Cerebral cavernous malformations 5

Summary

Cerebral cavernous malformations 5 (MONDO:0975952) is a disease caused by MAP3K3 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: MAP3K3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cerebral cavernous malformations 5
Mondo ID	MONDO:0975952
OMIM	621032
UMLS	C5975541
MedGen	1875071
GARD	0027335
Is cancer (heuristic)	no

Data availability: 5 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › cerebral cavernous malformation › famililal cerebral cavernous malformations › cerebral cavernous malformations 5

Related subtypes (4): cerebral cavernous malformation 2, cerebral cavernous malformation 3, cerebral cavernous malformation 1, cerebral cavernous malformation 4

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

5 retrieved; paginated sample, class counts are floors:

5 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
3600420	NM_002401.5(MAP3K3):c.1313C>G (p.Thr438Ser)	MAP3K3	Uncertain significance	criteria provided, single submitter
3600427	NM_002401.5(MAP3K3):c.91A>G (p.Met31Val)	MAP3K3	Uncertain significance	criteria provided, single submitter
3600453	NM_002401.5(MAP3K3):c.937C>T (p.Arg313Cys)	MAP3K3	Uncertain significance	criteria provided, single submitter
3600488	NM_002401.5(MAP3K3):c.397C>T (p.His133Tyr)	MAP3K3	Uncertain significance	criteria provided, multiple submitters, no conflicts
3870212	NM_002401.5(MAP3K3):c.1570A>G (p.Met524Val)	MAP3K3	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · Orphanet: 0 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
MAP3K3	Strong	Autosomal dominant	cerebral cavernous malformations 5

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MAP3K3	HGNC:6855	ENSG00000198909	Q99759	Mitogen-activated protein kinase kinase kinase 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MAP3K3	Mitogen-activated protein kinase kinase kinase 3	Component of a protein kinase signal transduction cascade.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

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

Family	Genes	Fold	FDR
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MAP3K3	Kinase	yes	2.7.11.25	PB1_dom, Prot_kinase_dom, Kinase-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MAP3K3	261	ubiquitous	marker	monocyte, mononuclear cell, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MAP3K3	3,530

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MAP3K3	Q99759	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

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

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interleukin-1 family signaling	1	271.9×	0.018	MAP3K3
Interleukin-1 signaling	1	124.1×	0.020	MAP3K3
Signaling by Interleukins	1	64.2×	0.026	MAP3K3
Cytokine Signaling in Immune system	1	40.8×	0.031	MAP3K3
Immune System	1	13.0×	0.077	MAP3K3

GO biological processes by enrichment

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

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of p38MAPK cascade	1	624.1×	0.008	MAP3K3
blood vessel development	1	374.5×	0.008	MAP3K3
MAPK cascade	1	153.2×	0.010	MAP3K3
protein autophosphorylation	1	145.3×	0.010	MAP3K3
positive regulation of canonical NF-kappaB signal transduction	1	72.6×	0.017	MAP3K3
intracellular signal transduction	1	38.1×	0.026	MAP3K3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

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

Symbol	Example approved molecule
MAP3K3	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAP3K3	28	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	MAP3K3
AXITINIB	4	MAP3K3
RUXOLITINIB	4	MAP3K3
NERATINIB	4	MAP3K3
BOSUTINIB	4	MAP3K3
NINTEDANIB	4	MAP3K3
SUNITINIB	4	MAP3K3
DASATINIB	4	MAP3K3
ERLOTINIB	4	MAP3K3
CRIZOTINIB	4	MAP3K3
MIDOSTAURIN	4	MAP3K3
GEFITINIB	4	MAP3K3
CANERTINIB	3	MAP3K3
ALVOCIDIB	3	MAP3K3
MOTESANIB	3	MAP3K3
LESTAURTINIB	3	MAP3K3
RUBOXISTAURIN	3	MAP3K3
FORETINIB	2	MAP3K3
SU-014813	2	MAP3K3
BMS-690514	2	MAP3K3
R-406	2	MAP3K3
AT-9283	2	MAP3K3
TOZASERTIB	2	MAP3K3
PELITINIB	2	MAP3K3
KW-2449	1	MAP3K3
AMG-900	1	MAP3K3
PF-03814735	1	MAP3K3
GSK-690693	1	MAP3K3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MAP3K3	189	Binding:189

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MAP3K3	2.7.11.25, 2.7.12.2	mitogen-activated protein kinase kinase kinase, mitogen-activated protein kinase kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
MAP3K3	189

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

28 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
FEDRATINIB	4	MAP3K3
AXITINIB	4	MAP3K3
RUXOLITINIB	4	MAP3K3
NERATINIB	4	MAP3K3
BOSUTINIB	4	MAP3K3
NINTEDANIB	4	MAP3K3
SUNITINIB	4	MAP3K3
DASATINIB	4	MAP3K3
ERLOTINIB	4	MAP3K3
CRIZOTINIB	4	MAP3K3
MIDOSTAURIN	4	MAP3K3
GEFITINIB	4	MAP3K3
CANERTINIB	3	MAP3K3
ALVOCIDIB	3	MAP3K3
MOTESANIB	3	MAP3K3
LESTAURTINIB	3	MAP3K3
RUBOXISTAURIN	3	MAP3K3
FORETINIB	2	MAP3K3
SU-014813	2	MAP3K3
BMS-690514	2	MAP3K3
R-406	2	MAP3K3
AT-9283	2	MAP3K3
TOZASERTIB	2	MAP3K3
PELITINIB	2	MAP3K3
KW-2449	1	MAP3K3
AMG-900	1	MAP3K3
PF-03814735	1	MAP3K3
GSK-690693	1	MAP3K3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MAP3K3
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.