Moyamoya disease 2

Summary

Moyamoya disease 2 (MONDO:0011784) is a disease caused by RNF213 (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: RNF213 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 101

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Moyamoya disease 2
Mondo ID	MONDO:0011784
MeSH	C536992
OMIM	607151
NCIT	C183312
UMLS	C1846689
MedGen	339584
GARD	0015410
Is cancer (heuristic)	no

Also known as: Moyamoya disease 2 · moyamoya disease 2, susceptibility to · Moyamoya disease caused by mutation in RNF213 · Moyamoya disease type 2 · MYMY2 · RNF213 Moyamoya disease

Data availability: 101 ClinVar variants · 5 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › cerebrovascular disorder › intracranial arterial disease › cerebral arterial disease › Moyamoya disease › Moyamoya disease 2

Related subtypes (7): moyamoya disease 1, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, moyamoya disease 3, Moyamoya disease 5, Moyamoya disease with early-onset achalasia, moyamoya disease 7, Moyamoya disease 8

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

101 retrieved; paginated sample, class counts are floors:

58 uncertain significance, 12 conflicting classifications of pathogenicity, 8 likely pathogenic, 8 benign/likely benign, 7 likely benign, 4 benign, 3 pathogenic, 1 risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
1686128	NM_001256071.3(RNF213):c.12391C>T (p.Arg4131Cys)	RNF213	Pathogenic	criteria provided, single submitter
870408	NM_001256071.3(RNF213):c.12353C>T (p.Ser4118Phe)	RNF213	Pathogenic	criteria provided, single submitter
39701	NM_001256071.3(RNF213):c.12037G>A (p.Asp4013Asn)	RNF213-AS1	Pathogenic	criteria provided, single submitter
585198	NM_001256071.3(RNF213):c.12553A>G (p.Lys4185Glu)	LOC126862663	Likely pathogenic	criteria provided, single submitter
1710243	NM_001256071.3(RNF213):c.14822T>A (p.Val4941Glu)	RNF213	Likely pathogenic	no assertion criteria provided
210001	NM_001256071.3(RNF213):c.12343_12345del (p.Lys4115del)	RNF213	Likely pathogenic	no assertion criteria provided
2430341	NM_001256071.3(RNF213):c.12050G>A (p.Cys4017Tyr)	RNF213	Likely pathogenic	criteria provided, single submitter
3065130	NM_001256071.3(RNF213):c.13641-2A>G	RNF213	Likely pathogenic	criteria provided, single submitter
417846	NM_001256071.3(RNF213):c.12040C>A (p.His4014Asn)	RNF213	Likely pathogenic	no assertion criteria provided
4687912	NM_001256071.3(RNF213):c.10947dup (p.Glu3650fs)	RNF213	Likely pathogenic	criteria provided, single submitter
637049	NM_001256071.3(RNF213):c.12059G>T (p.Cys4020Phe)	RNF213	Likely pathogenic	criteria provided, single submitter
1325497	NM_001256071.3(RNF213):c.2743C>T (p.Arg915Ter)	RNF213	risk factor	criteria provided, single submitter
792959	NM_001256071.3(RNF213):c.14650G>A (p.Val4884Ile)	LOC126862664	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1686127	NM_001256071.3(RNF213):c.4865C>T (p.Ala1622Val)	RNF213	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210003	NM_001256071.3(RNF213):c.14195A>C (p.Lys4732Thr)	RNF213	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210005	NM_001256071.3(RNF213):c.15487G>A (p.Val5163Ile)	RNF213	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210007	NM_001256071.3(RNF213):c.12055C>T (p.Arg4019Cys)	RNF213	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2500257	NM_001256071.3(RNF213):c.1699A>G (p.Met567Val)	RNF213	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2713736	NM_001256071.3(RNF213):c.12362A>G (p.Asn4121Ser)	RNF213	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
39700	NM_001256071.3(RNF213):c.14429G>A (p.Arg4810Lys)	RNF213	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
417841	NM_001256071.3(RNF213):c.5162C>T (p.Pro1721Leu)	RNF213	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
627493	NM_001256071.3(RNF213):c.2875G>T (p.Gly959Ter)	RNF213	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
684683	NM_001256071.3(RNF213):c.6169G>A (p.Asp2057Asn)	RNF213	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
417851	NM_001256071.3(RNF213):c.12185G>A (p.Arg4062Gln)	RNF213-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1342620	NC_000017.11:g.80392616_80422726del	ENDOV	Uncertain significance	criteria provided, single submitter
2430340	NM_001114753.3(ENG):c.1928G>A (p.Ser643Asn)	ENG	Uncertain significance	criteria provided, single submitter
210002	NM_001256071.3(RNF213):c.12711C>G (p.Asp4237Glu)	LOC126862663	Uncertain significance	no assertion criteria provided
585199	NM_001256071.3(RNF213):c.12562G>A (p.Ala4188Thr)	LOC126862663	Uncertain significance	criteria provided, single submitter
1908184	NM_001256071.3(RNF213):c.14585T>C (p.Leu4862Pro)	LOC126862664	Uncertain significance	criteria provided, single submitter
1033794	NM_001256071.3(RNF213):c.13997C>T (p.Thr4666Ile)	RNF213	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 5 · 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
RNF213	Strong	Autosomal dominant	Moyamoya disease 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RNF213	Orphanet:2573	Moyamoya disease
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

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RNF213	HGNC:14539	ENSG00000173821	Q63HN8	E3 ubiquitin-protein ligase RNF213	gencc,clinvar
ENDOV	HGNC:26640	ENSG00000173818	Q8N8Q3	Endonuclease V	clinvar
ENG	HGNC:3349	ENSG00000106991	P17813	Endoglin	clinvar
RNF213-AS1	HGNC:54402	ENSG00000263069		RNF213 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RNF213	E3 ubiquitin-protein ligase RNF213	Atypical E3 ubiquitin ligase that can catalyze ubiquitination of both proteins and lipids, and which is involved in various processes, such as lipid metabolism, angiogenesis and cell-autonomous immunity.
ENDOV	Endonuclease V	Endoribonuclease that specifically cleaves inosine-containing RNAs: cleaves RNA at the second phosphodiester bond 3’ to inosine.
ENG	Endoglin	Vascular endothelium glycoprotein that plays an important role in the regulation of angiogenesis.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

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
Enzyme (other)	1	3.0×	0.605
Transcription factor	1	2.1×	0.605
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RNF213	Transcription factor	no		Znf_RING, AAA+_ATPase, Znf_RING/FYVE/PHD
ENDOV	Enzyme (other)	yes	3.1.21.7	Endonuclease-V
ENG	Other/Unknown	no		TGFBR3/Endoglin-like_N
RNF213-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

3 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
metanephros cortex	1
pancreatic ductal cell	1
kidney epithelium	1
parotid gland	1
upper arm skin	1
cardiac atrium	1
right atrium auricular region	1
right lung	1
buccal mucosa cell	1
right uterine tube	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RNF213	252	ubiquitous	marker	granulocyte, metanephros cortex, pancreatic ductal cell
ENDOV	219	ubiquitous	marker	kidney epithelium, upper arm skin, parotid gland
ENG	265	ubiquitous	marker	right lung, right atrium auricular region, cardiac atrium
RNF213-AS1	169	broad	yes	buccal mucosa cell, right uterine tube, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ENG	3,236
RNF213	2,368
ENDOV	1,684
RNF213-AS1	0

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RNF213	Q63HN8	4
ENG	P17813	3
ENDOV	Q8N8Q3	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 4 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
Suppression of apoptosis	1	1631.4×	0.004	RNF213
Response of Mtb to phagocytosis	1	1427.5×	0.004	RNF213
Infection with Mycobacterium tuberculosis	1	1142.0×	0.004	RNF213
Bacterial Infection Pathways	1	335.9×	0.010	RNF213
Signaling by ALK in cancer	1	271.9×	0.010	RNF213
Signaling by ALK fusions and activated point mutants	1	150.3×	0.014	RNF213
Class I MHC mediated antigen processing & presentation	1	70.1×	0.027	RNF213
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.029	RNF213
Antigen processing: Ubiquitination & Proteasome degradation	1	37.2×	0.039	RNF213
Adaptive Immune System	1	29.8×	0.044	RNF213
Infectious disease	1	24.8×	0.048	RNF213
Disease	1	13.1×	0.077	RNF213
Immune System	1	13.0×	0.077	RNF213

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
lipid ubiquitination	1	5617.3×	0.006	RNF213
detection of hypoxia	1	2808.7×	0.006	ENG
positive regulation of vascular associated smooth muscle cell differentiation	1	2808.7×	0.006	ENG
cell migration involved in endocardial cushion formation	1	1404.3×	0.006	ENG
positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation	1	1404.3×	0.006	ENG
atrioventricular canal morphogenesis	1	1404.3×	0.006	ENG
central nervous system vasculogenesis	1	1123.5×	0.006	ENG
negative regulation of non-canonical Wnt signaling pathway	1	1123.5×	0.006	RNF213
cardiac atrium morphogenesis	1	936.2×	0.006	ENG
venous blood vessel morphogenesis	1	802.5×	0.006	ENG
atrial cardiac muscle tissue morphogenesis	1	802.5×	0.006	ENG
xenophagy	1	802.5×	0.006	RNF213
dorsal aorta morphogenesis	1	702.2×	0.007	ENG
cardiac ventricle morphogenesis	1	624.1×	0.007	ENG
vascular associated smooth muscle cell development	1	561.7×	0.007	ENG
positive regulation of systemic arterial blood pressure	1	468.1×	0.008	ENG
epithelial to mesenchymal transition involved in endocardial cushion formation	1	468.1×	0.008	ENG
ventricular trabecula myocardium morphogenesis	1	351.1×	0.009	ENG
smooth muscle tissue development	1	351.1×	0.009	ENG
lipid droplet formation	1	330.4×	0.009	RNF213
endocardial cushion morphogenesis	1	280.9×	0.010	ENG
regulation of transforming growth factor beta receptor signaling pathway	1	267.5×	0.010	ENG
artery morphogenesis	1	224.7×	0.012	ENG
outflow tract septum morphogenesis	1	216.1×	0.012	ENG
negative regulation of SMAD protein signal transduction	1	200.6×	0.012	ENG
negative regulation of endothelial cell proliferation	1	181.2×	0.013	ENG
branching involved in blood vessel morphogenesis	1	175.5×	0.013	ENG
sprouting angiogenesis	1	160.5×	0.013	RNF213
positive regulation of BMP signaling pathway	1	151.8×	0.014	ENG
regulation of lipid metabolic process	1	144.0×	0.014	RNF213

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RNF213	0	0
ENDOV	0	0
ENG	0	0
RNF213-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
RNF213	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ENDOV	3.1.21.7, 3.1.27.8	deoxyribonuclease V, Ribonuclease V

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

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

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ENDOV
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	RNF213, ENG, RNF213-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RNF213	1	—
ENDOV	0	—
ENG	0	—
RNF213-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.