Moyamoya disease 5

Summary

Moyamoya disease 5 (MONDO:0013542) is a disease caused by ACTA2 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: ACTA2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 20

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Moyamoya disease 5
Mondo ID	MONDO:0013542
OMIM	614042
UMLS	C3279690
MedGen	481320
GARD	0015746
Is cancer (heuristic)	no

Also known as: ACTA2 Moyamoya disease · Moyamoya disease 5 · Moyamoya disease caused by mutation in ACTA2 · Moyamoya disease type 5 · MYMY5

Data availability: 20 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › multisystemic smooth muscle dysfunction syndrome › Moyamoya disease 5

Related subtypes (1): aortic aneurysm, familial thoracic 6

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

20 retrieved; paginated sample, class counts are floors:

12 uncertain significance, 4 pathogenic/likely pathogenic, 2 pathogenic, 1 likely benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
18278	NM_001613.4(ACTA2):c.772C>T (p.Arg258Cys)	ACTA2	Pathogenic	criteria provided, multiple submitters, no conflicts
199670	NM_001613.4(ACTA2):c.353G>A (p.Arg118Gln)	ACTA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
264311	NM_001613.4(ACTA2):c.593G>A (p.Arg198His)	ACTA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29598	NM_001613.4(ACTA2):c.536G>A (p.Arg179His)	ACTA2	Pathogenic	criteria provided, multiple submitters, no conflicts
65449	NM_001613.4(ACTA2):c.115C>T (p.Arg39Cys)	ACTA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18277	NM_001613.4(ACTA2):c.773G>A (p.Arg258His)	ACTA2-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
263578	NM_001613.4(ACTA2):c.766C>T (p.Arg256Cys)	ACTA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
263402	NM_001613.4(ACTA2):c.323C>T (p.Thr108Met)	ACTA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
263430	NM_001613.4(ACTA2):c.977C>A (p.Thr326Asn)	ACTA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2672253	NM_001613.4(ACTA2):c.290G>A (p.Arg97His)	ACTA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
384419	NM_001613.4(ACTA2):c.296C>G (p.Ala99Gly)	ACTA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
389807	NM_001613.4(ACTA2):c.553C>T (p.Arg185Ter)	ACTA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
404176	NM_001613.4(ACTA2):c.203C>T (p.Thr68Ile)	ACTA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
423832	NM_001613.4(ACTA2):c.129+5G>A	ACTA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
469083	NM_001613.4(ACTA2):c.129+4A>G	ACTA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
580143	NM_001613.4(ACTA2):c.78C>A (p.Asp26Glu)	ACTA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
636991	NM_001613.4(ACTA2):c.107T>C (p.Ile36Thr)	ACTA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
919137	NM_001613.4(ACTA2):c.689C>G (p.Ala230Gly)	ACTA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
930272	NM_001613.4(ACTA2):c.641T>C (p.Ile214Thr)	ACTA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1090017	NM_001613.4(ACTA2):c.648G>A (p.Glu216=)	ACTA2-AS1	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 3 · 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
ACTA2	Strong	Autosomal dominant	Moyamoya disease 5	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACTA2	Orphanet:2573	Moyamoya disease
ACTA2	Orphanet:404463	Multisystemic smooth muscle dysfunction syndrome
ACTA2	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ACTA2	HGNC:130	ENSG00000107796	P62736	Actin, aortic smooth muscle	gencc,clinvar
ACTA2-AS1	HGNC:45169	ENSG00000180139		ACTA2 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACTA2	Actin, aortic smooth muscle	Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACTA2	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS
ACTA2-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood vessel layer	1
cauda epididymis	1
saphenous vein	1
popliteal artery	1
right coronary artery	1
tibial artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACTA2	289	ubiquitous	marker	cauda epididymis, blood vessel layer, saphenous vein
ACTA2-AS1	162		marker	right coronary artery, popliteal artery, tibial artery

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACTA2	774
ACTA2-AS1	0

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACTA2	P62736	95.43

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 2 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
Regulation of CDH1 Function	1	951.7×	0.006	ACTA2
NOTCH4 Intracellular Domain Regulates Transcription	1	571.0×	0.006	ACTA2
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	543.8×	0.006	ACTA2
Signaling by NOTCH4	1	496.5×	0.006	ACTA2
Formation of the dystrophin-glycoprotein complex (DGC)	1	308.6×	0.008	ACTA2
Smooth Muscle Contraction	1	265.6×	0.008	ACTA2
Signaling by NOTCH	1	175.7×	0.009	ACTA2
Activation of STAT3 by cadherin engagement	1	163.1×	0.009	ACTA2
Non-integrin membrane-ECM interactions	1	154.3×	0.009	ACTA2
Muscle contraction	1	77.2×	0.016	ACTA2
Extracellular matrix organization	1	63.1×	0.017	ACTA2
Signal Transduction	1	10.2×	0.098	ACTA2

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 hepatic stellate cell contraction	1	16852.0×	6e-04	ACTA2
positive regulation of hepatic stellate cell migration	1	8426.0×	6e-04	ACTA2
juxtaglomerular apparatus development	1	5617.3×	6e-04	ACTA2
glomerular mesangial cell development	1	4213.0×	6e-04	ACTA2
vascular associated smooth muscle contraction	1	3370.4×	6e-04	ACTA2
mesenchyme migration	1	3370.4×	6e-04	ACTA2
positive regulation of hepatic stellate cell activation	1	2808.7×	6e-04	ACTA2
cellular response to transforming growth factor beta stimulus	1	276.3×	0.005	ACTA2
regulation of blood pressure	1	221.7×	0.006	ACTA2
response to virus	1	144.0×	0.008	ACTA2
positive regulation of ERK1 and ERK2 cascade	1	85.1×	0.013	ACTA2
positive regulation of gene expression	1	38.7×	0.026	ACTA2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ACTA2	0	0
ACTA2-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ACTA2, ACTA2-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ACTA2	0	—
ACTA2-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.