Cerebral amyloid angiopathy

Summary

Cerebral amyloid angiopathy (MONDO:0005620) is a disease with 62 cohort genes (112 GWAS associations across 11 studies) and 31 clinical trials. Top therapeutic interventions include minocycline and ponezumab.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 62
• GWAS associations: 112
• ClinVar variants: 2
• Phenotypes (HPO): 13
• Clinical trials: 31

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		350	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0011970	Cerebral amyloid angiopathy	Very frequent (80-99%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001342	Cerebral hemorrhage	Frequent (30-79%)
HP:0002120	Cerebral cortical atrophy	Frequent (30-79%)
HP:0002138	Subarachnoid hemorrhage	Frequent (30-79%)
HP:0002315	Headache	Frequent (30-79%)
HP:0002344	Progressive neurologic deterioration	Frequent (30-79%)
HP:0012520	Dilation of Virchow-Robin spaces	Frequent (30-79%)
HP:0000726	Dementia	Occasional (5-29%)
HP:0002922	Increased CSF protein concentration	Occasional (5-29%)
HP:0012229	CSF pleocytosis	Occasional (5-29%)
HP:0025714	Cerebral cortical microinfarct	Occasional (5-29%)
HP:0030890	Hyperintensity of cerebral white matter on MRI	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	cerebral amyloid angiopathy
Mondo ID	MONDO:0005620
EFO	EFO:0006790
MeSH	D016657
Orphanet	85458
DOID	DOID:9246
ICD-10-CM	I68.0
NCIT	C84625
SNOMED CT	230724001
UMLS	C1510489
MedGen	267610
GARD	0010266
Is cancer (heuristic)	no

Also known as: CAA, familial · cerebral amyloid angiopathy, familial · cerebral amyloid angiopathy, genetic · dutch hereditary cerebral amyloid angiopathy · HCHWA · hereditary cerebral haemorrhage with amyloidosis - Dutch type · hereditary cerebral hemorrhage with amyloidosis - Dutch type

Data availability: 2 ClinVar variants · 112 GWAS associations (11 studies).

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › cerebrovascular disorder › cerebral amyloid angiopathy

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, vascular brain injury, 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

Subtypes (4): ACys amyloidosis, ADan amyloidosis, ABri amyloidosis, cerebral amyloid angiopathy, APP-related

Genetics & variants

GWAS landscape

112 GWAS associations across 11 studies. Top hits map to 26 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs429358	5e-40	APOE	?
rs6857	3e-21	LNCOB1, NECTIN2	T	0.67
rs5117	9e-18	APOC1	C	0.18
rs79524815	1e-08	HDAC9	G
rs10234094	2e-08	LINC-PINT	C	0.37
chr3:197113961	7e-08		C
rs6729667	1e-07	HPCAL1	G
rs34487851	2e-07	NCK2 - ECRG4	G
rs117114154	2e-07	LINC01151	G
rs71619047	3e-07	NDUFB5P1 - LINC00290	A
rs13207159	5e-07	ULBP3 - PPP1R14C	A
rs35067331	6e-07	TRAPPC12	T
chr2:23743850	6e-07		T
rs4803791	7e-07	RELB	A	0.12
rs77731990	7e-07	CACYBPP2 - MIR548AE1	G
rs58143459	7e-07	DDIT4L-AS1 - EMCN	C
rs4380195	1e-06	RPLP1P5 - MYCNUT	A	0.18
rs8059669	1e-06	CDH1	C
rs7604021	1e-06	DOCK10	A
rs77377847	1e-06	KCNH8 - EFHB	A
rs139792624	1e-06	LINC03000	G
chr15:41258121	1e-06		C
rs4145953	1e-06	POLD3	A
chr6:44535225	1e-06		G
rs2291354	1e-06	ATP10A	A
rs11584308	1e-06	KAZN	C
rs16989979	2e-06	LINC02484 - SEC63P2	T	0.33
rs764589	2e-06	LINC00922 - RNA5SP428	T
rs11694957	2e-06	DNER	T
rs1955	2e-06	AP4E1, DCAF13P3	A

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST005514	Chung J	2018	3,135	0	Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer’s disease.
GCST005515	Chung J	2018	3,135	0	Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer’s disease.
GCST005517	Chung J	2018	3,135	0	Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer’s disease.
GCST002588	Beecham GW	2014	1,673	1,134	Genome-wide association meta-analysis of neuropathologic features of Alzheimer’s disease and related dementias.
GCST90012828	Chibnik LB	2017	404	0	Susceptibility to neurofibrillary tangles: role of the PTPRD locus and limited pleiotropy with other neuropathologies.
GCST012481	Reddy JS	2021	0	0	Genome-wide analysis identifies a novel LINC-PINT splice variant associated with vascular amyloid pathology in Alzheimer’s disease.
GCST012482	Reddy JS	2021	0	0	Genome-wide analysis identifies a novel LINC-PINT splice variant associated with vascular amyloid pathology in Alzheimer’s disease.
GCST012483	Reddy JS	2021	0	0	Genome-wide analysis identifies a novel LINC-PINT splice variant associated with vascular amyloid pathology in Alzheimer’s disease.
GCST012484	Reddy JS	2021	0	0	Genome-wide analysis identifies a novel LINC-PINT splice variant associated with vascular amyloid pathology in Alzheimer’s disease.
GCST012485	Reddy JS	2021	0	0	Genome-wide analysis identifies a novel LINC-PINT splice variant associated with vascular amyloid pathology in Alzheimer’s disease.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	1
Tier 2: splice/UTR	1
Tier 3: regulatory	0
Tier 4: intronic/intergenic	48

MAF distribution

Bucket	Variants
common (>=0.05)	37
low_freq (0.01-0.05)	13
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	30
intergenic_variant	11
unknown	6
missense_variant	1
3_prime_UTR_variant	1
non_coding_transcript_exon_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs429358	19	44908684	T>C	0.05	missense_variant	APOE	5e-40	Tier 1: coding
rs6857	19	44888997	C>A,G,T	0.343	3_prime_UTR_variant	LNCOB1, NECTIN2	3e-21	Tier 2: splice/UTR
rs5117	19	44915533	T>A,C,G	0.41	intron_variant	APOC1	9e-18	Tier 4: intronic/intergenic
rs79524815	7	18658708	T>C,G	0.03	intron_variant	HDAC9	1e-08	Tier 4: intronic/intergenic
rs10234094	7	131007000	T>A,C	0.09	intron_variant	LINC-PINT	2e-08	Tier 4: intronic/intergenic
chr3:197113961				0.04			7e-08	Tier 4: intronic/intergenic
rs6729667	2	10349456	G>A,C,T	0.21	intron_variant	HPCAL1	1e-07	Tier 4: intronic/intergenic
rs34487851	2	106026098	A>G,T	0.05	intergenic_variant	NCK2 - ECRG4	2e-07	Tier 4: intronic/intergenic
rs117114154	8	122514319	C>G	0.06	intron_variant	LINC01151	2e-07	Tier 4: intronic/intergenic
rs71619047	4	181024414	G>A	0.04	intergenic_variant	NDUFB5P1 - LINC00290	3e-07	Tier 4: intronic/intergenic
rs13207159	6	150100552	G>A	0.25	intergenic_variant	ULBP3 - PPP1R14C	5e-07	Tier 4: intronic/intergenic
rs35067331	2	3470314	C>T	0.05	intron_variant	TRAPPC12	6e-07	Tier 4: intronic/intergenic
chr2:23743850				0.05			6e-07	Tier 4: intronic/intergenic
rs4803791	19	45020325	G>A,C	0.25	intron_variant	RELB	7e-07	Tier 4: intronic/intergenic
rs77731990	2	183692132	C>G,T	0.08	intergenic_variant	CACYBPP2 - MIR548AE1	7e-07	Tier 4: intronic/intergenic
rs58143459	4	100302156	T>C	0.19	intron_variant	DDIT4L-AS1 - EMCN	7e-07	Tier 4: intronic/intergenic
rs4380195	2	15873466	A>C,T	0.3	intergenic_variant	RPLP1P5 - MYCNUT	1e-06	Tier 4: intronic/intergenic
rs8059669	16	68811308	A>C	0.14	intron_variant	CDH1	1e-06	Tier 4: intronic/intergenic
rs7604021	2	224771342	T>A	0.41	intron_variant	DOCK10	1e-06	Tier 4: intronic/intergenic
rs77377847	3	19618125	C>A	0.03	intron_variant	KCNH8 - EFHB	1e-06	Tier 4: intronic/intergenic
rs139792624	5	164998088	A>G	0.03	intron_variant	LINC03000	1e-06	Tier 4: intronic/intergenic
chr15:41258121				0.04			1e-06	Tier 4: intronic/intergenic
rs4145953	11	74620834	A>C,G,T	0.2	intron_variant	POLD3	1e-06	Tier 4: intronic/intergenic
chr6:44535225				0.05			1e-06	Tier 4: intronic/intergenic
rs2291354	15	25707742	G>A	0.48	intron_variant	ATP10A	1e-06	Tier 4: intronic/intergenic
rs11584308	1	14479497	C>G	0.2	intron_variant	KAZN	1e-06	Tier 4: intronic/intergenic
rs16989979	4	34543724	G>A,T	0.241	intergenic_variant	LINC02484 - SEC63P2	2e-06	Tier 4: intronic/intergenic
rs764589	16	66149480	A>T	0.09	intergenic_variant	LINC00922 - RNA5SP428	2e-06	Tier 4: intronic/intergenic
rs11694957	2	229554341	C>G,T	0.33	intron_variant	DNER	2e-06	Tier 4: intronic/intergenic
rs1955	15	50945898	G>A,C	0.24	non_coding_transcript_exon_variant	AP4E1, DCAF13P3	2e-06	Tier 4: intronic/intergenic

ClinVar germline variants

2 retrieved; paginated sample, class counts are floors:

2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
2047418	NM_000484.4(APP):c.1969G>A (p.Gly657Arg)	APP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
638317	NM_000484.4(APP):c.2125G>A (p.Gly709Ser)	APP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 26 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC6A3	Orphanet:238455	Infantile dystonia-parkinsonism
SETBP1	Orphanet:436151	Intellectual disability-expressive aphasia-facial dysmorphism syndrome
SETBP1	Orphanet:798	Schinzel-Giedion syndrome
CPA6	Orphanet:163717	Familial mesial temporal lobe epilepsy
CPA6	Orphanet:36387	Genetic epilepsy with febrile seizure plus
CDH1	Orphanet:1331	Familial prostate cancer
CDH1	Orphanet:199306	Cleft lip/palate
CDH1	Orphanet:1997	Blepharo-cheilo-odontic syndrome
CDH1	Orphanet:227535	Hereditary breast cancer
CDH1	Orphanet:26106	Hereditary diffuse gastric cancer
CYP26B1	Orphanet:293925	Lethal occipital encephalocele-skeletal dysplasia syndrome
TRAPPC12	Orphanet:500144	Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome
GRIK2	Orphanet:528084	Non-specific syndromic intellectual disability
GRIK2	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
APOE	Orphanet:329481	Lipoprotein glomerulopathy
APOE	Orphanet:412	Dysbetalipoproteinemia
APP	Orphanet:100006	ABeta amyloidosis, Dutch type
APP	Orphanet:1020	Early-onset autosomal dominant Alzheimer disease
APP	Orphanet:324703	ABetaL34V amyloidosis
APP	Orphanet:324708	ABeta amyloidosis, Iowa type
APP	Orphanet:324713	ABeta amyloidosis, Italian type
APP	Orphanet:324718	ABetaA21G amyloidosis
APP	Orphanet:324723	ABeta amyloidosis, Arctic type
PLOD3	Orphanet:300284	Connective tissue disorder due to lysyl hydroxylase-3 deficiency
PMS1	Orphanet:144	Lynch syndrome
RELB	Orphanet:688594	Combined immunodeficiency due to RELB deficiency

Cohort genes → proteins

62 cohort genes, 45 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	61
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC6A3	HGNC:11049	ENSG00000142319	Q01959	Sodium-dependent dopamine transporter	gwas
EVA1C	HGNC:13239	ENSG00000166979	P58658	Protein eva-1 homolog C	gwas
HDAC9	HGNC:14065	ENSG00000048052	Q9UKV0	Histone deacetylase 9	gwas
ULBP3	HGNC:14895	ENSG00000131019	Q9BZM4	UL16-binding protein 3	gwas
PPP1R14C	HGNC:14952	ENSG00000198729	Q8TAE6	Protein phosphatase 1 regulatory subunit 14C	gwas
SETBP1	HGNC:15573	ENSG00000152217	Q9Y6X0	SET-binding protein	gwas
SPTLC3	HGNC:16253	ENSG00000172296	Q9NUV7	Serine palmitoyltransferase 3	gwas
CPA6	HGNC:17245	ENSG00000165078	Q8N4T0	Carboxypeptidase A6	gwas
CDH1	HGNC:1748	ENSG00000039068	P12830	Cadherin-1	gwas
CDH5	HGNC:1764	ENSG00000179776	P33151	Cadherin-5	gwas
NGRN	HGNC:18077	ENSG00000182768	Q9NPE2	Neugrin	gwas
ARHGAP20	HGNC:18357	ENSG00000137727	Q9P2F6	Rho GTPase-activating protein 20	gwas
KSR2	HGNC:18610	ENSG00000171435	Q6VAB6	Kinase suppressor of Ras 2	gwas
KCNH8	HGNC:18864	ENSG00000183960	Q96L42	Voltage-gated delayed rectifier potassium channel KCNH8	gwas
RNF144A	HGNC:20457	ENSG00000151692	P50876	E3 ubiquitin-protein ligase RNF144A	gwas
CYP26B1	HGNC:20581	ENSG00000003137	Q9NR63	Cytochrome P450 26B1	gwas
FSTL5	HGNC:21386	ENSG00000168843	Q8N475	Follistatin-related protein 5	gwas
TTYH3	HGNC:22222	ENSG00000136295	Q9C0H2	Protein tweety homolog 3	gwas
SPATS1	HGNC:22957	ENSG00000249481	Q496A3	Spermatogenesis-associated serine-rich protein 1	gwas
DOCK10	HGNC:23479	ENSG00000135905	Q96BY6	Dedicator of cytokinesis protein 10	gwas
ADCY9	HGNC:240	ENSG00000162104	O60503	Adenylate cyclase type 9	gwas
TRAPPC12	HGNC:24284	ENSG00000171853	Q8WVT3	Trafficking protein particle complex subunit 12	gwas
DNER	HGNC:24456	ENSG00000187957	Q8NFT8	Delta and Notch-like epidermal growth factor-related receptor	gwas
ECRG4	HGNC:24642	ENSG00000119147	Q9H1Z8	Augurin	gwas
YTHDC2	HGNC:24721	ENSG00000047188	Q9H6S0	3’-5’ RNA helicase YTHDC2	gwas
ADH1C	HGNC:251	ENSG00000248144	P00326	Alcohol dehydrogenase 1C	gwas
ELMOD1	HGNC:25334	ENSG00000110675	Q8N336	ELMO domain-containing protein 1	gwas
FAM124A	HGNC:26413	ENSG00000150510	Q86V42	Protein FAM124A	gwas
LINC-PINT	HGNC:26885	ENSG00000231721	A0A455ZAR2	Transcriptional regulator PINT87aa	gwas
FAM86EP	HGNC:28017	ENSG00000251669		family with sequence similarity 86 member E, pseudogene	gwas
EFR3A	HGNC:28970	ENSG00000132294	Q14156	Protein EFR3 homolog A	gwas
ARHGAP23	HGNC:29293	ENSG00000275832	Q9P227	Rho GTPase-activating protein 23	gwas
NUP35	HGNC:29797	ENSG00000163002	Q8NFH5	Nucleoporin NUP35	gwas
ADI1	HGNC:30576	ENSG00000182551	Q9BV57	Acireductone dioxygenase	gwas
MYCNUT	HGNC:32684	ENSG00000223850		MYCN upstream transcript	gwas
MIR2113	HGNC:37058	ENSG00000238367		microRNA 2113	gwas
LINC00290	HGNC:38515	ENSG00000248197		long intergenic non-protein coding RNA 290	gwas
NFIA-AS2	HGNC:40401	ENSG00000237928		NFIA antisense RNA 2	gwas
TRAPPC12-AS1	HGNC:41046	ENSG00000225234		TRAPPC12 antisense RNA 1	gwas
HS1BP3-IT1	HGNC:41474	ENSG00000231948		HS1BP3 intronic transcript 1	gwas
MIR548AU	HGNC:43483	ENSG00000283146		microRNA 548au	gwas
DCAF13P3	HGNC:43868	ENSG00000259378		DDB1 and CUL4 associated factor 13 pseudogene 3	gwas
LINC00861	HGNC:45133	ENSG00000245164		long intergenic non-protein coding RNA 861	gwas
GRIK2	HGNC:4580	ENSG00000164418	Q13002	Glutamate receptor ionotropic, kainate 2	gwas
KDM7A-DT	HGNC:48959	ENSG00000260231		KDM7A divergent transcript	gwas
KRT73-AS1	HGNC:49607	ENSG00000257495		KRT73 antisense RNA 1	gwas
LINC01317	HGNC:50523			long intergenic non-protein coding RNA 1317	gwas
HPCAL1	HGNC:5145	ENSG00000115756	P37235	Hippocalcin-like protein 1	gwas
SMILR	HGNC:51825	ENSG00000255364		smooth muscle induced lncRNA, enhancer of proliferation	gwas
MIR4432HG	HGNC:52005	ENSG00000228590		MIR4432 host gene	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC6A3	Sodium-dependent dopamine transporter	Mediates sodium- and chloride-dependent transport of dopamine.
EVA1C	Protein eva-1 homolog C	Binds heparin.
HDAC9	Histone deacetylase 9	Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4).
ULBP3	UL16-binding protein 3	Binds and activates the KLRK1/NKG2D receptor, mediating natural killer cell cytotoxicity.
PPP1R14C	Protein phosphatase 1 regulatory subunit 14C	Inhibitor of the PP1 regulatory subunit PPP1CA.
SPTLC3	Serine palmitoyltransferase 3	Component of the serine palmitoyltransferase multisubunit enzyme (SPT) that catalyzes the initial and rate-limiting step in sphingolipid biosynthesis by condensing L-serine and activated acyl-CoA (most commonly palmitoyl-CoA) to form long-…
CPA6	Carboxypeptidase A6	May be involved in the proteolytic inactivation of enkephalins and neurotensin in some brain areas.
CDH1	Cadherin-1	Cadherins are calcium-dependent cell adhesion proteins.
CDH5	Cadherin-5	Cadherins are calcium-dependent cell adhesion proteins.
NGRN	Neugrin	Plays an essential role in mitochondrial ribosome biogenesis.
ARHGAP20	Rho GTPase-activating protein 20	GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state.
KSR2	Kinase suppressor of Ras 2	Location-regulated scaffold connecting MEK to RAF.
KCNH8	Voltage-gated delayed rectifier potassium channel KCNH8	Pore-forming (alpha) subunit of a voltage-gated delayed rectifier potassium channel that mediates outward-rectifying potassium currents.
RNF144A	E3 ubiquitin-protein ligase RNF144A	E3 ubiquitin-protein ligase which accepts ubiquitin from E2 ubiquitin-conjugating enzymes UBE2L3 and UBE2L6 in the form of a thioester and then directly transfers the ubiquitin to targeted substrates.
CYP26B1	Cytochrome P450 26B1	A cytochrome P450 monooxygenase involved in the metabolism of retinoates (RAs), the active metabolites of vitamin A, and critical signaling molecules in animals.
TTYH3	Protein tweety homolog 3	Calcium-independent, swelling-dependent volume-regulated anion channel (VRAC-swell) which plays a pivotal role in the process of regulatory volume decrease (RVD) in the brain through the efflux of anions like chloride and organic osmolytes…
DOCK10	Dedicator of cytokinesis protein 10	Guanine nucleotide-exchange factor (GEF) that activates CDC42 and RAC1 by exchanging bound GDP for free GTP.
ADCY9	Adenylate cyclase type 9	Adenylyl cyclase that catalyzes the formation of the signaling molecule cAMP in response to activation of G protein-coupled receptors.
TRAPPC12	Trafficking protein particle complex subunit 12	Component of the TRAPP complex, which is involved in endoplasmic reticulum to Golgi apparatus trafficking at a very early stage.
DNER	Delta and Notch-like epidermal growth factor-related receptor	Activator of the NOTCH1 pathway.
ECRG4	Augurin	Probable hormone that may attenuate cell proliferation and induce senescence of oligodendrocyte and neural precursor cells in the central nervous system.
YTHDC2	3’-5’ RNA helicase YTHDC2	3’-5’ RNA helicase that plays a key role in the male and female germline by promoting transition from mitotic to meiotic divisions in stem cells.
ADH1C	Alcohol dehydrogenase 1C	Alcohol dehydrogenase.
ELMOD1	ELMO domain-containing protein 1	Acts as a GTPase-activating protein (GAP) toward guanine nucleotide exchange factors like ARL2, ARL3, ARF1 and ARF6, but not for GTPases outside the Arf family.
LINC-PINT	Transcriptional regulator PINT87aa	Enhances the binding of the PAF1 complex to target gene promoters and plays a role in negative regulation of transcription.
EFR3A	Protein EFR3 homolog A	Component of a complex required to localize phosphatidylinositol 4-kinase (PI4K) to the plasma membrane.
ARHGAP23	Rho GTPase-activating protein 23	GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state.
NUP35	Nucleoporin NUP35	Functions as a component of the nuclear pore complex (NPC).
ADI1	Acireductone dioxygenase	Catalyzes 2 different reactions between oxygen and the acireductone 1,2-dihydroxy-3-keto-5-methylthiopentene (DHK-MTPene) depending upon the metal bound in the active site.
GRIK2	Glutamate receptor ionotropic, kainate 2	Ionotropic glutamate receptor that functions as a cation-permeable ligand-gated ion channel, gated by L-glutamate and the glutamatergic agonist kainic acid.
HPCAL1	Hippocalcin-like protein 1	May be involved in the calcium-dependent regulation of rhodopsin phosphorylation.
APOC1	Apolipoprotein C-I	Inhibitor of lipoprotein binding to the low density lipoprotein (LDL) receptor, LDL receptor-related protein, and very low density lipoprotein (VLDL) receptor.
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.
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.
MCC	Colorectal mutant cancer protein	Candidate for the putative colorectal tumor suppressor gene located at 5q21.
NCALD	Neurocalcin-delta	May be involved in the calcium-dependent regulation of rhodopsin phosphorylation.
NEDD1	Protein NEDD1	Required for mitosis progression.
PLOD3	Multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3	Multifunctional enzyme that catalyzes a series of essential post-translational modifications on Lys residues in procollagen.
PMS1	PMS1 protein homolog 1	Probably involved in the repair of mismatches in DNA.
NECTIN2	Nectin-2	Modulator of T-cell signaling.
RELB	Transcription factor RelB	NF-kappa-B is a pleiotropic transcription factor which is present in almost all cell types and is involved in many biological processed such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis.

Protein-family classification

Druggable: 10 · Difficult: 9 · Unknown: 43 · Druggable fraction: 0.16

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
Other/Unknown	43	1.2×	0.163
Scaffold/PPI	6	1.7×	0.591
Ion channel	1	1.8×	0.985
Enzyme (other)	5	1.0×	0.985
Antibody/Immunoglobulin	2	0.9×	0.985
Protease	1	0.6×	0.985
Kinase	1	0.5×	0.985
Transcription factor	3	0.4×	0.985

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC6A3	Other/Unknown	no		Na/ntran_symport, Na/ntran_symport_dopamine, SNS_sf
EVA1C	Other/Unknown	no		Lectin_gal-bd_dom, EVA1_dom, Lectin_gal-bd_sf
HDAC9	Enzyme (other)	yes	3.5.1.98	HDACs, Ureohydrolase_dom_sf, His_deacetylse_dom
ULBP3	Other/Unknown	no		MHC_I-like_Ag-recog, MHC_I/II-like_Ag-recog, MHC_I-like_Ag-recog_sf
PPP1R14C	Other/Unknown	no		CPI-17, CPI-17_sf
SETBP1	Other/Unknown	no		AT_hook_DNA-bd_motif
SPTLC3	Enzyme (other)	yes	2.3.1.50	Aminotrans_II_pyridoxalP_BS, Aminotransferase_I/II_large, PyrdxlP-dep_Trfase_major
CPA6	Protease	yes		Peptidase_M14, M14A_act_pep, CPAH
CDH1	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Cadherin_pro_dom
CDH5	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Cadherin-like_sf
NGRN	Other/Unknown	no		NGRN/Rrg9
ARHGAP20	Scaffold/PPI	no		RA_dom, RhoGAP_dom, PH_domain
KSR2	Kinase	yes	2.7.11.25	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
KCNH8	Ion channel	yes		PAS, cNMP-bd_dom, PAS-assoc_C
RNF144A	Transcription factor	no	2.3.2.31	Znf_RING, IBR_dom, Znf_RING/FYVE/PHD
CYP26B1	Other/Unknown	no		Cyt_P450, Cyt_P450_E_grp-IV, Cyt_P450_CS
FSTL5	Antibody/Immunoglobulin	yes		EF_hand_dom, Kazal_dom, Ig_sub2
TTYH3	Other/Unknown	no		Tweety
SPATS1	Other/Unknown	no		SASRP1
DOCK10	Scaffold/PPI	no		PH_domain, PH-like_dom_sf, DOCK_C/D_N
ADCY9	Other/Unknown	no		A/G_cyclase, A/G_cyclase_CS, Nucleotide_cyclase
TRAPPC12	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt
DNER	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
ECRG4	Other/Unknown	no		Augurin
YTHDC2	Scaffold/PPI	no		R3H_dom, Helicase_C-like, Ankyrin_rpt
ADH1C	Enzyme (other)	yes	1.1.1.1	ADH_Zn_CS, GroES-like_sf, ADH-like_C
ELMOD1	Other/Unknown	no		ELMO_dom, ELMO_domain-containing
FAM124A	Other/Unknown	no		FAM124, FAM124_dom
LINC-PINT	Other/Unknown	no		LINC-PINT
FAM86EP	Other/Unknown	no
EFR3A	Other/Unknown	no		ARM-type_fold, EFR3-like_ARM, EFR3_Homologs
ARHGAP23	Scaffold/PPI	no		RhoGAP_dom, PDZ, PH_domain
NUP35	Transcription factor	no		RRM_NUP35_dom, Nucleotide-bd_a/b_plait_sf, Nucleoporin_NUP53
ADI1	Enzyme (other)	yes	1.13.11.53	ARD, RmlC_Cupin_sf, RmlC-like_jellyroll
MYCNUT	Other/Unknown	no
MIR2113	Other/Unknown	no
LINC00290	Other/Unknown	no
NFIA-AS2	Other/Unknown	no
TRAPPC12-AS1	Other/Unknown	no
HS1BP3-IT1	Other/Unknown	no
MIR548AU	Other/Unknown	no
DCAF13P3	Other/Unknown	no
LINC00861	Other/Unknown	no
GRIK2	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt
KDM7A-DT	Other/Unknown	no
KRT73-AS1	Other/Unknown	no
LINC01317	Other/Unknown	no
HPCAL1	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
SMILR	Other/Unknown	no
MIR4432HG	Other/Unknown	no

Expression context

Cohort genes with no expression data: 1.

46 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)	2
broad (>20)	59
unknown	1

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	7
primordial germ cell in gonad	6
corpus callosum	5
cerebellar vermis	5
sural nerve	5
secondary oocyte	4
buccal mucosa cell	4
C1 segment of cervical spinal cord	4
endothelial cell	4
liver	4
olfactory segment of nasal mucosa	3
monocyte	3
oocyte	3
upper arm skin	3
ventricular zone	3
mucosa of transverse colon	3
cerebellar cortex	3
pons	3
left testis	3
right lobe of liver	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC6A3	84	tissue_specific	marker	substantia nigra, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
EVA1C	239	ubiquitous	marker	olfactory segment of nasal mucosa, left uterine tube, mucosa of stomach
HDAC9	277	ubiquitous	marker	oocyte, monocyte, secondary oocyte
ULBP3	180	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, kidney epithelium, epithelial cell of pancreas
PPP1R14C	229	broad	marker	upper arm skin, cardiac muscle of right atrium, left ventricle myocardium
SETBP1	280	ubiquitous	marker	ventricular zone, buccal mucosa cell, caput epididymis
SPTLC3	228	ubiquitous	marker	buccal mucosa cell, placenta, skin of abdomen
CPA6	103	broad	marker	buccal mucosa cell, mucosa of transverse colon, urethra
CDH1	245	broad	marker	jejunal mucosa, esophagus squamous epithelium, gingival epithelium
CDH5	252	broad	marker	right lung, upper lobe of left lung, upper lobe of lung
NGRN	134	ubiquitous	marker	dorsolateral prefrontal cortex, superior frontal gyrus, Brodmann (1909) area 9
ARHGAP20	215	broad	marker	cortical plate, Brodmann (1909) area 46, cauda epididymis
KSR2	114	broad	marker	Brodmann (1909) area 23, middle temporal gyrus, postcentral gyrus
KCNH8	168	broad	marker	corpus callosum, endothelial cell, C1 segment of cervical spinal cord
RNF144A	253	ubiquitous	marker	cerebellar hemisphere, cerebellar cortex, cerebellum
CYP26B1	239	broad	marker	pons, upper arm skin, cerebellar vermis
FSTL5	126	broad	marker	cerebellar vermis, endothelial cell, pons
TTYH3	215	ubiquitous	marker	ventricular zone, ganglionic eminence, embryo
SPATS1	63	tissue_specific	yes	right uterine tube, primordial germ cell in gonad, left testis
DOCK10	246	ubiquitous	marker	corpus callosum, medial globus pallidus, C1 segment of cervical spinal cord
ADCY9	296	ubiquitous	marker	secondary oocyte, choroid plexus epithelium, vastus lateralis
TRAPPC12	135	ubiquitous	marker	left testis, right testis, testis
DNER	214	broad	marker	lateral nuclear group of thalamus, cerebellar vermis, substantia nigra pars reticulata
ECRG4	230	broad	marker	bronchial epithelial cell, mucosa of stomach, bronchus
YTHDC2	294	ubiquitous	marker	endothelial cell, blood vessel layer, upper leg skin
ADH1C	199	tissue_specific	marker	mucosa of transverse colon, jejunal mucosa, nasal cavity epithelium
ELMOD1	192	broad	marker	lateral nuclear group of thalamus, upper arm skin, cortical plate
FAM124A	205	broad	marker	inferior vagus X ganglion, corpus callosum, C1 segment of cervical spinal cord
LINC-PINT	250	ubiquitous	marker	cardiac muscle of right atrium, calcaneal tendon, sural nerve
FAM86EP	132		yes	right uterine tube, primordial germ cell in gonad, adenohypophysis

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APP	11,686
CDH1	8,738
APOE	6,793
YTHDC2	4,175
RELB	4,103
CDH5	3,741
HDAC9	3,047
HPCAL1	2,565
MCC	2,532
CYP26B1	2,349

Intra-cohort edges

A	B	Sources
APOC1	APOE	string_interaction
APOE	APP	intact, string_interaction
CDH1	CDH5	string_interaction
NECTIN2	ULBP3	string_interaction
RNF144A	TRAPPC12	string_interaction

Structural data

PDB: 26 · AlphaFold-only: 19 · No structure: 17

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
APP	P05067	256
APOE	P02649	29
CDH1	P12830	22
PLOD3	O60568	18
SLC6A3	Q01959	17
KSR2	Q6VAB6	9
APOC1	P02654	8
NECTIN2	Q92692	7
ADCY9	O60503	6
YTHDC2	Q9H6S0	6
NUP35	Q8NFH5	5
DOCK10	Q96BY6	4
HDAC9	Q9UKV0	2
RNF144A	P50876	2
TTYH3	Q9C0H2	2
ADH1C	P00326	2
ADI1	Q9BV57	2
GRIK2	Q13002	2
MCC	P23508	2
NEDD1	Q8NHV4	2
ULBP3	Q9BZM4	1
ARHGAP20	Q9P2F6	1
EFR3A	Q14156	1
HPCAL1	P37235	1
PMS1	P54277	1
RELB	Q01201	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CYP26B1	Q9NR63	90.99
CPA6	Q8N4T0	90.93
ELMOD1	Q8N336	90.80
SPTLC3	Q9NUV7	87.25
NCALD	P61601	86.88
FSTL5	Q8N475	83.57
CDH5	P33151	78.46
DNER	Q8NFT8	70.51
EVA1C	P58658	70.39
NGRN	Q9NPE2	68.87
TRAPPC12	Q8WVT3	68.52
ECRG4	Q9H1Z8	66.76
KCNH8	Q96L42	64.41
PPP1R14C	Q8TAE6	64.37
FAM124A	Q86V42	63.48
SPATS1	Q496A3	58.12
ARHGAP23	Q9P227	49.82
SETBP1	Q9Y6X0	43.30
LINC-PINT	A0A455ZAR2	36.45

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 287. Enrichment computed across 62 evidence-associated genes (31 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 31 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Activation of Ca-permeable Kainate Receptor	2	73.7×	0.030	GRIK2, NCALD
Adherens junctions interactions	3	24.0×	0.030	CDH1, CDH5, NECTIN2
Cell-cell junction organization	3	24.0×	0.030	CDH1, CDH5, NECTIN2
Cell junction organization	3	18.1×	0.042	CDH1, CDH5, NECTIN2
Plasma lipoprotein assembly	2	46.0×	0.048	APOC1, APOE
Defective CYP26B1 causes RHFCA	1	368.4×	0.066	CYP26B1
Defective neurotransmitter clearance by SLC6A3 causes Parkinsonism-dystonia infantile (PKDYS)	1	368.4×	0.066	SLC6A3
Defective transport of neurotransmitters by SLC6A3 causes Parkinsonism-dystonia infantile (PKDYS)	1	368.4×	0.066	SLC6A3
RA biosynthesis pathway	2	30.7×	0.066	CYP26B1, ADH1C
Plasma lipoprotein clearance	2	30.7×	0.066	APOC1, APOE
NR1H2 and NR1H3-mediated signaling	2	25.4×	0.066	APOC1, APOE
Cell-Cell communication	3	13.3×	0.066	CDH1, CDH5, NECTIN2
Dopamine clearance from the synaptic cleft	1	184.2×	0.071	SLC6A3
Ionotropic activity of kainate receptors	1	184.2×	0.071	NCALD
Activation of Na-permeable kainate receptors	1	184.2×	0.071	GRIK2
Activation of kainate receptors upon glutamate binding	1	184.2×	0.071	NCALD
Aggregated β-amyloid induces FXII autocatalysis	1	184.2×	0.071	APP
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	2	19.9×	0.071	APOC1, APOE
Response of endothelial cells to shear stress	2	19.4×	0.071	CDH5, ADCY9
Signaling by Nuclear Receptors	3	9.9×	0.071	ADH1C, APOC1, APOE
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	3	8.4×	0.071	ULBP3, CDH1, NECTIN2
Neuronal System	4	5.7×	0.071	SLC6A3, KCNH8, ADCY9, NCALD
Cellular responses to mechanical stimuli	2	16.7×	0.078	CDH5, ADCY9
Transmission across Chemical Synapses	3	7.4×	0.091	SLC6A3, ADCY9, NCALD
Plasma lipoprotein assembly, remodeling, and clearance	2	14.7×	0.092	APOC1, APOE
Signal Transduction	8	2.6×	0.095	CDH1, CDH5, KSR2, ADCY9, ADH1C, APOC1, APOE, APP
Aggregated β-amyloid interacts with fibrinogen	1	92.1×	0.115	APP
VLDL assembly	1	73.7×	0.129	APOC1
Chylomicron clearance	1	73.7×	0.129	APOE
Methionine salvage pathway	1	61.4×	0.129	ADI1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 41 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
very-low-density lipoprotein particle clearance	2	164.4×	0.012	APOC1, APOE
positive regulation of amyloid fibril formation	2	164.4×	0.012	APOE, APP
chylomicron remnant clearance	2	137.0×	0.012	APOC1, APOE
modulation of excitatory postsynaptic potential	2	102.8×	0.017	GRIK2, APP
negative regulation of long-term synaptic potentiation	2	63.2×	0.031	APOE, APP
central nervous system development	4	11.3×	0.031	CYP26B1, DNER, ECRG4, APP
phospholipid efflux	2	54.8×	0.036	APOC1, APOE
endothelial cell morphogenesis	2	51.4×	0.036	CDH5, PLOD3
regulation of long-term neuronal synaptic plasticity	2	48.4×	0.036	GRIK2, APP
high-density lipoprotein particle remodeling	2	39.1×	0.045	APOC1, APOE
retinoic acid metabolic process	2	39.1×	0.045	CYP26B1, ADH1C
lipid transport involved in lipid storage	1	411.0×	0.046	APOE
negative regulation of phosphatidylcholine catabolic process	1	411.0×	0.046	APOC1
sphingoid biosynthetic process	1	411.0×	0.046	SPTLC3
coreceptor-mediated virion attachment to host cell	1	411.0×	0.046	NECTIN2
regulation of striated muscle cell differentiation	1	411.0×	0.046	HDAC9
maintenance of location in cell	1	411.0×	0.046	APOE
intermediate-density lipoprotein particle clearance	1	411.0×	0.046	APOE
detection of cold stimulus involved in thermoception	1	411.0×	0.046	GRIK2
protein O-linked glycosylation via galactose	1	411.0×	0.046	PLOD3
positive regulation of lipid transport across blood-brain barrier	1	411.0×	0.046	APOE
regulation of cellular response to very-low-density lipoprotein particle stimulus	1	411.0×	0.046	APOE
cholesterol efflux	2	25.7×	0.046	APOC1, APOE
adherens junction organization	2	24.9×	0.046	CDH1, CDH5
regulation of Rho protein signal transduction	2	24.9×	0.046	ARHGAP20, DOCK10
response to interleukin-1	2	24.9×	0.046	YTHDC2, APP
intracellular calcium ion homeostasis	3	10.6×	0.046	CDH5, GRIK2, APOE
calcium-dependent cell-cell adhesion	2	23.5×	0.046	CDH1, CDH5
triglyceride homeostasis	2	23.5×	0.046	APOC1, APOE
homophilic cell-cell adhesion	3	10.3×	0.046	CDH1, CDH5, NECTIN2

Therapeutics

Drug target analysis

Approved (phase 4): 4 · Phase ≥3: 5 · Phased (≥1): 5 · Undrugged: 57

Druggability breadth: 16 of 62 evidence-associated genes (26%) 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
SLC6A3	CETIRIZINE
HDAC9	CELECOXIB
CYP26B1	BEXAROTENE
APP	FLORBETAPIR F 18

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC6A3	466	4
APP	40	4
HDAC9	28	4
CYP26B1	4	4
GRIK2	2	3
EVA1C	0	0
ULBP3	0	0
PPP1R14C	0	0
SETBP1	0	0
SPTLC3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CETIRIZINE	4	SLC6A3
BEPRIDIL	4	SLC6A3
CANDESARTAN CILEXETIL	4	SLC6A3
BEXAROTENE	4	CYP26B1, SLC6A3
CLOTRIMAZOLE	4	SLC6A3
AMINOCAPROIC ACID	4	SLC6A3
SIMVASTATIN	4	SLC6A3
NABUMETONE	4	SLC6A3
PROPIVERINE	4	SLC6A3
ACETOPHENAZINE	4	SLC6A3
MESORIDAZINE	4	SLC6A3
VALPROIC ACID	4	SLC6A3
NIRAPARIB	4	SLC6A3
INDACATEROL	4	SLC6A3
IMIPRAMINE	4	SLC6A3
HALOFANTRINE	4	SLC6A3
RIMONABANT	4	SLC6A3
ARIPIPRAZOLE	4	SLC6A3
AMOXAPINE	4	SLC6A3
IDARUBICIN	4	SLC6A3
DESVENLAFAXINE	4	SLC6A3
EZETIMIBE	4	SLC6A3
SAQUINAVIR	4	SLC6A3
PONATINIB	4	SLC6A3
DESLORATADINE	4	SLC6A3
AFATINIB	4	SLC6A3
DULOXETINE	4	SLC6A3
PEMOLINE	4	SLC6A3
CELECOXIB	4	HDAC9, SLC6A3
UMECLIDINIUM	4	SLC6A3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 7.

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

Symbol	Assays	Type breakdown
APP	1,744	Binding:1699, Functional:44, ADMET:1
HDAC9	1,625	Binding:1612, ADMET:8, Functional:4, Toxicity:1
SLC6A3	1,043	Binding:993, Functional:24, ADMET:24, Toxicity:2
GRIK2	92	Binding:66, Functional:26
KSR2	28	Binding:28
KCNH8	21	Binding:20, Toxicity:1
CDH1	18	Binding:18
ADCY9	18	Binding:16, Functional:2
ADH1C	12	Binding:12
DNER	10	Binding:10
CYP26B1	6	Binding:6
SPTLC3	1	Binding:1
ADI1	1	ADMET:1
HPCAL1	1	Binding:1
PLOD3	1	Binding:1
RELB	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HDAC9	3.5.1.98	histone deacetylase
SPTLC3	2.3.1.50	serine C-palmitoyltransferase
KSR2	2.7.11.25	mitogen-activated protein kinase kinase kinase
RNF144A	2.3.2.31	RBR-type E3 ubiquitin transferase
ADH1C	1.1.1.1	alcohol dehydrogenase
ADI1	1.13.11.53, 1.13.11.54	acireductone dioxygenase (Ni2+-requiring), acireductone dioxygenase [iron(II)-requiring]
PLOD3	1.14.11.4, 2.4.1.50, 2.4.1.66	procollagen-lysine 5-dioxygenase, procollagen galactosyltransferase, procollagen glucosyltransferase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SLC6A3	1,043
HDAC9	1,625
APP	1,744

Pharmacogenomics

Cohort genes with a PharmGKB record: 45; 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)
CETIRIZINE	4	SLC6A3
BEPRIDIL	4	SLC6A3
CANDESARTAN CILEXETIL	4	SLC6A3
BEXAROTENE	4	CYP26B1, SLC6A3
CLOTRIMAZOLE	4	SLC6A3
AMINOCAPROIC ACID	4	SLC6A3
SIMVASTATIN	4	SLC6A3
NABUMETONE	4	SLC6A3
PROPIVERINE	4	SLC6A3
ACETOPHENAZINE	4	SLC6A3
MESORIDAZINE	4	SLC6A3
VALPROIC ACID	4	SLC6A3
NIRAPARIB	4	SLC6A3
INDACATEROL	4	SLC6A3
IMIPRAMINE	4	SLC6A3
HALOFANTRINE	4	SLC6A3
RIMONABANT	4	SLC6A3
ARIPIPRAZOLE	4	SLC6A3
AMOXAPINE	4	SLC6A3
IDARUBICIN	4	SLC6A3
DESVENLAFAXINE	4	SLC6A3
EZETIMIBE	4	SLC6A3
SAQUINAVIR	4	SLC6A3
PONATINIB	4	SLC6A3
DESLORATADINE	4	SLC6A3
AFATINIB	4	SLC6A3
DULOXETINE	4	SLC6A3
PEMOLINE	4	SLC6A3
CELECOXIB	4	HDAC9, SLC6A3
UMECLIDINIUM	4	SLC6A3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	SLC6A3, HDAC9, CYP26B1, APP
B	Phased (≥1) drug, not yet approved	1	GRIK2
C	Druggable family + PDB, no drug	5	KSR2, ADH1C, ADI1, PLOD3, NECTIN2
D	Druggable family + AlphaFold only, no drug	4	SPTLC3, CPA6, KCNH8, FSTL5
E	Difficult family or no structure, no drug	48	EVA1C, ULBP3, PPP1R14C, SETBP1, CDH1, CDH5, NGRN, ARHGAP20, RNF144A, TTYH3 (+38 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
APOE	0	APP
EVA1C	0	—
ULBP3	0	—
PPP1R14C	0	—
SETBP1	0	—
SPTLC3	1	—
CPA6	0	—
CDH1	18	—
CDH5	0	—
NGRN	0	—
ARHGAP20	0	—
KSR2	28	—
KCNH8	21	—
RNF144A	0	—
FSTL5	0	—
TTYH3	0	—
SPATS1	0	—
DOCK10	0	—
ADCY9	18	—
TRAPPC12	0	—
DNER	10	—
ECRG4	0	—
YTHDC2	0	—
ADH1C	12	—
ELMOD1	0	—
FAM124A	0	—
LINC-PINT	0	—
FAM86EP	0	—
EFR3A	0	—
ARHGAP23	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 31.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	21
PHASE2	5
PHASE3	4
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07250035	PHASE3	NOT_YET_RECRUITING	Jiedu Huayu Oral Prescription in the Treatment of Intracranial Hemorrhage Associated With Cerebral Amyloid Angiopathy
NCT03542656	PHASE3	COMPLETED	Application of Amyloid PET in Cerebral Amyloid Angiopathy
NCT03969732	PHASE3	UNKNOWN	Multimodal Biomarkers for Diagnosis and Prognosis in CAA
NCT04604587	PHASE3	UNKNOWN	MRI-visible Enlarged Perivascular Spaces and the Alteration of Lymphatic Drainage System in CAA
NCT05709314	PHASE2	RECRUITING	A Study of AMDX-2011P in Participants With CAA
NCT06393712	PHASE2	RECRUITING	A Phase 2 Trial of ALN-APP in Patients With Cerebral Amyloid Angiopathy
NCT06421532	PHASE2	ENROLLING_BY_INVITATION	Stimulating Amyloid Clearance in Cerebral Amyloid Angiopathy
NCT07026994	PHASE2	RECRUITING	Colchicine for the Prevention of Recurrence in Cerebral Amyloid Angiopathy RElated IntraCerebral Hemorrhage
NCT01821118	PHASE2	COMPLETED	Study Evaluating the Safety,Tolerability and Efficacy of PF-04360365 in Adults With Probable Cerebral Amyloid Angiopathy
NCT05680389	PHASE1/PHASE2	UNKNOWN	Antibiotics Against Amyloid Angiopathy
NCT04204642	Not specified	RECRUITING	SEarchiNg biomarkErs Cerebral Amyloid Angiopathy (SENECA)
NCT05734378	Not specified	RECRUITING	Prognosis of Cerebral Small Vessel Disease
NCT06128824	Not specified	ACTIVE_NOT_RECRUITING	High Frequency Imaging in Cerebral Amyloid Angiopathy
NCT06714097	Not specified	RECRUITING	Application of Digital Twins’ Technology in Patients Who Had a Stroke, With Moyamoya Disease and With Cerebral Amyloid Angiopathy (CAA) During the Secondary Prevention Phase: A Proof of Concept Using a Randomized Control Trial (Clinical Study 6, STRATIF-AI Project)
NCT06933212	Not specified	RECRUITING	Effect of the Mediterranean Diet in Patients Affected by CADASIL and Cerebral Amyloid Angiopathy.
NCT01382849	Not specified	WITHDRAWN	F-18-AV-45 Uptake, Spot Sign Presence and Cerebral Amyloid Angiopathy (CAA) in Primary Intracranial Hemorrhage (ICH)
NCT01856699	Not specified	UNKNOWN	Superficial Siderosis in Patients With Suspected Cerebral Amyloid Angiopathy
NCT02361411	Not specified	UNKNOWN	Methods of Etiological Diagnosis of Cerebral Amyloid Angiopathy
NCT03464344	Not specified	COMPLETED	Cortical Superficial Siderosis and Risk of Recurrent Intracerebral Hemorrhage in Cerebral Amyloid Angiopathy.
NCT03824197	Not specified	COMPLETED	Auburn University Research on Olive Oil for Alzheimer’s Disease (AU-ROOAD)
NCT04654026	Not specified	UNKNOWN	the Safety and Efficacy of Antiplatelet Therapy in Patients of CAA
NCT04757597	Not specified	UNKNOWN	Remote Ischemic Conditioning for Cerebral Amyloid Angiopathy-related Intracerebral Hemorrhage
NCT04825808	Not specified	COMPLETED	Detailed Clinical and MRI Characteristics in Primary Non-traumatic Convexity Subarachnoid Haemorrhage Elderly Patients.
NCT05082194	Not specified	COMPLETED	Balance Eyesight and Muscle Tension in the Cervical Spine in Cerebral Amyloid Angiopathy
NCT05207475	Not specified	UNKNOWN	Safety and Efficacy of Remote Ischemic Conditioning on Cerebral Amyloid Angiopathy. (RIC-CAA)
NCT05394636	Not specified	COMPLETED	Cerebellar Superficial Siderosis in Cerebral Amyloid Angiopathy
NCT05486897	Not specified	COMPLETED	Periventricular White Matter Hyperintensities in Cerebral Amyloid Angiopathy and Hypertensive Arteriopathy
NCT05499169	Not specified	TERMINATED	Coach Pilot Study: Assessing Cognitive Function and Related Small Vessel Disease Markers After Intracerebral Hemorrhage
NCT05565144	Not specified	COMPLETED	Brain Hemorrhage and Functional Outcome in Stroke Patients With CAA Features on Pre-thrombolysis MRI Treated With Intravenous Thrombolysis (Thrombolysis in CAA) ( Thromb in CAA )
NCT06888882	Not specified	COMPLETED	Dilated Perivascular Spaces in the Dentate Nucleus on MRI in Patients With Hypertensive Angiopathy or Cerebral Amyloid Angiopathy
NCT06960538	Not specified	COMPLETED	Enpowering Progression Risk of Cerebral Amyloid Angiopathy

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
MINOCYCLINE	4	1
PONEZUMAB	2	1