Arteriovenous malformations of the brain

Summary

Arteriovenous malformations of the brain (MONDO:0007154) is a disease with 20 cohort genes and 27 clinical trials. The dominant Reactome pathway is MAP2K and MAPK activation (3 cohort genes). Top therapeutic interventions include bevacizumab and lovastatin.

At a glance

• Prevalence: 1-9 / 100 000 (Europe)
• Cohort genes: 20
• ClinVar variants: 46
• Phenotypes (HPO): 11
• Clinical trials: 27

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	6	Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

11 HPO clinical features (Orphanet curated; top 11 by frequency):

HPO ID	Term	Frequency
HP:0100659	Abnormality of the cerebral vasculature	Very frequent (80-99%)
HP:0100761	Visceral angiomatosis	Very frequent (80-99%)
HP:0100784	Peripheral arteriovenous fistula	Very frequent (80-99%)
HP:0000505	Visual impairment	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001342	Cerebral hemorrhage	Frequent (30-79%)
HP:0002354	Memory impairment	Frequent (30-79%)
HP:0030746	Intraventricular hemorrhage	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0002315	Headache	Occasional (5-29%)
HP:5200044	Reduced attention regulation	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	arteriovenous malformations of the brain
Mondo ID	MONDO:0007154
MeSH	D002538
OMIM	108010
Orphanet	46724
DOID	DOID:0060688
ICD-11	153256729
NCIT	C2936
SNOMED CT	234142008
UMLS	C0917804
MedGen	214590
GARD	0003020
Is cancer (heuristic)	no

Also known as: arteriovenous malformation of the brain, somatic · arteriovenous malformations of the brain · cerebral arteriovenous malformation · intracranial arteriovenous malformation · intracranial AVM · intracranial haemorrhage in brain arteriovenous malformations, susceptibility to · intracranial haemorrhage in brain cerebrovascular malformations, susceptibility to, somatic mutation · intracranial hemorrhage in brain cerebrovascular malformations, susceptibility to, somatic mutation

Data availability: 46 ClinVar variants.

Disease family

Classification path: human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › benign neoplasm › cardiovascular organ benign neoplasm › benign blood vessel neoplasm › hemangioma › arteriovenous hemangioma/malformation › arteriovenous malformations of the brain

Related subtypes (6): vein of Galen aneurysm, cerebrofacial arteriovenous metameric syndrome, facial arteriovenous malformation, Cobb syndrome, Foix-Alajouanine syndrome, dural sinus malformation

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

46 retrieved; paginated sample, class counts are floors:

11 uncertain significance, 10 pathogenic, 9 conflicting classifications of pathogenicity, 7 likely pathogenic, 4 likely benign, 3 pathogenic/likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
690297	NM_004333.6(BRAF):c.1906C>T (p.Gln636Ter)	BRAF	Pathogenic	no assertion criteria provided
545104	NM_001114753.3(ENG):c.920dup (p.Asn307fs)	ENG	Pathogenic	criteria provided, multiple submitters, no conflicts
12582	NM_004985.5(KRAS):c.35G>A (p.Gly12Asp)	KRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12583	NM_004985.5(KRAS):c.35G>T (p.Gly12Val)	KRAS	Pathogenic	criteria provided, multiple submitters, no conflicts
12587	NM_004985.5(KRAS):c.458A>T (p.Asp153Val)	KRAS	Pathogenic	reviewed by expert panel
40452	NM_004985.5(KRAS):c.65A>G (p.Gln22Arg)	KRAS	Pathogenic	reviewed by expert panel
45117	NM_004985.5(KRAS):c.183A>T (p.Gln61His)	KRAS	Pathogenic	criteria provided, single submitter
45122	NM_004985.5(KRAS):c.35G>C (p.Gly12Ala)	KRAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
545103	NM_014319.5(LEMD3):c.2639C>G (p.Thr880Ser)	LEMD3	Pathogenic	criteria provided, single submitter
2691257	NM_001243133.2(NLRP3):c.29G>T (p.Arg10Met)	NLRP3	Pathogenic	no assertion criteria provided
468331	NM_007217.4(PDCD10):c.474+5G>A	PDCD10	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
545101	NM_031220.4(PITPNM3):c.274C>T (p.Arg92Ter)	PITPNM3	Pathogenic	criteria provided, single submitter
545102	NM_006513.4(SARS1):c.971T>C (p.Ile324Thr)	SARS1	Pathogenic	criteria provided, single submitter
545108	NM_001792.5(CDH2):c.2075A>G (p.Asn692Ser)	CDH2	Likely pathogenic	criteria provided, single submitter
545109	NM_017563.5(IL17RD):c.676G>A (p.Gly226Ser)	IL17RD	Likely pathogenic	criteria provided, single submitter
545107	NM_001395002.1(MAP4K4):c.1694G>A (p.Arg565Gln)	MAP4K4	Likely pathogenic	criteria provided, single submitter
545106	NM_001367977.2(SCUBE2):c.2057G>A (p.Cys686Tyr)	NRIP3-DT	Likely pathogenic	criteria provided, single submitter
545110	NM_024870.4(PREX2):c.3355G>A (p.Ala1119Thr)	PREX2	Likely pathogenic	criteria provided, single submitter
545105	NM_000362.5(TIMP3):c.311T>C (p.Leu104Pro)	TIMP3	Likely pathogenic	criteria provided, single submitter
545111	NM_001284236.3(ZFYVE16):c.3442G>T (p.Asp1148Tyr)	ZFYVE16	Likely pathogenic	criteria provided, single submitter
13961	NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)	BRAF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
523531	NM_021098.3(CACNA1H):c.6884C>T (p.Ser2295Phe)	CACNA1H	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
545112	NM_005228.5(EGFR):c.1881-858G>T	EGFR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180145	NM_017563.5(IL17RD):c.572C>T (p.Pro191Leu)	IL17RD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180857	NM_004985.5(KRAS):c.184GAG[1] (p.Glu63del)	KRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2454057	NM_004985.5(KRAS):c.168C>T (p.Leu56=)	KRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
503538	NM_004985.5(KRAS):c.407G>A (p.Ser136Asn)	KRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
620625	NM_033360.4(KRAS):c.*101_*106del	KRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
626130	NM_033360.4(KRAS):c.112-5C>T	KRAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
523543	NM_032119.4(ADGRV1):c.5188A>T (p.Ile1730Phe)	ADGRV1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 54 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SARS1	Orphanet:2512	Autosomal recessive primary microcephaly
SARS1	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
BRAF	Orphanet:1340	Cardiofaciocutaneous syndrome
BRAF	Orphanet:146	Differentiated thyroid carcinoma
BRAF	Orphanet:251615	Pilomyxoid astrocytoma
BRAF	Orphanet:389	Langerhans cell histiocytosis
BRAF	Orphanet:500	Noonan syndrome with multiple lentigines
BRAF	Orphanet:54595	Craniopharyngioma
BRAF	Orphanet:58017	Classic hairy cell leukemia
BRAF	Orphanet:626	Large/giant congenital melanocytic nevus
BRAF	Orphanet:648	Noonan syndrome
BRAF	Orphanet:840	Syringocystadenoma papilliferum
BRAF	Orphanet:96253	Cushing disease
TIMP3	Orphanet:59181	Sorsby fundus dystrophy
CACNA1H	Orphanet:642671	Familial hyperaldosteronism type IV
CACNA1H	Orphanet:64280	Childhood absence epilepsy
NLRP3	Orphanet:1451	CINCA syndrome
NLRP3	Orphanet:47045	Familial cold urticaria
NLRP3	Orphanet:575	Muckle-Wells syndrome
NLRP3	Orphanet:647815	Keratitis fugax hereditaria
ADGRV1	Orphanet:231178	Usher syndrome type 2
ADGRV1	Orphanet:36387	Genetic epilepsy with febrile seizure plus
CDH2	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
IL17RD	Orphanet:478	Kallmann syndrome
PITPNM3	Orphanet:1872	Cone rod dystrophy
LEMD3	Orphanet:166119	Isolated osteopoikilosis
LEMD3	Orphanet:1879	Melorheostosis with osteopoikilosis
LEMD3	Orphanet:94063	12q14 microdeletion syndrome
EGFR	Orphanet:251576	Gliosarcoma
EGFR	Orphanet:251579	Giant cell glioblastoma
ENG	Orphanet:231160	Familial cerebral saccular aneurysm
ENG	Orphanet:275777	Heritable pulmonary arterial hypertension
ENG	Orphanet:329971	Generalized juvenile polyposis/juvenile polyposis coli
ENG	Orphanet:774	Hereditary hemorrhagic telangiectasia
GLI2	Orphanet:220386	Semilobar holoprosencephaly
GLI2	Orphanet:280195	Septopreoptic holoprosencephaly
GLI2	Orphanet:280200	Microform holoprosencephaly
GLI2	Orphanet:420584	Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome
GLI2	Orphanet:93924	Lobar holoprosencephaly
GLI2	Orphanet:93925	Alobar holoprosencephaly
GLI2	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
GLI2	Orphanet:95494	Combined pituitary hormone deficiencies, genetic forms
KRAS	Orphanet:1333	Familial pancreatic carcinoma
KRAS	Orphanet:1340	Cardiofaciocutaneous syndrome
KRAS	Orphanet:144	Lynch syndrome
KRAS	Orphanet:146	Differentiated thyroid carcinoma
KRAS	Orphanet:2396	Encephalocraniocutaneous lipomatosis
KRAS	Orphanet:251615	Pilomyxoid astrocytoma
KRAS	Orphanet:2612	Linear nevus sebaceus syndrome
KRAS	Orphanet:268114	RAS-associated autoimmune leukoproliferative disease

Cohort genes → proteins

20 cohort genes, 19 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	20

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SARS1	HGNC:10537	ENSG00000031698	P49591	Serine–tRNA ligase, cytoplasmic	clinvar
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	clinvar
TIMP3	HGNC:11822	ENSG00000100234	P35625	Metalloproteinase inhibitor 3	clinvar
CACNA1H	HGNC:1395	ENSG00000196557	O95180	Voltage-dependent T-type calcium channel subunit alpha-1H	clinvar
NLRP3	HGNC:16400	ENSG00000162711	Q96P20	NACHT, LRR and PYD domains-containing protein 3	clinvar
ADGRV1	HGNC:17416	ENSG00000164199	Q8WXG9	Adhesion G-protein coupled receptor V1	clinvar
CDH2	HGNC:1759	ENSG00000170558	P19022	Cadherin-2	clinvar
IL17RD	HGNC:17616	ENSG00000144730	Q8NFM7	Interleukin-17 receptor D	clinvar
ZFYVE16	HGNC:20756	ENSG00000039319	Q7Z3T8	Zinc finger FYVE domain-containing protein 16	clinvar
PITPNM3	HGNC:21043	ENSG00000091622	Q9BZ71	Membrane-associated phosphatidylinositol transfer protein 3	clinvar
PREX2	HGNC:22950	ENSG00000046889	Q70Z35	Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 protein	clinvar
LEMD3	HGNC:28887	ENSG00000174106	Q9Y2U8	Inner nuclear membrane protein Man1	clinvar
EGFR	HGNC:3236	ENSG00000146648	P00533	Epidermal growth factor receptor	clinvar
ENG	HGNC:3349	ENSG00000106991	P17813	Endoglin	clinvar
GLI2	HGNC:4318	ENSG00000074047	P10070	Zinc finger protein GLI2	clinvar
NRIP3-DT	HGNC:55524	ENSG00000253973		NRIP3 divergent transcript	clinvar
KRAS	HGNC:6407	ENSG00000133703	P01116	GTPase KRas	clinvar
MAP4K4	HGNC:6866	ENSG00000071054	O95819	Mitogen-activated protein kinase kinase kinase kinase 4	clinvar
NOTCH4	HGNC:7884	ENSG00000204301	Q99466	Neurogenic locus notch homolog protein 4	clinvar
PDCD10	HGNC:8761	ENSG00000114209	Q9BUL8	Programmed cell death protein 10	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SARS1	Serine–tRNA ligase, cytoplasmic	Catalyzes the attachment of serine to tRNA(Ser) in a two-step reaction: serine is first activated by ATP to form Ser-AMP and then transferred to the acceptor end of tRNA(Ser).
BRAF	Serine/threonine-protein kinase B-raf	Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus.
TIMP3	Metalloproteinase inhibitor 3	Mediates a variety of processes including matrix regulation and turnover, inflammation, and angiogenesis, through reversible inhibition of zinc protease superfamily enzymes, primarily matrix metalloproteinases (MMPs).
CACNA1H	Voltage-dependent T-type calcium channel subunit alpha-1H	Voltage-sensitive calcium channel that gives rise to T-type calcium currents.
NLRP3	NACHT, LRR and PYD domains-containing protein 3	Sensor component of the NLRP3 inflammasome, which mediates inflammasome activation in response to defects in membrane integrity, leading to secretion of inflammatory cytokines IL1B and IL18 and pyroptosis.
ADGRV1	Adhesion G-protein coupled receptor V1	G-protein coupled receptor which has an essential role in the development of hearing and vision.
CDH2	Cadherin-2	Calcium-dependent cell adhesion protein; preferentially mediates homotypic cell-cell adhesion by dimerization with a CDH2 chain from another cell.
IL17RD	Interleukin-17 receptor D	Feedback inhibitor of fibroblast growth factor mediated Ras-MAPK signaling and ERK activation.
ZFYVE16	Zinc finger FYVE domain-containing protein 16	May be involved in regulating membrane trafficking in the endosomal pathway.
PITPNM3	Membrane-associated phosphatidylinositol transfer protein 3	Catalyzes the transfer of phosphatidylinositol and phosphatidylcholine between membranes (in vitro).
PREX2	Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 protein	Functions as a RAC1 guanine nucleotide exchange factor (GEF), activating Rac proteins by exchanging bound GDP for free GTP.
LEMD3	Inner nuclear membrane protein Man1	Can function as a specific repressor of TGF-beta, activin, and BMP signaling through its interaction with the R-SMAD proteins.
EGFR	Epidermal growth factor receptor	Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses.
ENG	Endoglin	Vascular endothelium glycoprotein that plays an important role in the regulation of angiogenesis.
GLI2	Zinc finger protein GLI2	Functions as a transcription regulator in the hedgehog (Hh) pathway.
KRAS	GTPase KRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
MAP4K4	Mitogen-activated protein kinase kinase kinase kinase 4	Serine/threonine kinase that plays a role in the response to environmental stress and cytokines such as TNF.
NOTCH4	Neurogenic locus notch homolog protein 4	Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination.
PDCD10	Programmed cell death protein 10	Promotes cell proliferation.

Protein-family classification

Druggable: 7 · Difficult: 4 · Unknown: 9 · Druggable fraction: 0.35

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	3	4.2×	0.236
Ion channel	1	5.6×	0.577
Scaffold/PPI	2	1.7×	0.754
Enzyme (other)	2	1.2×	0.804
GPCR	1	1.2×	0.804
Transcription factor	2	0.8×	0.835
Other/Unknown	9	0.8×	0.885

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SARS1	Enzyme (other)	yes	6.1.1.11	aa-tRNA-synt_IIb, Ser-tRNA-ligase_type_1, aa-tRNA-synth_II
BRAF	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
TIMP3	Other/Unknown	no		Netrin_domain, TIMP, TIMP-like_OB-fold
CACNA1H	Ion channel	yes		VDCC_T_a1, Ion_trans_dom, Volt_channel_dom_sf
NLRP3	Other/Unknown	no		Leu-rich_rpt, DAPIN, NACHT_NTPase
ADGRV1	GPCR	yes		GPCR_2_secretin-like, Calx_beta, EPTP
CDH2	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Cadherin_pro_dom
IL17RD	Other/Unknown	no		SEFIR_dom, IL17R_D_N, Toll_tir_struct_dom_sf
ZFYVE16	Transcription factor	no		Znf_FYVE, Znf_FYVE_PHD, Znf_RING/FYVE/PHD
PITPNM3	Other/Unknown	no		PI_transfer, DDHD_dom, HAD_sf
PREX2	Scaffold/PPI	no		DH_dom, DEP_dom, GDS_CDC24_CS
LEMD3	Other/Unknown	no		LEM_dom, LEM/LEM-like_dom_sf, Nucleotide-bd_a/b_plait_sf
EGFR	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
ENG	Other/Unknown	no		TGFBR3/Endoglin-like_N
GLI2	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like
NRIP3-DT	Other/Unknown	no
KRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
MAP4K4	Kinase	yes		Prot_kinase_dom, CNH_dom, Ser/Thr_kinase_AS
NOTCH4	Scaffold/PPI	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom
PDCD10	Other/Unknown	no		PDCD10, PDC10_dimerisation_sf, PDCD10_N

Expression context

Cohort genes with no expression data: 0.

18 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)	20
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endothelial cell	4
calcaneal tendon	2
ventricular zone	2
germinal epithelium of ovary	2
nipple	2
right lung	2
body of pancreas	1
frontal pole	1
islet of Langerhans	1
buccal mucosa cell	1
colonic epithelium	1
decidua	1
pigmented layer of retina	1
synovial joint	1
lower esophagus	1
lower esophagus muscularis layer	1
muscle layer of sigmoid colon	1
leukocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SARS1	291	ubiquitous	marker	islet of Langerhans, body of pancreas, frontal pole
BRAF	265	ubiquitous	marker	buccal mucosa cell, colonic epithelium, calcaneal tendon
TIMP3	299	ubiquitous	marker	synovial joint, decidua, pigmented layer of retina
CACNA1H	166	broad	marker	lower esophagus muscularis layer, muscle layer of sigmoid colon, lower esophagus
NLRP3	172	broad	marker	monocyte, mononuclear cell, leukocyte
ADGRV1	196	broad	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland
CDH2	233	ubiquitous	marker	heart right ventricle, ventricular zone, stromal cell of endometrium
IL17RD	236	broad	yes	secondary oocyte, oocyte, mammary duct
ZFYVE16	293	ubiquitous	marker	corpus callosum, endothelial cell, inferior vagus X ganglion
PITPNM3	222	broad	marker	pancreatic ductal cell, endothelial cell, Brodmann (1909) area 23
PREX2	241	broad	marker	calcaneal tendon, endothelial cell, visceral pleura
LEMD3	289	ubiquitous	marker	endothelial cell, cerebellar vermis, germinal epithelium of ovary
EGFR	285	ubiquitous	marker	nipple, gingiva, gingival epithelium
ENG	265	ubiquitous	marker	right lung, right atrium auricular region, cardiac atrium
GLI2	211	ubiquitous	marker	tibia, germinal epithelium of ovary, ventricular zone
NRIP3-DT	111		yes	cerebellar cortex, cerebellum, cerebellar hemisphere
KRAS	298	ubiquitous	marker	trigeminal ganglion, pylorus, nipple
MAP4K4	295	ubiquitous	marker	C1 segment of cervical spinal cord, cortical plate, ganglionic eminence
NOTCH4	132	broad	marker	apex of heart, right lung, omental fat pad
PDCD10	295	ubiquitous	marker	jejunal mucosa, mucosa of sigmoid colon, colonic mucosa

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EGFR	18,421
KRAS	14,509
BRAF	7,394
CDH2	5,623
NLRP3	3,797
ENG	3,236
GLI2	3,112
TIMP3	2,921
LEMD3	2,735
NOTCH4	2,670

Intra-cohort edges

A	B	Sources
BRAF	EGFR	biogrid_interaction
BRAF	KRAS	biogrid_interaction, intact, string_interaction
BRAF	PREX2	intact
CDH2	EGFR	biogrid_interaction
MAP4K4	PDCD10	string_interaction

Structural data

PDB: 15 · AlphaFold-only: 4 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRAS	P01116	511
EGFR	P00533	388
BRAF	P15056	131
NLRP3	Q96P20	24
MAP4K4	O95819	18
PDCD10	Q9BUL8	10
SARS1	P49591	9
CACNA1H	O95180	5
LEMD3	Q9Y2U8	3
ENG	P17813	3
NOTCH4	Q99466	3
ZFYVE16	Q7Z3T8	2
TIMP3	P35625	1
PITPNM3	Q9BZ71	1
PREX2	Q70Z35	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CDH2	P19022	79.68
IL17RD	Q8NFM7	69.68
GLI2	P10070	42.68
ADGRV1	Q8WXG9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 205. Enrichment computed across 20 evidence-associated genes (17 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 17 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
MAP2K and MAPK activation	3	50.4×	0.005	BRAF, IL17RD, KRAS
EGFR Transactivation by Gastrin	2	134.3×	0.009	EGFR, KRAS
GRB2 events in EGFR signaling	2	89.6×	0.009	EGFR, KRAS
SHC1 events in EGFR signaling	2	84.0×	0.009	EGFR, KRAS
Constitutive Signaling by EGFRvIII	2	84.0×	0.009	EGFR, KRAS
Signaling by ERBB2 ECD mutants	2	79.0×	0.009	EGFR, KRAS
GRB2 events in ERBB2 signaling	2	74.6×	0.009	EGFR, KRAS
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	2	67.2×	0.010	EGFR, KRAS
SHC1 events in ERBB2 signaling	2	56.0×	0.012	EGFR, KRAS
Signaling by ERBB2 TMD/JMD mutants	2	56.0×	0.012	EGFR, KRAS
Signaling by ERBB2 KD Mutants	2	49.8×	0.013	EGFR, KRAS
RAF activation	2	39.5×	0.019	BRAF, KRAS
Signaling by high-kinase activity BRAF mutants	2	37.3×	0.020	BRAF, KRAS
Signaling by RAF1 mutants	2	32.8×	0.021	BRAF, KRAS
NCAM signaling for neurite out-growth	2	32.0×	0.021	CACNA1H, KRAS
Negative regulation of MAPK pathway	2	31.2×	0.021	BRAF, KRAS
Signaling by moderate kinase activity BRAF mutants	2	29.9×	0.021	BRAF, KRAS
Paradoxical activation of RAF signaling by kinase inactive BRAF	2	29.9×	0.021	BRAF, KRAS
Signaling downstream of RAS mutants	2	29.9×	0.021	BRAF, KRAS
RAF/MAP kinase cascade	3	10.8×	0.025	BRAF, EGFR, KRAS
Signaling by RAS GAP mutants	1	223.9×	0.040	KRAS
Signaling by RAS GTPase mutants	1	223.9×	0.040	KRAS
Signaling by BRAF and RAF1 fusions	2	20.1×	0.040	BRAF, KRAS
PLCG1 events in ERBB2 signaling	1	167.9×	0.049	EGFR
Signaling by MRAS-complex mutants	1	167.9×	0.049	BRAF
Activation of RAS in B cells	1	134.3×	0.051	KRAS
Synthesis of PI	1	134.3×	0.051	PITPNM3
Signalling to p38 via RIT and RIN	1	134.3×	0.051	BRAF
Defective LFNG causes SCDO3	1	134.3×	0.051	NOTCH4
RUNX2 regulates chondrocyte maturation	1	134.3×	0.051	GLI2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 19 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of peptidyl-serine phosphorylation	3	121.0×	6e-04	BRAF, EGFR, PDCD10
striated muscle cell differentiation	2	104.3×	0.019	CDH2, KRAS
negative regulation of transforming growth factor beta receptor signaling pathway	3	27.4×	0.019	IL17RD, LEMD3, ENG
MAPK cascade	3	24.2×	0.020	BRAF, KRAS, MAP4K4
mammary gland development	2	68.2×	0.026	GLI2, NOTCH4
positive regulation of DNA replication	2	61.2×	0.027	EGFR, GLI2
branching involved in blood vessel morphogenesis	2	55.4×	0.028	ENG, NOTCH4
cell-cell adhesion	3	16.0×	0.034	ADGRV1, CDH2, EGFR
response to mineralocorticoid	1	887.0×	0.034	KRAS
negative regulation of vascular endothelial growth factor production	1	887.0×	0.034	SARS1
negative regulation of cardiocyte differentiation	1	887.0×	0.034	EGFR
seryl-tRNA aminoacylation	1	443.5×	0.035	SARS1
detection of hypoxia	1	443.5×	0.035	ENG
mesenchymal cell migration	1	443.5×	0.035	CDH2
positive regulation of vascular associated smooth muscle cell differentiation	1	443.5×	0.035	ENG
positive regulation of synaptic vesicle clustering	1	443.5×	0.035	CDH2
ventral midline development	1	295.6×	0.035	GLI2
floor plate formation	1	295.6×	0.035	GLI2
forebrain astrocyte development	1	295.6×	0.035	KRAS
spinal cord ventral commissure morphogenesis	1	295.6×	0.035	GLI2
positive regulation of ARF protein signal transduction	1	295.6×	0.035	MAP4K4
intrinsic apoptotic signaling pathway in response to hydrogen peroxide	1	295.6×	0.035	PDCD10
CD4-positive or CD8-positive, alpha-beta T cell lineage commitment	1	295.6×	0.035	BRAF
regulation of oligodendrocyte progenitor proliferation	1	295.6×	0.035	CDH2
positive regulation of protein kinase C signaling	1	295.6×	0.035	EGFR
neuroligin clustering involved in postsynaptic membrane assembly	1	295.6×	0.035	CDH2
cell migration involved in endocardial cushion formation	1	221.7×	0.035	ENG
hindgut morphogenesis	1	221.7×	0.035	GLI2
detection of biotic stimulus	1	221.7×	0.035	NLRP3
tube development	1	221.7×	0.035	GLI2

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Cobimetinib, Lovastatin, Sirolimus, Trametinib.

Drug target analysis

Approved (phase 4): 6 · Phase ≥3: 7 · Phased (≥1): 7 · Undrugged: 13

Druggability breadth: 12 of 20 evidence-associated genes (60%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
BRAF	VEMURAFENIB
CACNA1H	PIMOZIDE
NLRP3	CLOMIPHENE
EGFR	LEVODOPA
KRAS	VEMURAFENIB
MAP4K4	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EGFR	175	4
MAP4K4	62	4
BRAF	48	4
NLRP3	11	4
KRAS	11	4
CACNA1H	10	4
TIMP3	1	3
SARS1	0	0
ADGRV1	0	0
CDH2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	BRAF, EGFR, KRAS
PONATINIB	4	BRAF, EGFR, MAP4K4
FEDRATINIB	4	BRAF, EGFR
SORAFENIB	4	BRAF, EGFR, MAP4K4
DASATINIB ANHYDROUS	4	BRAF, EGFR
RUXOLITINIB	4	BRAF
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF
DABRAFENIB	4	BRAF, KRAS
COBIMETINIB	4	BRAF
NILOTINIB	4	BRAF
ABEMACICLIB	4	BRAF, EGFR, MAP4K4
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF
PAZOPANIB	4	BRAF, MAP4K4
DASATINIB	4	BRAF, EGFR, MAP4K4
ERLOTINIB	4	BRAF, EGFR
GEFITINIB	4	BRAF, EGFR, MAP4K4
IMATINIB	4	BRAF, EGFR
PIMOZIDE	4	CACNA1H
MIBEFRADIL	4	CACNA1H
NIMODIPINE	4	CACNA1H
TACRINE	4	CACNA1H
CLOMIPHENE	4	NLRP3
GLYBURIDE	4	NLRP3
LEVODOPA	4	EGFR
CLOTRIMAZOLE	4	EGFR
ERLOTINIB HYDROCHLORIDE	4	EGFR
CISPLATIN	4	EGFR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
EGFR	6,531	Binding:6211, Functional:173, ADMET:138, Toxicity:9
BRAF	1,442	Binding:1400, Functional:37, ADMET:5
KRAS	861	Binding:829, Functional:32
NLRP3	534	Binding:527, Functional:6, ADMET:1
MAP4K4	407	Binding:400, ADMET:5, Functional:1, Toxicity:1
CACNA1H	124	Binding:102, Functional:17, ADMET:4, Toxicity:1
GLI2	6	Binding:6
CDH2	4	Binding:3, Functional:1
SARS1	2	ADMET:1, Binding:1
NOTCH4	2	Binding:2
TIMP3	1	Binding:1
PDCD10	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SARS1	6.1.1.11	serine-tRNA ligase
BRAF	2.7.10.2, 2.7.11.1	non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase
EGFR	2.7.10.1	receptor protein-tyrosine kinase
KRAS	3.6.5.2	small monomeric GTPase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
BRAF	1,442
CACNA1H	124
NLRP3	534
EGFR	6,531
KRAS	861
MAP4K4	407

Pharmacogenomics

Cohort genes with a PharmGKB record: 19; 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)
VEMURAFENIB	4	BRAF, EGFR, KRAS
PONATINIB	4	BRAF, EGFR, MAP4K4
FEDRATINIB	4	BRAF, EGFR
SORAFENIB	4	BRAF, EGFR, MAP4K4
DASATINIB ANHYDROUS	4	BRAF, EGFR
RUXOLITINIB	4	BRAF
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF
DABRAFENIB	4	BRAF, KRAS
COBIMETINIB	4	BRAF
NILOTINIB	4	BRAF
ABEMACICLIB	4	BRAF, EGFR, MAP4K4
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF
PAZOPANIB	4	BRAF, MAP4K4
DASATINIB	4	BRAF, EGFR, MAP4K4
ERLOTINIB	4	BRAF, EGFR
GEFITINIB	4	BRAF, EGFR, MAP4K4
IMATINIB	4	BRAF, EGFR
PIMOZIDE	4	CACNA1H
MIBEFRADIL	4	CACNA1H
NIMODIPINE	4	CACNA1H
TACRINE	4	CACNA1H
CLOMIPHENE	4	NLRP3
GLYBURIDE	4	NLRP3
LEVODOPA	4	EGFR
CLOTRIMAZOLE	4	EGFR
ERLOTINIB HYDROCHLORIDE	4	EGFR
CISPLATIN	4	EGFR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	6	BRAF, CACNA1H, NLRP3, EGFR, KRAS, MAP4K4
B	Phased (≥1) drug, not yet approved	1	TIMP3
C	Druggable family + PDB, no drug	1	SARS1
D	Druggable family + AlphaFold only, no drug	1	ADGRV1
E	Difficult family or no structure, no drug	11	CDH2, IL17RD, ZFYVE16, PITPNM3, PREX2, LEMD3, ENG, GLI2, NRIP3-DT, NOTCH4 (+1 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SARS1	2	—
ADGRV1	0	—
CDH2	4	—
IL17RD	0	—
ZFYVE16	0	—
PITPNM3	0	—
PREX2	0	—
LEMD3	0	—
ENG	0	—
GLI2	6	—
NRIP3-DT	0	—
NOTCH4	2	—
PDCD10	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 27.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	24
PHASE3	1
PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01758211	PHASE3	UNKNOWN	Functional Magnetic Resonance Imagine(fMRI)Navigation in Intracranial Arteriovenous Malformation Surgery
NCT04297033	PHASE2	UNKNOWN	Lovastatin for Treatment of Brain Arteriovenous Malformations
NCT02314377	PHASE1	COMPLETED	Bevacizumab Therapy for Brain Arteriovenous Malformation
NCT03676868	Not specified	RECRUITING	Biology of Cerebral Arteriovenous Malformations and Prognosis of Cerebral Arteriovenous Malformations
NCT03731000	Not specified	RECRUITING	PHIL® Embolic System Pediatric IDE
NCT04572568	Not specified	RECRUITING	Registry of Multimodality Treatment for Brain Arteriovenous Malformation in Mainland China
NCT05776706	Not specified	NOT_YET_RECRUITING	Clinical Trial for the Validation of AR Based Neuronavigation System
NCT05933330	Not specified	ACTIVE_NOT_RECRUITING	Hereditary Hemorrhagic Telangiectasia and Neurovascular Manifestations, in the Danish HHT Database
NCT06259292	Not specified	RECRUITING	Comprehensive HHT Outcomes Registry of the United States (CHORUS)
NCT06479343	Not specified	RECRUITING	Efficacy and Safety of the Liquid Embolic System (Tonbridge) for Endovascular Treatment of Cerebrovascular Malformations
NCT07103304	Not specified	NOT_YET_RECRUITING	Liquid Biopsies for Detecting Somatic Mutations in Sporadic Cerebral Arteriovenous Malformations.
NCT07314047	Not specified	RECRUITING	The Liquid Embolic Agent for the Treatment of Brain Arteriovenous Malformation
NCT07353736	Not specified	NOT_YET_RECRUITING	Cerebral Arteriovenous Malformation With Aneurysm: Epidemiology, Clinical Features, and Prognosis
NCT01689402	Not specified	COMPLETED	MRI for the Early Evaluation of Acute Intracerebral Hemorrhage
NCT01803685	Not specified	UNKNOWN	Nationwide Treatment Survey of Intracranial Arteriovenous Malformation in China
NCT02085278	Not specified	COMPLETED	Safety of Apollo Micro Catheter in Pediatric Patients
NCT02180958	Not specified	COMPLETED	Evaluation of ONYX in ENDOVASCULAR Treatment of Cerebral AVMs
NCT02602990	Not specified	COMPLETED	Treatment of Cerebral Arteriovenous Malformations With SQUID™ Liquid Embolic Agent
NCT02868008	Not specified	UNKNOWN	Multimodal Imaging Techniques in Assessing the Surgical Risk for Eloquent Arteriovenous Malformations
NCT03209804	Not specified	COMPLETED	Surgical Management of Cerebral Arteriovenous Malformations Within Hybrid Operation Room
NCT03367975	Not specified	UNKNOWN	NIRS Monitoring During Intracranial Interventions
NCT03413852	Not specified	UNKNOWN	Treatment of Cerebral Arteriovenous Malformations With SQUID Liquid Embolic Agent (CHOICE)
NCT03995823	Not specified	COMPLETED	Evaluation of Nidus Occlusion After Gamma Knife Radiosurgery of Cerebral Arteriovenous Malformations Using Magnetic Resonance Imaging
NCT04328181	Not specified	UNKNOWN	Comparison of Imaging Quality Between Spectral Photon Counting Computed Tomography (SPCCT) and Dual Energy Computed Tomography (DECT)
NCT04553549	Not specified	COMPLETED	Safety and Feasibility of the Infinity Catheter for Radial Access
NCT04593966	Not specified	UNKNOWN	Pediatric and Adult Cerebral Arteriovenous Malformation Neurofunctional Outcomes
NCT05058482	Not specified	UNKNOWN	Non-adhesive Liquid Embolic System in the Embolization of Cerebral Arteriovenous Malformations

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
BEVACIZUMAB	4	1
LOVASTATIN	4	1