	ENSG00000131504	O60610	Protein diaphanous homolog 1	clinvar
DNAJC13	HGNC:30343	ENSG00000138246	O75165	DnaJ homolog subfamily C member 13	clinvar
ATRIP	HGNC:33499	ENSG00000164053	Q8WXE1	ATR-interacting protein	clinvar
GRIN2A	HGNC:4585	ENSG00000183454	Q12879	Glutamate receptor ionotropic, NMDA 2A	clinvar
APOE	HGNC:613	ENSG00000130203	P02649	Apolipoprotein E	gwas
ITM2B	HGNC:6174	ENSG00000136156	Q9Y287	Integral membrane protein 2B	clinvar
APP	HGNC:620	ENSG00000142192	P05067	Amyloid-beta precursor protein	clinvar
SMAD4	HGNC:6770	ENSG00000141646	Q13485	SMAD family member 4	clinvar
MTHFR	HGNC:7436	ENSG00000177000	P42898	Methylenetetrahydrofolate reductase (NADPH)	clinvar
NOTCH3	HGNC:7883	ENSG00000074181	Q9UM47	Neurogenic locus notch homolog protein 3	clinvar
POLG	HGNC:9179	ENSG00000140521	P54098	DNA polymerase subunit gamma-1	clinvar
PRNP	HGNC:9449	ENSG00000171867	F7VJQ1	Alternative prion protein	clinvar
HTRA1	HGNC:9476	ENSG00000166033	Q92743	Serine protease HTRA1	clinvar
PSEN2	HGNC:9509	ENSG00000143801	P49810	Presenilin-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC20A2	Sodium-dependent phosphate transporter 2	Sodium-phosphate symporter which preferentially transports the monovalent form of phosphate with a stoichiometry of two sodium ions per phosphate ion.
SNCA	Alpha-synuclein	Neuronal protein that plays several roles in synaptic activity such as regulation of synaptic vesicle trafficking and subsequent neurotransmitter release.
SYK	Tyrosine-protein kinase SYK	Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR).
TSC2	Tuberin	Catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule…
TUBB2A	Tubulin beta-2A chain	Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.
C1R	Complement C1r subcomponent	Serine protease component of the complement C1 complex, a multiprotein complex that initiates the classical pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that st…
UBQLN2	Ubiquilin-2	Plays an important role in the regulation of different protein degradation mechanisms and pathways including ubiquitin-proteasome system (UPS), autophagy and the endoplasmic reticulum-associated protein degradation (ERAD) pathway.
CNTNAP2	Contactin-associated protein-like 2	Required for gap junction formation.
CACNA1A	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp…
KRIT1	Krev interaction trapped protein 1	Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity.
PCNT	Pericentrin	Integral component of the filamentous matrix of the centrosome involved in the initial establishment of organized microtubule arrays in both mitosis and meiosis.
NMNAT2	Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 2	Nicotinamide/nicotinate-nucleotide adenylyltransferase that acts as an axon maintenance factor.
THSD1	Thrombospondin type-1 domain-containing protein 1	Is a positive regulator of nascent focal adhesion assembly, involved in the modulation of endothelial cell attachment to the extracellular matrix.
VPS13A	Intermembrane lipid transfer protein VPS13A	Mediates the transfer of lipids between membranes at organelle contact sites.
CCM2	Cerebral cavernous malformations 2 protein	Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity.
COL4A1	Collagen alpha-1(IV) chain	Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a ‘chicken-wire’ meshwork together with laminins, proteoglycans and entactin/nidogen.
COL4A2	Collagen alpha-2(IV) chain	Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a ‘chicken-wire’ meshwork together with laminins, proteoglycans and entactin/nidogen.
TMEM106B	Transmembrane protein 106B	In neurons, involved in the transport of late endosomes/lysosomes.
CHMP2B	Charged multivesicular body protein 2b	Probable core component of the endosomal sorting required for transport complex III (ESCRT-III) which is involved in multivesicular bodies (MVBs) formation and sorting of endosomal cargo proteins into MVBs.
COLGALT1	Procollagen galactosyltransferase 1	Beta-galactosyltransferase that transfers beta-galactose to hydroxylysine residues of type I collagen.
DIAPH1	Protein diaphanous homolog 1	Actin nucleation and elongation factor required for the assembly of F-actin structures, such as actin cables and stress fibers.
DNAJC13	DnaJ homolog subfamily C member 13	Involved in membrane trafficking through early endosomes, such as the early endosome to recycling endosome transport implicated in the recycling of transferrin and the early endosome to late endosome transport implicated in degradation of…
ATRIP	ATR-interacting protein	Required for checkpoint signaling after DNA damage.
GRIN2A	Glutamate receptor ionotropic, NMDA 2A	Component of N-methyl-D-aspartate (NMDA) receptors (NMDARs) that function as heterotetrameric, ligand-gated cation channels with high calcium permeability and voltage-dependent block by Mg(2+).
APOE	Apolipoprotein E	APOE is an apolipoprotein, a protein associating with lipid particles, that mainly functions in lipoprotein-mediated lipid transport between organs via the plasma and interstitial fluids.
ITM2B	Integral membrane protein 2B	Plays a regulatory role in the processing of the amyloid-beta A4 precursor protein (APP) and acts as an inhibitor of the amyloid-beta peptide aggregation and fibrils deposition.
APP	Amyloid-beta precursor protein	Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis.
SMAD4	SMAD family member 4	In muscle physiology, plays a central role in the balance between atrophy and hypertrophy.
MTHFR	Methylenetetrahydrofolate reductase (NADPH)	Catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine.
NOTCH3	Neurogenic locus notch homolog protein 3	Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination.
POLG	DNA polymerase subunit gamma-1	Catalytic subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA).
HTRA1	Serine protease HTRA1	Serine protease with a variety of targets, including extracellular matrix proteins such as fibronectin.
PSEN2	Presenilin-2	Catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein).

Protein-family classification

Druggable: 9 · Difficult: 2 · Unknown: 23 · Druggable fraction: 0.26

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	3	3.2×	0.388
Other/Unknown	23	1.2×	0.388
Ion channel	1	3.3×	0.616
Transporter	1	2.3×	0.623
Enzyme (other)	3	1.1×	0.692
Scaffold/PPI	2	1.0×	0.692
Kinase	1	0.8×	0.714

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC20A2	Transporter	yes		Phos_transporter
SNCA	Other/Unknown	no		Synuclein, Synuclein_alpha
SYK	Kinase	yes	2.7.10.2	Prot_kinase_dom, SH2, Ser-Thr/Tyr_kinase_cat_dom
TSC2	Other/Unknown	no		Rap/Ran_GAP_dom, Tuberin, ARM-like
TUBB2A	Other/Unknown	no		Tubulin, Beta_tubulin, Tubulin_FtsZ_GTPase
C1R	Protease	yes	3.4.21.41	Sushi_SCR_CCP_dom, EGF, CUB_dom
UBQLN2	Other/Unknown	no		Ubiquitin-like_dom, STI1_HS-bd, UBA-like_sf
CNTNAP2	Other/Unknown	no		FA58C, EGF, Laminin_G
CACNA1A	Ion channel	yes		VDCCAlpha1, CACNA1A, Ion_trans_dom
KRIT1	Scaffold/PPI	no		FERM_domain, Ankyrin_rpt, PH-like_dom_sf
PCNT	Other/Unknown	no		PACT_domain, AKAP9/Pericentrin
NMNAT2	Enzyme (other)	yes	2.7.7.1	Cyt_trans-like, Rossmann-like_a/b/a_fold, NMNAT_euk
THSD1	Other/Unknown	no		TSP1_rpt, TSP1_rpt_sf, THSD1
VPS13A	Other/Unknown	no		VPS13_VAB, VPS13, VPS13_N
CCM2	Other/Unknown	no		PTB/PI_dom, PH-like_dom_sf, Malcavernin
COL4A1	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold
COL4A2	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold
TMEM106B	Other/Unknown	no		TMEM106, TMEM106_C, TMEM106_N
CHMP2B	Other/Unknown	no		Snf7_fam
COLGALT1	Enzyme (other)	yes	2.4.1.50	Glyco_trans_25, Nucleotide-diphossugar_trans, Collagen_mod_GT25
DIAPH1	Other/Unknown	no		Drf_DAD, FH3_dom, GTPase-bd
DNAJC13	Other/Unknown	no		DnaJ_domain, ARM-like, ARM-type_fold
ATRIP	Other/Unknown	no		ATRIP
GRIN2A	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt
APOE	Other/Unknown	no		ApoA_E, Apolipoprotein_A1/A4/E
ITM2B	Other/Unknown	no		BRICHOS_dom, ITM2
APP	Other/Unknown	no		Kunitz_BPTI, Amyloid_glyco_extra, Amyloid_glyco
SMAD4	Other/Unknown	no		SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_dom_sf
MTHFR	Enzyme (other)	yes	1.5.1.20	Mehydrof_redctse-like, Fadh2_euk, FAD-linked_oxidoreductase-like
NOTCH3	Scaffold/PPI	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom
POLG	Other/Unknown	no		DNA-dir_DNA_pol_A_palm_dom, DNA-dir_DNA_pol_A_mt, RNaseH-like_sf
PRNP	Other/Unknown	no		Prion, Prion_copper_b_octapeptide, Prion/Doppel_prot_b-ribbon_dom
HTRA1	Protease	yes	3.4.21.107	IGFBP-like, PDZ, Peptidase_S1C
PSEN2	Protease	yes		Peptidase_A22A, Pept_A22A_PS2, Preselin/SPP

Expression context

Cohort genes with no expression data: 0.

33 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)	34
unknown	0

Top tissues across cohort

Tissue	Cohort genes
pons	3
calcaneal tendon	3
granulocyte	3
leukocyte	2
monocyte	2
cerebellar cortex	2
cerebellar hemisphere	2
right hemisphere of cerebellum	2
endothelial cell	2
corpus callosum	2
middle temporal gyrus	2
apex of heart	2
ventricular zone	2
placenta	2
right coronary artery	2
saphenous vein	2
corpus epididymis	2
Brodmann (1909) area 23	2
metanephric glomerulus	2
renal glomerulus	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC20A2	276	ubiquitous	marker	left lobe of thyroid gland, right lobe of thyroid gland, thyroid gland
SNCA	280	ubiquitous	marker	trabecular bone tissue, orbitofrontal cortex, pons
SYK	239	broad	marker	monocyte, mononuclear cell, leukocyte
TSC2	282	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
TUBB2A	293	ubiquitous	marker	endothelial cell, dorsal root ganglion, pons
C1R	134	ubiquitous	marker	right lobe of liver, liver, right ovary
UBQLN2	295	ubiquitous	marker	cerebellar vermis, pons, postcentral gyrus
CNTNAP2	127	broad	marker	corpus callosum, superior frontal gyrus, C1 segment of cervical spinal cord
CACNA1A	237	broad	marker	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex
KRIT1	138	ubiquitous	marker	calcaneal tendon, colonic epithelium, corpus callosum
PCNT	283	ubiquitous	marker	gastrocnemius, body of tongue, hindlimb stylopod muscle
NMNAT2	208	broad	marker	middle temporal gyrus, cortical plate, frontal pole
THSD1	138	broad	marker	ventricular zone, right lung, apex of heart
VPS13A	287	ubiquitous	marker	jejunal mucosa, biceps brachii, skeletal muscle tissue of biceps brachii
CCM2	243	ubiquitous	marker	putamen, nucleus accumbens, anterior cingulate cortex
COL4A1	283	ubiquitous	marker	visceral pleura, placenta, right coronary artery
COL4A2	284	ubiquitous	marker	saphenous vein, decidua, placenta
TMEM106B	286	ubiquitous	marker	caput epididymis, corpus epididymis, cauda epididymis
CHMP2B	300	ubiquitous	marker	medial globus pallidus, amniotic fluid, mucosa of sigmoid colon
COLGALT1	275	ubiquitous	marker	stromal cell of endometrium, granulocyte, monocyte
DIAPH1	291	ubiquitous	marker	granulocyte, lower esophagus mucosa, leukocyte
DNAJC13	297	ubiquitous	marker	calcaneal tendon, buccal mucosa cell, saphenous vein
ATRIP	170	ubiquitous	yes	left testis, right testis, testis
GRIN2A	199	broad	marker	Brodmann (1909) area 23, endothelial cell, middle temporal gyrus
APOE	267	ubiquitous	marker	left adrenal gland, left adrenal gland cortex, right adrenal gland cortex
ITM2B	295	ubiquitous	marker	renal glomerulus, metanephric glomerulus, germinal epithelium of ovary
APP	295	ubiquitous	marker	prefrontal cortex, renal medulla, Brodmann (1909) area 9
SMAD4	288	ubiquitous	marker	ventricular zone, ganglionic eminence, calcaneal tendon
MTHFR	254	ubiquitous	marker	corpus epididymis, sural nerve, apex of heart
NOTCH3	273	ubiquitous	marker	popliteal artery, tibial artery, right coronary artery

Protein interactions among cohort

Intra-cohort edges: 14.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APP	11,686
SNCA	7,615
SMAD4	7,320
UBQLN2	6,872
APOE	6,793
TUBB2A	5,621
SYK	5,172
NOTCH3	4,403
TSC2	4,135
PCNT	3,934

Intra-cohort edges

A	B	Sources
APOE	APP	intact, string_interaction
APOE	MTHFR	string_interaction
APOE	PSEN2	string_interaction
APOE	SNCA	intact, string_interaction
APOE	TMEM106B	string_interaction
APP	GRIN2A	biogrid_interaction
APP	ITM2B	intact, string_interaction
APP	NMNAT2	biogrid_interaction
APP	PSEN2	intact, string_interaction
CCM2	KRIT1	biogrid_interaction, intact, string_interaction
CHMP2B	TMEM106B	biogrid_interaction, string_interaction
CNTNAP2	HTRA1	intact
COL4A1	COL4A2	intact, string_interaction
COL4A2	COLGALT1	string_interaction

Structural data

PDB: 28 · AlphaFold-only: 6 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
APP	P05067	256
SNCA	P37840	232
SYK	P43405	93
PRNP	F7VJQ1	70
GRIN2A	Q12879	37
POLG	P54098	36
TMEM106B	Q9NUM4	29
APOE	P02649	29
HTRA1	Q92743	18
KRIT1	O00522	15
C1R	P00736	12
SMAD4	Q13485	12
ATRIP	Q8WXE1	11
COLGALT1	Q8NBJ5	10
CCM2	Q9BSQ5	8
NOTCH3	Q9UM47	6
UBQLN2	Q9UHD9	4
CACNA1A	O00555	4
COL4A1	P02462	4
COL4A2	P08572	4
MTHFR	P42898	4
TUBB2A	Q13885	3
TSC2	P49815	2
PSEN2	P49810	2
CNTNAP2	Q9UHC6	1
CHMP2B	Q9UQN3	1
DIAPH1	O60610	1
ITM2B	Q9Y287	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DNAJC13	O75165	82.91
NMNAT2	Q9BZQ4	80.34
SLC20A2	Q08357	72.63
THSD1	Q9NS62	59.46
PCNT	O95613
VPS13A	Q96RL7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 353. Enrichment computed across 34 evidence-associated genes (29 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 29 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Scavenging by Class A Receptors	3	62.2×	0.005	COL4A1, COL4A2, APOE
Noncanonical activation of NOTCH3	2	98.5×	0.018	NOTCH3, PSEN2
NCAM1 interactions	3	25.7×	0.018	COL4A1, COL4A2, PRNP
Amyloid fiber formation	4	14.2×	0.018	SNCA, APOE, ITM2B, APP
Anchoring fibril formation	2	52.5×	0.038	COL4A1, COL4A2
Collagen biosynthesis and modifying enzymes	3	17.6×	0.038	COL4A1, COL4A2, COLGALT1
Fibronectin matrix formation	2	39.4×	0.045	COL4A1, COL4A2
Crosslinking of collagen fibrils	2	39.4×	0.045	COL4A1, COL4A2
ECM proteoglycans	3	15.5×	0.045	COL4A1, COL4A2, APP
Attachment of bacteria to epithelial cells	2	34.2×	0.049	COL4A1, COL4A2
NOTCH3 Activation and Transmission of Signal to the Nucleus	2	32.8×	0.049	NOTCH3, PSEN2
Insertion of tail-anchored proteins into the endoplasmic reticulum membrane	2	32.8×	0.049	APP, PRNP
Macroautophagy	3	11.9×	0.053	TSC2, TUBB2A, CHMP2B
Defective SLC20A2 causes idiopathic basal ganglia calcification 1 (IBGC1)	1	393.8×	0.061	SLC20A2
Laminin interactions	2	26.2×	0.061	COL4A1, COL4A2
Nuclear signaling by ERBB4	2	23.9×	0.065	APOE, PSEN2
Sealing of the nuclear envelope (NE) by ESCRT-III	2	23.9×	0.065	TUBB2A, CHMP2B
Late endosomal microautophagy	2	22.5×	0.069	PCNT, CHMP2B
Aggregated β-amyloid induces FXII autocatalysis	1	196.9×	0.085	APP
Collagen chain trimerization	2	17.9×	0.085	COL4A1, COL4A2
Signaling by PDGF	2	17.5×	0.085	COL4A1, COL4A2
Assembly and cell surface presentation of NMDA receptors	2	17.5×	0.085	TUBB2A, GRIN2A
Cytokine Signaling in Immune system	4	5.6×	0.085	SNCA, SYK, TUBB2A, APP
Disease	7	3.2×	0.085	SLC20A2, SYK, TUBB2A, THSD1, ATRIP, APP, SMAD4
Aggrephagy	2	17.1×	0.085	TUBB2A, PCNT
Loss of Function of SMAD4 in Cancer	1	131.3×	0.089	SMAD4
SMAD4 MH2 Domain Mutants in Cancer	1	131.3×	0.089	SMAD4
SMAD2/3 MH2 Domain Mutants in Cancer	1	131.3×	0.089	SMAD4
Sodium-coupled phosphate cotransporters	1	131.3×	0.089	SLC20A2
Metabolism of proteins	7	3.0×	0.089	SNCA, TUBB2A, THSD1, APOE, ITM2B, APP, SMAD4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 34 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
collagen-activated tyrosine kinase receptor signaling pathway	3	114.4×	4e-04	SYK, COL4A1, COL4A2
negative regulation of long-term synaptic potentiation	3	114.4×	4e-04	APOE, APP, PRNP
cellular response to amyloid-beta	4	46.1×	4e-04	SYK, CACNA1A, APP, PRNP
cellular response to copper ion	3	55.1×	0.003	SNCA, APP, PRNP
positive regulation of amyloid fibril formation	2	198.3×	0.004	APOE, APP
response to interleukin-1	3	45.1×	0.004	SNCA, APP, MTHFR
positive regulation of calcium-mediated signaling	3	37.2×	0.006	SYK, APP, PRNP
negative regulation of platelet-derived growth factor receptor signaling pathway	2	110.1×	0.011	SNCA, APOE
adult locomotory behavior	3	26.6×	0.013	SNCA, VPS13A, APP
endothelium development	2	76.2×	0.017	KRIT1, CCM2
ionotropic glutamate receptor signaling pathway	2	76.2×	0.017	GRIN2A, APP
neuron projection maintenance	2	66.1×	0.019	APP, PRNP
lysosomal protein catabolic process	2	62.0×	0.019	VPS13A, TMEM106B
regulation of long-term neuronal synaptic plasticity	2	58.3×	0.019	SNCA, APP
response to amyloid-beta	2	58.3×	0.019	CACNA1A, PRNP
learning or memory	3	21.2×	0.019	GRIN2A, APP, PRNP
collagen fibril organization	3	19.8×	0.019	COL4A1, COL4A2, COLGALT1
intracellular copper ion homeostasis	2	55.1×	0.020	APP, PRNP
negative regulation of amyloid-beta formation	2	52.2×	0.022	APOE, PRNP
positive regulation of endocytosis	2	47.2×	0.024	SNCA, APOE
blood vessel morphogenesis	2	47.2×	0.024	SYK, COL4A1
negative regulation of endothelial cell migration	2	45.1×	0.025	KRIT1, APOE
obsolete positive regulation of cell proliferation involved in heart valve morphogenesis	1	495.6×	0.027	SMAD4
neutral lipid metabolic process	1	495.6×	0.027	SNCA
lipid transport involved in lipid storage	1	495.6×	0.027	APOE
positive regulation of interleukin-3 production	1	495.6×	0.027	SYK
regulation of superoxide anion generation	1	495.6×	0.027	SYK
positive regulation of SNARE complex assembly	1	495.6×	0.027	SNCA
regulation of acyl-CoA biosynthetic process	1	495.6×	0.027	SNCA
negative regulation of dopamine uptake involved in synaptic transmission	1	495.6×	0.027	SNCA

Therapeutics

Drugs indicated for this disease

0 approved, 5 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Donepezil	Phase 3 (in late-stage trials)
Galantamine	Phase 3 (in late-stage trials)
RAC-3-N-BUTYLPHTHALIDE	Phase 3 (in late-stage trials)
Risperidone	Phase 3 (in late-stage trials)
Rivastigmine	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Tadalafil, Udenafil.

Drug target analysis

Approved (phase 4): 8 · Phase ≥3: 10 · Phased (≥1): 11 · Undrugged: 23

Druggability breadth: 21 of 34 evidence-associated genes (62%) 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
SNCA	ESTRADIOL
SYK	FEDRATINIB
TUBB2A	COLCHICINE
CACNA1A	NIMODIPINE
GRIN2A	MEMANTINE HYDROCHLORIDE
APP	FLORBETAPIR F 18
POLG	ADEFOVIR DIPIVOXIL
PSEN2	NIROGACESTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SYK	54	4
APP	40	4
GRIN2A	37	4
SNCA	31	4
TUBB2A	21	4
PSEN2	8	4
ATRIP	3	3
CACNA1A	2	4
C1R	1	3
NOTCH3	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ESTRADIOL	4	SNCA
ESTRONE	4	SNCA
TETRACYCLINE	4	SNCA
PHYTONADIONE	4	SNCA
CEFTRIAXONE	4	SNCA
FLORBETAPIR	4	APP, SNCA
ESTRIOL	4	SNCA
RIFAMPIN	4	SNCA
TRETINOIN	4	APP, SNCA
TESTOSTERONE	4	SNCA
BRILLIANT BLUE G	4	SNCA
BROMOCRIPTINE	4	SNCA
PERGOLIDE	4	SNCA
DOPAMINE	4	SNCA
MENADIONE	4	SNCA
GENTIAN VIOLET	4	APP, SNCA
SELEGILINE	4	SNCA
RETINOL	4	APP, SNCA
FEDRATINIB	4	SYK
NERATINIB	4	SYK
INFIGRATINIB PHOSPHATE	4	SYK
INFIGRATINIB	4	SYK
ENTRECTINIB	4	SYK
FOSTAMATINIB	4	SYK
CERITINIB	4	SYK
BOSUTINIB	4	SYK
GILTERITINIB	4	SYK
FOSTAMATINIB DISODIUM	4	SYK
PAZOPANIB	4	SYK
DASATINIB	4	SYK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 6.

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

Symbol	Assays	Type breakdown
TUBB2A	1,758	Binding:1718, Functional:34, ADMET:6
APP	1,744	Binding:1699, Functional:44, ADMET:1
SYK	873	Binding:863, Functional:10
PSEN2	479	Binding:460, Functional:12, ADMET:6, Unclassified:1
SNCA	459	Binding:458, Functional:1
GRIN2A	324	Binding:296, Functional:23, ADMET:4, Toxicity:1
POLG	33	Binding:30, ADMET:2, Functional:1
ATRIP	31	Binding:31
C1R	29	Binding:29
HTRA1	28	Binding:28
CACNA1A	19	Binding:18, Functional:1
SMAD4	6	Binding:6
DIAPH1	3	Binding:3
NOTCH3	3	Binding:3
SLC20A2	1	Binding:1
TSC2	1	Binding:1
UBQLN2	1	Binding:1
COLGALT1	1	Binding:1
DNAJC13	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SYK	2.7.10.2, 2.7.12.1	non-specific protein-tyrosine kinase, dual-specificity kinase
C1R	3.4.21.41	complement subcomponent C1r
NMNAT2	2.7.7.1, 2.7.7.18	nicotinamide-nucleotide adenylyltransferase, nicotinate-nucleotide adenylyltransferase
COLGALT1	2.4.1.50	procollagen galactosyltransferase
MTHFR	1.5.1.20, 1.5.1.53	methylenetetrahydrofolate reductase [NAD(P)H], methylenetetrahydrofolate reductase (NADPH)
HTRA1	3.4.21.107, 3.4.21.108	peptidase Do, HtrA2 peptidase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SNCA	459
SYK	873
TUBB2A	1,758
GRIN2A	324
APP	1,744
PSEN2	479

Pharmacogenomics

Cohort genes with a PharmGKB record: 34; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
ESTRADIOL	4	SNCA
ESTRONE	4	SNCA
TETRACYCLINE	4	SNCA
PHYTONADIONE	4	SNCA
CEFTRIAXONE	4	SNCA
FLORBETAPIR	4	APP, SNCA
ESTRIOL	4	SNCA
RIFAMPIN	4	SNCA
TRETINOIN	4	APP, SNCA
TESTOSTERONE	4	SNCA
BRILLIANT BLUE G	4	SNCA
BROMOCRIPTINE	4	SNCA
PERGOLIDE	4	SNCA
DOPAMINE	4	SNCA
MENADIONE	4	SNCA
GENTIAN VIOLET	4	APP, SNCA
SELEGILINE	4	SNCA
RETINOL	4	APP, SNCA
FEDRATINIB	4	SYK
NERATINIB	4	SYK
INFIGRATINIB PHOSPHATE	4	SYK
INFIGRATINIB	4	SYK
ENTRECTINIB	4	SYK
FOSTAMATINIB	4	SYK
CERITINIB	4	SYK
BOSUTINIB	4	SYK
GILTERITINIB	4	SYK
FOSTAMATINIB DISODIUM	4	SYK
PAZOPANIB	4	SYK
DASATINIB	4	SYK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	8	SNCA, SYK, TUBB2A, CACNA1A, GRIN2A, APP, POLG, PSEN2
B	Phased (≥1) drug, not yet approved	3	C1R, ATRIP, NOTCH3
C	Druggable family + PDB, no drug	3	COLGALT1, MTHFR, HTRA1
D	Druggable family + AlphaFold only, no drug	2	SLC20A2, NMNAT2
E	Difficult family or no structure, no drug	18	TSC2, UBQLN2, CNTNAP2, KRIT1, PCNT, THSD1, VPS13A, CCM2, COL4A1, COL4A2 (+8 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
APOE	0	APP
ITM2B	0	APP
SLC20A2	1	—
TSC2	1	—
UBQLN2	1	—
CNTNAP2	0	—
KRIT1	0	—
PCNT	0	—
NMNAT2	0	—
THSD1	0	—
VPS13A	0	—
CCM2	0	—
COL4A1	0	—
COL4A2	0	—
TMEM106B	0	—
CHMP2B	0	—
COLGALT1	1	—
DIAPH1	3	—
DNAJC13	1	—
SMAD4	6	—
MTHFR	0	—
PRNP	0	—
HTRA1	28	—

Clinical trials & evidence

Clinical trials

Clinical trials: 88.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	56
PHASE3	12
PHASE2	11
PHASE4	4
PHASE1	3
PHASE2/PHASE3	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00950430	PHASE4	ENROLLING_BY_INVITATION	Imaging of Brain Amyloid Plaques in the Aging Population
NCT00165763	PHASE4	COMPLETED	Efficacy and Safety of Donepezil Hydrochloride (Aricept) in Vascular Dementia
NCT00847860	PHASE4	COMPLETED	Cilostazol Verse Asprin for Vascular Dementia in Poststroke Patients With White Matter Lesions
NCT00947531	PHASE4	COMPLETED	A Clinical Trial to Evaluate the Safety and Efficacy of 20 ml Cerebrolysin in Patients With Vascular Dementia
NCT03804229	PHASE3	ACTIVE_NOT_RECRUITING	Efficacy and Safety of Butylphthalide Soft Capsule for the Treatment of Vascular Dementia
NCT00099216	PHASE3	COMPLETED	Efficacy and Safety of Rivastigmine Capsules in Patients With Probable Vascular Dementia
NCT00130338	PHASE3	COMPLETED	Rivastigmine Capsules in Patients With Probable Vascular Dementia
NCT00209456	PHASE3	COMPLETED	Dopamine Transporter Scintigraphy Imaging (DAT-Imaging) in Patients With Lewy Body Dementia
NCT00249158	PHASE3	COMPLETED	A Study of the Effectiveness and Safety of Risperidone in the Treatment of Behavioral Disturbances in Patients With Dementia
NCT00261573	PHASE3	COMPLETED	A Study of the Safety and Effectiveness of Galantamine Versus Placebo in the Treatment of Patients With Vascular Dementia or Mixed Dementia
NCT00621647	PHASE3	COMPLETED	Seroquel- Agitation Associated With Dementia
NCT02098824	PHASE2/PHASE3	UNKNOWN	Symptomatic Treatment of Vascular Cognitive Impairment
NCT02453932	PHASE3	COMPLETED	Efficacy and Safety of Tianzhi Granule in Mild to Moderate Vascular Dementia
NCT03682185	PHASE3	COMPLETED	The Healthy Patterns Sleep Study
NCT03789760	PHASE3	COMPLETED	The Clinical Trial of Chinese Herbal Medicine (SaiLuoTong) Capsule
NCT03986424	PHASE3	COMPLETED	Local Study of Akatinol Memantine in VaD in Russia
NCT04552041	PHASE3	COMPLETED	Prospekta in the Treatment of Cognitive, Behavioral and Psychiatric Disorders in Patients With Vascular Dementia.
NCT01466543	PHASE2	UNKNOWN	Effect of Zydena (Udenafil) on Cerebral Blood Flow and Peripheral Blood Viscosity
NCT01475578	PHASE2	COMPLETED	Study of STA-1 Capsule in Patients With Vascular Dementia (Marrow-Sea Deficiency)
NCT01608217	PHASE2	COMPLETED	Delta-THC in Dementia
NCT01761227	PHASE2	COMPLETED	Efficacy and Safety of Fufangdanshen Tablets in Mild to Moderate Vascular Dementia
NCT01953705	PHASE2	UNKNOWN	n-3 PUFA for Vascular Cognitive Aging
NCT01965756	PHASE2	COMPLETED	Effect of Insulin Sensitizer Metformin on AD Biomarkers
NCT01978730	PHASE2	UNKNOWN	The Clinical Trial of Chinese Herbal Medicine SaiLuoTong Capsule
NCT02467413	PHASE2	WITHDRAWN	BAC in Patient With Alzheimer’s Disease or Vascular Dementia
NCT03230071	PHASE2	COMPLETED	Efficacy and Safety of TMBCZG in Mild to Moderate Vascular Dementia
NCT04109963	PHASE2	UNKNOWN	Trial of Remote Ischemic Pre-conditioning in Vascular Cognitive Impairment
NCT04248270	PHASE1/PHASE2	UNKNOWN	A Noval Tau Tracer in Young Onset Dementia
NCT05371639	PHASE2	UNKNOWN	Efficacy and Safety of Tian Ma Bian Chun Zhi Gan Tablets in Mild to Moderate Vascular Dementia
NCT00457769	PHASE1	UNKNOWN	Aricept to Improve Functional Tasks in Vascular Dementia
NCT03702543	PHASE1	UNKNOWN	Managing Vascular Dementia Risk Factors With SymTrend
NCT04567745	PHASE1	COMPLETED	Automated Retinal Image Analysis System (EyeQuant) for Computation of Vascular Biomarkers
NCT03653156	Not specified	RECRUITING	China Cognition and Aging Study
NCT04114994	Not specified	RECRUITING	Longitudinal Cognitive Assessment by BoCA
NCT04335994	Not specified	RECRUITING	ENhancing Outcomes in Cognitive Impairment Through Use of Home Sleep ApNea Testing
NCT05491980	Not specified	ACTIVE_NOT_RECRUITING	Florida Cerebrovascular Disease Biorepository and Genomics Center
NCT05954741	Not specified	RECRUITING	Multidimensional Rehabilitation Programs for Cognitive Impairment in Comorbid Outpatients: a Randomized Controlled Trial
NCT06034509	Not specified	RECRUITING	Cognitive and Vascular Functioning Following TBI
NCT06079216	Not specified	NOT_YET_RECRUITING	Making Connections Thru Music
NCT06120361	Not specified	RECRUITING	The Swedish BioFINDER - Primary Care Study

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
RIVASTIGMINE	4	6
DONEPEZIL	4	3
GALANTAMINE	4	3
QUETIAPINE	4	2
ASPIRIN	4	1
CILOSTAZOL	4	1
DRONABINOL	4	1
IOFLUPANE I 123	4	1
SODIUM CHLORIDE	4	1
UDENAFIL	3	1
PITTSBURGH COMPOUND B	2	1
CHEMBL5282669	0	1
CHEMBL5189046	0	1
CHEMBL1385	0	1
CHEMBL3764305	0	1
CHEMBL1836264	0	1