Moyamoya disease

disease

On this page

Also known as idiopathic Moyamoya diseaseMoyamoya disease, primaryMoyamoya disease, secondaryMYMYprogressive intracranial arterial occlusion

Summary

Moyamoya disease (MONDO:0016820) is a disease (an umbrella term covering 8 Mondo subtypes) caused by SAMHD1 (GenCC Strong), with 23 cohort genes (83 GWAS associations across 4 studies) and 45 clinical trials. Top therapeutic interventions include sodium chloride and rac-3-n-butylphthalide.

At a glance

Prevalence: 1-9 / 100 000 (China) [Orphanet-validated]
Causal gene: SAMHD1 (GenCC Strong)
Umbrella term: 8 Mondo subtypes
Cohort genes: 23
GWAS associations: 83
ClinVar variants: 6
Phenotypes (HPO): 5
Clinical trials: 45

Clinical features

Epidemiology

Prevalence records

10 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 1 000 000	0.43	China	Validated
Annual incidence	<1 / 1 000 000	0.048	Taiwan, Province of China	Validated
Annual incidence	<1 / 1 000 000	0.086	United States	Validated
Point prevalence	1-9 / 100 000	3.92	China	Validated
Point prevalence	1-9 / 1 000 000	0.44	Taiwan, Province of China	Validated
Point prevalence	1-9 / 1 000 000	0.33	France	Validated
Annual incidence	<1 / 1 000 000	0.035	Europe	Not yet validated
Point prevalence	1-9 / 1 000 000		Europe	Not yet validated
Annual incidence	1-9 / 1 000 000	0.74	Japan	Not yet validated
Point prevalence	1-9 / 100 000	6.2	Japan	Not yet validated

Signs & symptoms

Clinical features (HPO)

5 HPO clinical features (Orphanet curated; top 5 by frequency):

HPO ID	Term	Frequency
HP:0001009	Telangiectasia	Very frequent (80-99%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0100659	Abnormality of the cerebral vasculature	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Moyamoya disease
Mondo ID	MONDO:0016820
MeSH	D009072
OMIM	252350
Orphanet	2573
DOID	DOID:13099
ICD-10-CM	I67.5
ICD-11	1746892088, 369231682
NCIT	C84895
SNOMED CT	89142007
UMLS	C0026654
MedGen	7726
GARD	0007064
MedDRA	10028047
NORD	1457
Is cancer (heuristic)	no

Also known as: idiopathic Moyamoya disease · Moyamoya disease, primary · Moyamoya disease, secondary · MYMY · progressive intracranial arterial occlusion

Data availability: 6 ClinVar variants · 83 GWAS associations (4 studies) · 5 GenCC gene-disease records · 13 cell lines.

Disease family

An umbrella term covering 8 Mondo subtypes.

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

Subtypes (8): moyamoya disease 1, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, Moyamoya disease 2, moyamoya disease 3, Moyamoya disease 5, Moyamoya disease with early-onset achalasia, moyamoya disease 7, Moyamoya disease 8

Genetics & variants

GWAS landscape

83 GWAS associations across 4 studies. Top hits map to 24 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs112735431	1e-228	RNF213-AS1, RNF213	?	95.7
rs9916351	5e-54	RNF213	A	1.96
rs10782008	2e-44	RNF213	G	2
rs11869363	7e-38	RNF213	A	1.79
rs2107595	1e-29	HDAC9 - TWIST1	A	1.64
rs3813803	1e-24	SMPDL3B	G	1.65
chr5:79616083	9e-23		G	20.67
rs74388387	2e-22	MAGI2	C	1.61
rs118177209	5e-21	RPL18P1 - ATP5MC2P2	A	3.59
rs681239	1e-20	WNT9A - CICP26	G	1.61
rs41301888	3e-20	ENDOV	T	9.64
rs11870849	8e-20	ENDOV	T	9.37
rs75485498	1e-19	RNF115, CD160	A	30.22
rs9651118	2e-19	MTHFR	A	1.54
rs7525578	4e-19	RAP1A	T	14.79
rs9902358	1e-17	CARD14	A	1.44
rs9907978	8e-17	RNF213	A	1.59
rs28670551	8e-17	ENDOV - NPTX1	T	6.63
rs3869145	3e-16	EHMT2, EHMT2-AS1	A	9.8
rs79994440	3e-16	SDK2	A	32.06
rs849139	1e-15	JAZF1	A	1.43
rs4969426	2e-14	RPTOR	T	1.43
rs9895958	2e-14	ENDOV - NPTX1	G	4.74
rs201661014	3e-14	DOCK9	A	1.41
rs12530920	3e-14	HDAC9 - TWIST1	?	1.77
rs74790219	9e-14	RNF213	G	4.47
rs6958010	2e-13	JAZF1	A	1.37
rs6565681	8e-13	RNF213, RNF213-AS1	A	4.61
rs9614159	8e-12	HORMAD2 - LIF-AS1	A	1.4
rs476382	2e-11	ATP7BP1 - RPS4XP18	G	1.43

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST005575	Duan L	2017	755	2,031	Novel Susceptibility Loci for Moyamoya Disease Revealed by a Genome-Wide Association Study.
GCST90705091	Hirano Y	2026	401	47,255	Integrative GWAS and snRNA-seq Reveal a Mesenchymal-Like Endothelial Signature in Moyamoya Disease.
GCST90310003	Jeon JP	2023	216	0	Genome-wide association study identifies novel susceptibilities to adult moyamoya disease.
GCST000860	Kamada F	2010	72	0	A genome-wide association study identifies RNF213 as the first Moyamoya disease gene.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	4
Tier 2: splice/UTR	3
Tier 3: regulatory	2
Tier 4: intronic/intergenic	41

MAF distribution

Bucket	Variants
common (>=0.05)	41
low_freq (0.01-0.05)	8
rare (<0.01)	0
unknown	1

Functional consequences

Consequence	Count
intron_variant	25
unknown	9
missense_variant	4
non_coding_transcript_exon_variant	4
intergenic_variant	3
3_prime_UTR_variant	3
regulatory_region_variant	2

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs112735431	17	80385145	G>A,C		missense_variant	RNF213-AS1, RNF213	1e-228	Tier 1: coding
rs9916351	17	80265733	T>C	0.35	intron_variant	RNF213	5e-54	Tier 4: intronic/intergenic
rs10782008	17	80332071	G>A	0.37	missense_variant	RNF213	2e-44	Tier 1: coding
rs11869363	17	80292960	A>C,G,T	0.5	intron_variant	RNF213	7e-38	Tier 4: intronic/intergenic
rs2107595	7	19009765	G>A,C,T	0.32	regulatory_region_variant	HDAC9 - TWIST1	1e-29	Tier 3: regulatory
rs3813803	1	27955781	T>A,C	0.27	missense_variant	SMPDL3B	1e-24	Tier 1: coding
chr5:79616083				0.046			9e-23	Tier 4: intronic/intergenic
rs74388387	7	79037327	A>C	0.19	intron_variant	MAGI2	2e-22	Tier 4: intronic/intergenic
rs118177209	14	49070901	C>T	0.04	non_coding_transcript_exon_variant	RPL18P1 - ATP5MC2P2	5e-21	Tier 4: intronic/intergenic
rs681239	1	227951971	A>C,G,T	0.4	intergenic_variant	WNT9A - CICP26	1e-20	Tier 4: intronic/intergenic
rs41301888	17	80431051	C>T	0.162	intron_variant	ENDOV	3e-20	Tier 4: intronic/intergenic
rs11870849	17	80437273	C>A,T	0.127	3_prime_UTR_variant	ENDOV	8e-20	Tier 2: splice/UTR
rs75485498	1	145740567	C>A,T	0.029	3_prime_UTR_variant	RNF115, CD160	1e-19	Tier 2: splice/UTR
rs9651118	1	11802157	T>A,C	0.35	intron_variant	MTHFR	2e-19	Tier 4: intronic/intergenic
rs7525578	1	111674339	C>T	0.057	intron_variant	RAP1A	4e-19	Tier 4: intronic/intergenic
rs9902358	17	80182963	G>A,C,T	0.46	intron_variant	CARD14	1e-17	Tier 4: intronic/intergenic
rs9907978	17	80327580	A>G	0.24	intron_variant	RNF213	8e-17	Tier 4: intronic/intergenic
rs28670551	17	80454724	C>T	0.138	non_coding_transcript_exon_variant	ENDOV - NPTX1	8e-17	Tier 4: intronic/intergenic
rs3869145	6	31883577	G>A,C,T	0.064	non_coding_transcript_exon_variant	EHMT2, EHMT2-AS1	3e-16	Tier 4: intronic/intergenic
rs79994440	17	73590873	G>A	0.014	intron_variant	SDK2	3e-16	Tier 4: intronic/intergenic
rs849139	7	28139777	C>T	0.46	intron_variant	JAZF1	1e-15	Tier 4: intronic/intergenic
rs4969426	17	80789008	A>C,G,T	0.23	intron_variant	RPTOR	2e-14	Tier 4: intronic/intergenic
rs9895958	17	80455959	A>G,T	0.164	intergenic_variant	ENDOV - NPTX1	2e-14	Tier 4: intronic/intergenic
rs201661014	13	99056316	A>C,G	0.39	intron_variant	DOCK9	3e-14	Tier 4: intronic/intergenic
rs12530920	7	19016174	A>C,G	0.05	regulatory_region_variant	HDAC9 - TWIST1	3e-14	Tier 3: regulatory
rs74790219	17	80318979	A>G	0.231	intron_variant	RNF213	9e-14	Tier 4: intronic/intergenic
rs6958010	7	28099020	T>A,G	0.45	intron_variant	JAZF1	2e-13	Tier 4: intronic/intergenic
rs6565681	17	80374694	A>C,G,T	0.475	intron_variant	RNF213, RNF213-AS1	8e-13	Tier 4: intronic/intergenic
rs9614159	22	30205254	G>A	0.2	intron_variant	HORMAD2 - LIF-AS1	8e-12	Tier 4: intronic/intergenic
rs476382	18	22525019	T>A,C,G	0.23	intron_variant	ATP7BP1 - RPS4XP18	2e-11	Tier 4: intronic/intergenic

ClinVar germline variants

6 retrieved; paginated sample, class counts are floors:

2 uncertain significance, 2 conflicting classifications of pathogenicity, 1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1184843	NM_001256071.3(RNF213):c.11986_11989delinsGGGTTAG (p.Pro3996_Cys3997delinsGlyLeuGly)	RNF213	Pathogenic	criteria provided, single submitter
694602	GRCh37/hg19 Xq28(chrX:148882560-149686856)x2	MAGEA8	Likely pathogenic	no assertion criteria provided
500968	NM_138694.4(PKHD1):c.7091T>A (p.Ile2364Asn)	PKHD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
550124	NM_138694.4(PKHD1):c.9629C>G (p.Ser3210Cys)	PKHD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
636991	NM_001613.4(ACTA2):c.107T>C (p.Ile36Thr)	ACTA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1184842	NM_001256071.3(RNF213):c.12341C>G (p.Thr4114Arg)	RNF213-AS1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 26 · Orphanet: 31 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 1

Dual-evidence genes (GWAS + Mendelian — highest-confidence targets)

Gene	HGNC	Evidence routes
RNF213	RNF213	GWAS, Orphanet

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
SAMHD1	Strong	Autosomal recessive	Moyamoya disease	9
NF1	Moderate	Autosomal dominant	Moyamoya disease	9
PCNT	Moderate	Autosomal recessive	Moyamoya disease	6
BRCC3	Limited	Autosomal dominant	Moyamoya disease	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RNF213	Orphanet:2573	Moyamoya disease
SAMHD1	Orphanet:481662	Familial Chilblain lupus
SAMHD1	Orphanet:51	Aicardi-Goutières syndrome
PCNT	Orphanet:2637	Microcephalic osteodysplastic primordial dwarfism type II
PCNT	Orphanet:808	Seckel syndrome
BRCC3	Orphanet:280679	Moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome
NF1	Orphanet:139474	17q11.2 microduplication syndrome
NF1	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
NF1	Orphanet:293199	Pleomorphic rhabdomyosarcoma
NF1	Orphanet:363700	Neurofibromatosis type 1 due to NF1 mutation or intragenic deletion
NF1	Orphanet:638	Neurofibromatosis-Noonan syndrome
NF1	Orphanet:86834	Juvenile myelomonocytic leukemia
NF1	Orphanet:97685	17q11 microdeletion syndrome
NF1	Orphanet:99756	Alveolar rhabdomyosarcoma
NF1	Orphanet:99757	Embryonal rhabdomyosarcoma
TCN2	Orphanet:859	Transcobalamin deficiency
ACTA2	Orphanet:2573	Moyamoya disease
ACTA2	Orphanet:404463	Multisystemic smooth muscle dysfunction syndrome
ACTA2	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
CARD14	Orphanet:2897	Pityriasis rubra pilaris
SBF2	Orphanet:99956	Charcot-Marie-Tooth disease type 4B2
JAZF1	Orphanet:213711	Endometrial stromal sarcoma
JAZF1	Orphanet:536	Systemic lupus erythematosus
LRP1	Orphanet:2340	Keratosis follicularis spinulosa decalvans
LRP1	Orphanet:79100	Atrophoderma vermiculata
MTHFR	Orphanet:395	Homocystinuria due to methylene tetrahydrofolate reductase deficiency
MTHFR	Orphanet:563609	Isolated anencephaly
MTHFR	Orphanet:563612	Isolated exencephaly
PKHD1	Orphanet:53035	Caroli disease
PKHD1	Orphanet:731	Autosomal recessive polycystic kidney disease
PLOD1	Orphanet:1900	Kyphoscoliotic Ehlers-Danlos syndrome due to lysyl hydroxylase 1 deficiency

Cohort genes → proteins

23 cohort genes, 22 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	14
gwas_and_clinvar	1
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RNF213	HGNC:14539	ENSG00000173821	Q63HN8	E3 ubiquitin-protein ligase RNF213	gwas,clinvar
SAMHD1	HGNC:15925	ENSG00000101347	Q9Y3Z3	Deoxynucleoside triphosphate triphosphohydrolase SAMHD1	gencc
PCNT	HGNC:16068	ENSG00000160299	O95613	Pericentrin	gencc
BRCC3	HGNC:24185	ENSG00000185515	P46736	Lys-63-specific deubiquitinase BRCC36	gencc
NF1	HGNC:7765	ENSG00000196712	P21359	Neurofibromin	gencc
TCN2	HGNC:11653	ENSG00000185339	P20062	Transcobalamin-2	gwas
ACTA2	HGNC:130	ENSG00000107796	P62736	Actin, aortic smooth muscle	clinvar
HDAC9	HGNC:14065	ENSG00000048052	Q9UKV0	Histone deacetylase 9	gwas
SPTLC3	HGNC:16253	ENSG00000172296	Q9NUV7	Serine palmitoyltransferase 3	gwas
CARD14	HGNC:16446	ENSG00000141527	Q9BXL6	Caspase recruitment domain-containing protein 14	gwas
SBF2	HGNC:2135	ENSG00000133812	Q86WG5	Myotubularin-related protein 13	gwas
CTAGE1	HGNC:24346	ENSG00000212710	Q96RT6	cTAGE family member 2	gwas
HORMAD2	HGNC:28383	ENSG00000176635	Q8N7B1	HORMA domain-containing protein 2	gwas
JAZF1	HGNC:28917	ENSG00000153814	Q86VZ6	Juxtaposed with another zinc finger protein 1	gwas
TSC22D2	HGNC:29095	ENSG00000196428	O75157	TSC22 domain family protein 2	gwas
FADS1	HGNC:3574	ENSG00000149485	O60427	Acyl-CoA (8-3)-desaturase	gwas
FADS2	HGNC:3575	ENSG00000134824	O95864	Acyl-CoA 6-desaturase	gwas
RNF213-AS1	HGNC:54402	ENSG00000263069		RNF213 antisense RNA 1	clinvar
LRP1	HGNC:6692	ENSG00000123384	Q07954	Prolow-density lipoprotein receptor-related protein 1	gwas
MAGEA8	HGNC:6806	ENSG00000156009	P43361	Melanoma-associated antigen 8	clinvar
MTHFR	HGNC:7436	ENSG00000177000	P42898	Methylenetetrahydrofolate reductase (NADPH)	gwas
PKHD1	HGNC:9016	ENSG00000170927	P08F94	Fibrocystin	clinvar
PLOD1	HGNC:9081	ENSG00000083444	Q02809	Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1	gwas

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.
SAMHD1	Deoxynucleoside triphosphate triphosphohydrolase SAMHD1	Protein that acts both as a host restriction factor involved in defense response to virus and as a regulator of DNA end resection at stalled replication forks.
PCNT	Pericentrin	Integral component of the filamentous matrix of the centrosome involved in the initial establishment of organized microtubule arrays in both mitosis and meiosis.
BRCC3	Lys-63-specific deubiquitinase BRCC36	Metalloprotease that specifically cleaves ‘Lys-63’-linked polyubiquitin chains.
NF1	Neurofibromin	Stimulates the GTPase activity of Ras.
TCN2	Transcobalamin-2	Primary vitamin B12-binding and transport protein.
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.
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).
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-…
CARD14	Caspase recruitment domain-containing protein 14	Acts as a scaffolding protein that can activate the inflammatory transcription factor NF-kappa-B and p38/JNK MAP kinase signaling pathways.
SBF2	Myotubularin-related protein 13	Guanine nucleotide exchange factor (GEF) which activates RAB21 and possibly RAB28.
HORMAD2	HORMA domain-containing protein 2	Essential for synapsis surveillance during meiotic prophase via the recruitment of ATR activity.
JAZF1	Juxtaposed with another zinc finger protein 1	Acts as a transcriptional corepressor of orphan nuclear receptor NR2C2.
TSC22D2	TSC22 domain family protein 2	Reduces the level of nuclear PKM isoform M2 which results in repression of cyclin CCND1 transcription and reduced cell growth.
FADS1	Acyl-CoA (8-3)-desaturase	Acts as a front-end fatty acyl-coenzyme A (CoA) desaturase that introduces a cis double bond at carbon 5 located between a preexisting double bond and the carboxyl end of the fatty acyl chain.
FADS2	Acyl-CoA 6-desaturase	Involved in the biosynthesis of highly unsaturated fatty acids (HUFA) from the essential polyunsaturated fatty acids (PUFA) linoleic acid (LA) (18:2n-6) and alpha-linolenic acid (ALA) (18:3n-3) precursors, acting as a fatty acyl-coenzyme A…
LRP1	Prolow-density lipoprotein receptor-related protein 1	Endocytic receptor involved in endocytosis and in phagocytosis of apoptotic cells.
MAGEA8	Melanoma-associated antigen 8	Not known, though may play a role in embryonal development and tumor transformation or aspects of tumor progression.
MTHFR	Methylenetetrahydrofolate reductase (NADPH)	Catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine.
PKHD1	Fibrocystin	Promotes ciliogenesis in renal epithelial cells and therefore participates in the tubules formation and/ or ensures the maintenance of the architecture of the lumen of the kidney.
PLOD1	Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1	Part of a complex composed of PLOD1, P3H3 and P3H4 that catalyzes hydroxylation of lysine residues in collagen alpha chains and is required for normal assembly and cross-linkling of collagen fibrils.

Protein-family classification

Druggable: 8 · Difficult: 4 · Unknown: 11 · 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
Enzyme (other)	5	2.6×	0.266
Phosphatase	1	3.6×	0.772
Protease	1	1.6×	0.772
Antibody/Immunoglobulin	1	1.3×	0.772
Transcription factor	3	1.1×	0.772
Other/Unknown	11	0.9×	0.837
Scaffold/PPI	1	0.8×	0.837

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RNF213	Transcription factor	no		Znf_RING, AAA+_ATPase, Znf_RING/FYVE/PHD
SAMHD1	Transcription factor	no	3.1.5.B1	SAM, HD/PDEase_dom, HD_domain
PCNT	Other/Unknown	no		PACT_domain, AKAP9/Pericentrin
BRCC3	Protease	yes		JAMM/MPN+_dom, MPN_BRCC36, MPN
NF1	Other/Unknown	no		CRAL-TRIO_dom, RasGAP_dom, Rho_GTPase_activation_prot
TCN2	Other/Unknown	no		Cbl-bd_prot, Terpenoid_cyclase/PrenylTrfase, Cobalamin_Transport
ACTA2	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS
HDAC9	Enzyme (other)	yes	3.5.1.98	HDACs, Ureohydrolase_dom_sf, His_deacetylse_dom
SPTLC3	Enzyme (other)	yes	2.3.1.50	Aminotrans_II_pyridoxalP_BS, Aminotransferase_I/II_large, PyrdxlP-dep_Trfase_major
CARD14	Scaffold/PPI	no		CARD, PDZ, Guanylate_kin-like_dom
SBF2	Phosphatase	yes		cDENN_dom, PH_domain, GRAM
CTAGE1	Other/Unknown	no		cTAGE_MIA/OTOR
HORMAD2	Other/Unknown	no		HORMA_dom, HORMA_dom_sf, HORMA_MeioticProgression
JAZF1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, ZnF-Chromatin_assoc
TSC22D2	Other/Unknown	no		TSC22/Bun, TSC22/BUN_CS, TSC22_domain_protein_2
FADS1	Enzyme (other)	yes	1.14.19.30	Cyt_B5-like_heme/steroid-bd, FA_desaturase_dom, Fatty_acid_desaturase
FADS2	Enzyme (other)	yes	1.14.19.3	Cyt_B5-like_heme/steroid-bd, FA_desaturase_dom, Fatty_acid_desaturase
RNF213-AS1	Other/Unknown	no
LRP1	Other/Unknown	no		LDLR_classB_rpt, EGF-type_Asp/Asn_hydroxyl_site, EGF
MAGEA8	Other/Unknown	no		MHD_dom, MAGE_N, MAGE
MTHFR	Enzyme (other)	yes	1.5.1.20	Mehydrof_redctse-like, Fadh2_euk, FAD-linked_oxidoreductase-like
PKHD1	Antibody/Immunoglobulin	yes		IPT_dom, PbH1, Pectin_lyase_fold/virulence
PLOD1	Other/Unknown	no		Procol_lys_dOase, Oxoglu/Fe-dep_dioxygenase_dom, Pro_4_hyd_alph

Expression context

Cohort genes with no expression data: 0.

19 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)	1
broad (>20)	22
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	4
metanephros cortex	3
monocyte	2
calcaneal tendon	2
colonic epithelium	2
cauda epididymis	2
oocyte	2
secondary oocyte	2
placenta	2
skin of abdomen	2
left testis	2
right testis	2
testis	2
right adrenal gland cortex	2
sural nerve	2
stromal cell of endometrium	2
apex of heart	2
granulocyte	1
pancreatic ductal cell	1
mononuclear cell	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
SAMHD1	291	ubiquitous	marker	monocyte, mononuclear cell, pericardium
PCNT	283	ubiquitous	marker	gastrocnemius, body of tongue, hindlimb stylopod muscle
BRCC3	281	ubiquitous	marker	parotid gland, oral cavity, buccal mucosa cell
NF1	283	ubiquitous	marker	colonic epithelium, calcaneal tendon, adrenal tissue
TCN2	198	ubiquitous	marker	gall bladder, metanephros cortex, right lung
ACTA2	289	ubiquitous	marker	cauda epididymis, blood vessel layer, saphenous vein
HDAC9	277	ubiquitous	marker	oocyte, monocyte, secondary oocyte
SPTLC3	228	ubiquitous	marker	buccal mucosa cell, placenta, skin of abdomen
CARD14	179	tissue_specific	yes	lower esophagus mucosa, skin of leg, skin of abdomen
SBF2	257	ubiquitous	marker	epithelial cell of pancreas, colonic epithelium, calcaneal tendon
CTAGE1	13	tissue_specific	yes	right testis, left testis, testis
HORMAD2	66	tissue_specific	marker	right testis, left testis, testis
JAZF1	251	ubiquitous	marker	trabecular bone tissue, cauda epididymis, right adrenal gland cortex
TSC22D2	289	ubiquitous	marker	buccal mucosa cell, secondary oocyte, oocyte
FADS1	280	ubiquitous	marker	upper leg skin, ventral tegmental area, superior vestibular nucleus
FADS2	229	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland cortex
RNF213-AS1	169	broad	yes	buccal mucosa cell, right uterine tube, sural nerve
LRP1	293	ubiquitous	marker	stromal cell of endometrium, descending thoracic aorta, ascending aorta
MAGEA8	76	tissue_specific	yes	placenta, primordial germ cell in gonad, decidua
MTHFR	254	ubiquitous	marker	corpus epididymis, sural nerve, apex of heart
PKHD1	51	tissue_specific	marker	kidney epithelium, renal medulla, metanephros cortex
PLOD1	279	ubiquitous	marker	stromal cell of endometrium, smooth muscle tissue, apex of heart

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NF1	5,540
PCNT	3,934
MTHFR	3,492
BRCC3	3,428
HDAC9	3,047
LRP1	2,662
RNF213	2,368
SAMHD1	2,186
PLOD1	1,929
CARD14	1,902

Intra-cohort edges

A	B	Sources
MTHFR	TCN2	string_interaction
NF1	RNF213	string_interaction

Structural data

PDB: 9 · AlphaFold-only: 13 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SAMHD1	Q9Y3Z3	76
NF1	P21359	26
TCN2	P20062	11
LRP1	Q07954	7
RNF213	Q63HN8	4
BRCC3	P46736	4
MTHFR	P42898	4
HDAC9	Q9UKV0	2
MAGEA8	P43361	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACTA2	P62736	95.43
FADS2	O95864	95.39
FADS1	O60427	94.82
PLOD1	Q02809	93.04
SPTLC3	Q9NUV7	87.25
CARD14	Q9BXL6	75.89
SBF2	Q86WG5	73.74
HORMAD2	Q8N7B1	72.61
CTAGE1	Q96RT6	70.45
JAZF1	Q86VZ6	70.25
TSC22D2	O75157	48.04
PCNT	O95613
PKHD1	P08F94

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 98. Enrichment computed across 23 evidence-associated genes (15 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 15 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Linoleic acid (LA) metabolism	2	152.3×	0.007	FADS1, FADS2
alpha-linolenic acid (ALA) metabolism	2	95.2×	0.008	FADS1, FADS2
Metabolism of vitamins and cofactors	3	23.3×	0.008	TCN2, LRP1, MTHFR
Metabolism	6	4.7×	0.025	TCN2, SAMHD1, SPTLC3, SBF2, LRP1, MTHFR
Defective TCN2 causes TCN2 deficiency	1	761.3×	0.026	TCN2
Defective CD320 causes MMATC	1	380.7×	0.042	TCN2
Metabolism of water-soluble vitamins and cofactors	2	24.2×	0.042	TCN2, MTHFR
RAS signaling downstream of NF1 loss-of-function variants	1	108.8×	0.093	NF1
Suppression of apoptosis	1	108.8×	0.093	RNF213
Response of Mtb to phagocytosis	1	95.2×	0.093	RNF213
Transport of RCbl within the body	1	95.2×	0.093	TCN2
Nucleotide catabolism	1	84.6×	0.096	SAMHD1
Infection with Mycobacterium tuberculosis	1	76.1×	0.098	RNF213
Regulation of CDH1 Function	1	63.4×	0.110	ACTA2
Scavenging of heme from plasma	1	58.6×	0.111	LRP1
Defects in cobalamin (B12) metabolism	1	54.4×	0.112	TCN2
Cobalamin (Cbl, vitamin B12) transport and metabolism	1	42.3×	0.117	TCN2
Metabolism of folate and pterines	1	42.3×	0.117	MTHFR
Defects in vitamin and cofactor metabolism	1	40.1×	0.117	TCN2
NOTCH4 Intracellular Domain Regulates Transcription	1	38.1×	0.117	ACTA2
Binding and Uptake of Ligands by Scavenger Receptors	1	36.2×	0.117	LRP1
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	36.2×	0.117	ACTA2
Signaling by NOTCH4	1	33.1×	0.117	ACTA2
Chaperone Mediated Autophagy	1	33.1×	0.117	PCNT
Diseases of signal transduction by growth factor receptors and second messengers	2	7.6×	0.117	RNF213, NF1
DNA Double Strand Break Response	1	31.7×	0.117	BRCC3
Notch-HLH transcription pathway	1	27.2×	0.128	HDAC9
Metabolism of fat-soluble vitamins	1	25.4×	0.128	LRP1
Rab regulation of trafficking	1	24.6×	0.128	SBF2
PI Metabolism	1	23.8×	0.128	SBF2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 22 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of cell-matrix adhesion	2	117.8×	0.017	NF1, PKHD1
lipid metabolic process	4	16.6×	0.017	JAZF1, FADS1, FADS2, LRP1
arachidonate metabolite production involved in inflammatory response	1	766.0×	0.020	FADS2
positive regulation of mast cell apoptotic process	1	766.0×	0.020	NF1
regulation of glial cell differentiation	1	766.0×	0.020	NF1
sphingoid biosynthetic process	1	766.0×	0.020	SPTLC3
regulation of striated muscle cell differentiation	1	766.0×	0.020	HDAC9
positive regulation of hepatic stellate cell contraction	1	766.0×	0.020	ACTA2
observational learning	1	766.0×	0.020	NF1
lipid ubiquitination	1	766.0×	0.020	RNF213
positive regulation of cellular response to oxidative stress	1	766.0×	0.020	FADS2
regulation of cholangiocyte proliferation	1	766.0×	0.020	PKHD1
positive regulation of transcytosis	1	766.0×	0.020	LRP1
alpha-linolenic acid metabolic process	2	80.6×	0.020	FADS1, FADS2
linoleic acid metabolic process	2	63.8×	0.020	FADS1, FADS2
unsaturated fatty acid biosynthetic process	2	58.9×	0.020	FADS1, FADS2
regulation of ERK1 and ERK2 cascade	2	52.8×	0.020	NF1, PKHD1
long-chain fatty acid biosynthetic process	2	40.3×	0.020	FADS1, FADS2
response to hypoxia	3	13.1×	0.021	MTHFR, NF1, PLOD1
dGTP catabolic process	1	383.0×	0.026	SAMHD1
deoxyribonucleotide catabolic process	1	383.0×	0.026	SAMHD1
positive regulation of lipid transport	1	383.0×	0.026	LRP1
response to vitamin B2	1	383.0×	0.026	MTHFR
dATP catabolic process	1	383.0×	0.026	SAMHD1
gamma-aminobutyric acid secretion, neurotransmission	1	383.0×	0.026	NF1
positive regulation of hepatic stellate cell migration	1	383.0×	0.026	ACTA2
positive regulation of reverse cholesterol transport	1	383.0×	0.026	LRP1
Schwann cell proliferation	1	255.3×	0.028	NF1
forebrain astrocyte development	1	255.3×	0.028	NF1
Schwann cell migration	1	255.3×	0.028	NF1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 22

Druggability breadth: 9 of 23 evidence-associated genes (39%) 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
HDAC9	CELECOXIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HDAC9	28	4
RNF213	0	0
SAMHD1	0	0
PCNT	0	0
BRCC3	0	0
NF1	0	0
TCN2	0	0
ACTA2	0	0
SPTLC3	0	0
CARD14	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CELECOXIB	4	HDAC9
PHENYLBUTANOIC ACID	4	HDAC9
SODIUM PHENYLBUTYRATE	4	HDAC9
ROMIDEPSIN	4	HDAC9
BELINOSTAT	4	HDAC9
PANOBINOSTAT	4	HDAC9
VORINOSTAT	4	HDAC9
GIVINOSTAT	4	HDAC9
CURCUMIN	3	HDAC9
CAFFEIC ACID	3	HDAC9
PRACINOSTAT	3	HDAC9
TACEDINALINE	3	HDAC9
ENTINOSTAT	3	HDAC9
TUCIDINOSTAT	3	HDAC9
ABEXINOSTAT	3	HDAC9
EBSELEN	3	HDAC9
NANATINOSTAT	2	HDAC9
AR-42	2	HDAC9
CHLOROGENIC ACID	2	HDAC9
DACINOSTAT	2	HDAC9
FIMEPINOSTAT	2	HDAC9
QUISINOSTAT	2	HDAC9
DOMATINOSTAT	2	HDAC9
PYROXAMIDE	1	HDAC9
CUDC-101	1	HDAC9
R-306465	1	HDAC9
GAMMA-AMINOBUTYRIC ACID	1	HDAC9
TRICHOSTATIN	1	HDAC9

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 6.

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

Symbol	Assays	Type breakdown
HDAC9	1,625	Binding:1612, ADMET:8, Functional:4, Toxicity:1
FADS1	21	Binding:21
FADS2	11	Binding:11
SAMHD1	4	Binding:3, Functional:1
RNF213	1	Binding:1
BRCC3	1	Binding:1
SPTLC3	1	Binding:1
PLOD1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SAMHD1	3.1.5.B1
HDAC9	3.5.1.98	histone deacetylase
SPTLC3	2.3.1.50	serine C-palmitoyltransferase
FADS1	1.14.19.30	acyl-lipid (8-3)-desaturase
FADS2	1.14.19.3	acyl-CoA 6-desaturase
MTHFR	1.5.1.20, 1.5.1.53	methylenetetrahydrofolate reductase [NAD(P)H], methylenetetrahydrofolate reductase (NADPH)

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
HDAC9	1,625

Pharmacogenomics

Cohort genes with a PharmGKB record: 22; 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)
CELECOXIB	4	HDAC9
PHENYLBUTANOIC ACID	4	HDAC9
SODIUM PHENYLBUTYRATE	4	HDAC9
ROMIDEPSIN	4	HDAC9
BELINOSTAT	4	HDAC9
PANOBINOSTAT	4	HDAC9
VORINOSTAT	4	HDAC9
GIVINOSTAT	4	HDAC9
CURCUMIN	3	HDAC9
CAFFEIC ACID	3	HDAC9
PRACINOSTAT	3	HDAC9
TACEDINALINE	3	HDAC9
ENTINOSTAT	3	HDAC9
TUCIDINOSTAT	3	HDAC9
ABEXINOSTAT	3	HDAC9
EBSELEN	3	HDAC9
NANATINOSTAT	2	HDAC9
AR-42	2	HDAC9
CHLOROGENIC ACID	2	HDAC9
DACINOSTAT	2	HDAC9
FIMEPINOSTAT	2	HDAC9
QUISINOSTAT	2	HDAC9
DOMATINOSTAT	2	HDAC9
PYROXAMIDE	1	HDAC9
CUDC-101	1	HDAC9
R-306465	1	HDAC9
GAMMA-AMINOBUTYRIC ACID	1	HDAC9
TRICHOSTATIN	1	HDAC9

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	HDAC9
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	BRCC3, MTHFR
D	Druggable family + AlphaFold only, no drug	5	SPTLC3, SBF2, FADS1, FADS2, PKHD1
E	Difficult family or no structure, no drug	15	RNF213, SAMHD1, PCNT, NF1, TCN2, ACTA2, CARD14, CTAGE1, HORMAD2, JAZF1 (+5 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RNF213	1	—
SAMHD1	4	—
PCNT	0	—
BRCC3	1	—
NF1	0	—
TCN2	0	—
ACTA2	0	—
SPTLC3	1	—
CARD14	0	—
SBF2	0	—
CTAGE1	0	—
HORMAD2	0	—
JAZF1	0	—
TSC22D2	0	—
FADS1	21	—
FADS2	11	—
RNF213-AS1	0	—
LRP1	0	—
MAGEA8	0	—
MTHFR	0	—
PKHD1	0	—
PLOD1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 45.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	41
PHASE1	2
PHASE3	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04205578	PHASE3	UNKNOWN	NBP in Patients With Moyamoya Disease of High Risk for Ischemic Cerebrovascular Events
NCT03162588	PHASE1/PHASE2	COMPLETED	Multiple Burrhole Therapy With Erythropoietin for Unstable Moyamoya
NCT07065409	PHASE1	RECRUITING	Treatment of Moyamoya Disease With iPSC-derived Exosomes
NCT07286110	PHASE1	NOT_YET_RECRUITING	Chinese Herbal Therapy (Qiqi Shengmai Formula) for Moyamoya Vasculopathy: The CHIMES Trial
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT03546309	Not specified	RECRUITING	Safety and Efficacy of RIC in Pediatric Moyamoya Disease Patients Treated With Revascularization Therapy
NCT05332756	Not specified	RECRUITING	Long-term Outcomes of Conservative Management in Patients with Moyamoya Disease and Their First-degree Relatives (LAMORA)
NCT05491980	Not specified	ACTIVE_NOT_RECRUITING	Florida Cerebrovascular Disease Biorepository and Genomics Center
NCT05619068	Not specified	RECRUITING	The Evolution and Prognosis of Moyamoya Disease
NCT05961748	Not specified	RECRUITING	Registry of Multicenter Brain-Heart Comorbidity in China
NCT06041659	Not specified	RECRUITING	Functional Magnetic Resonance-Based Observations of Brain Networks in Moyamoya Disease Patients Under Anesthesia
NCT06051552	Not specified	NOT_YET_RECRUITING	Prognostic Prediction Model in Patients With Moyamoya Disease Undergoing Revascularization Surgery
NCT06330818	Not specified	RECRUITING	Imaging in Moyamoya Disease - Study to Investigate Different Imaging Technologies for a Better Understanding of Various Imaging Techniques to Evaluate Cerebral Hemodynamics, Disease-activity and Possibly the Etiology in Moyamoya Patients
NCT06477107	Not specified	ENROLLING_BY_INVITATION	A Study of Cerebral Perfusion With tDCS in Chronic Hypoperfusion
NCT06634004	Not specified	ENROLLING_BY_INVITATION	Biomarker-Led Optimization of Successful Surgical Outcomes in Moyamoya
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)
NCT06724029	Not specified	RECRUITING	Neurosurgical Outcome Network
NCT06817434	Not specified	RECRUITING	Study on Evaluating the Effectiveness of Statins in the Treatment of Moyamoya Disease
NCT06832839	Not specified	RECRUITING	Study on the Mechanism of Cognitive Impairment in Patients with Moyamoya Disease
NCT07140731	Not specified	RECRUITING	The Symani Restore Study
NCT07144930	Not specified	RECRUITING	Cognitive-Motor Incorporated Training and Its Relations in Cerebrovascular Diseases With Cognitive and Motor Impairments
NCT07304947	Not specified	RECRUITING	Cardiac Index-Guided Intraoperative Hemodynamic Management in Pediatric Moyamoya Surgery
NCT07377695	Not specified	RECRUITING	Remimazolam Consumption: TCI vs. Manual Infusion
NCT07517354	Not specified	RECRUITING	Family-Based Moyamoya Susceptibility and Early Detection
NCT01419275	Not specified	COMPLETED	Quantifying Collateral Perfusion in Cerebrovascular Disease-Moyamoya Disease and Stroke Patients
NCT02074111	Not specified	UNKNOWN	Moyamoya Disease Biomarkers in Patients With Intracranial Atherosclerotic Stroke
NCT02305407	Not specified	UNKNOWN	Neurocognitive and Radiological Assessments in Adult Moyamoya Undergoing Surgery
NCT02510586	Not specified	UNKNOWN	Sevoflurane and Hyperperfusion Syndrome
NCT02982135	Not specified	UNKNOWN	Direct Bypass Versus Indirect Bypass in Treatment of Adults Hemorrhagic Moyamoya Disease
NCT03072914	Not specified	COMPLETED	Effects of Remote Ischemic Preconditioning With Postconditioning on Neurologic Outcome
NCT03516851	Not specified	WITHDRAWN	Precision Bypass in Patients With Moyamoya Disease
NCT03543748	Not specified	UNKNOWN	Efficacy and Safety of rTMS for Cognitive Rehabilitation in Moyamoya Disease
NCT03613701	Not specified	UNKNOWN	Relationship Between Endothelial Progenitor Cells and Revascularization Effect of Moyamoya Disease
NCT03627975	Not specified	UNKNOWN	Effect of Surgical Revascularization on Hemorrhagic Moyamoya Disease
NCT03785171	Not specified	UNKNOWN	Predicative Value of Multimodal MRI in Moyamoya Disease
NCT03821181	Not specified	UNKNOWN	The Effect of RIC on TIA/Stroke in Children With Moyamoya Disease
NCT03882060	Not specified	UNKNOWN	Effect of Recombinant Human EPO on the Postoperative Neurologic Outcome in Pediatric Moyamoya Patients
NCT04012268	Not specified	COMPLETED	The Safety and Efficacy of RIC on Adult Moyamoya Disease
NCT04064658	Not specified	SUSPENDED	Effects of Remote Ischemic Pre-Conditioning in Moyamoya Disease Patients
NCT04696094	Not specified	UNKNOWN	The Role of m6A RNA Modification in Moyamoya Disease

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SODIUM CHLORIDE	4	1
RAC-3-N-BUTYLPHTHALIDE	3	1

Cohort genes: RNF213, SAMHD1, PCNT, BRCC3, NF1, TCN2, ACTA2, HDAC9, SPTLC3, CARD14, SBF2, CTAGE1, HORMAD2, JAZF1, TSC22D2, FADS1, FADS2, RNF213-AS1, LRP1, MAGEA8, MTHFR, PKHD1, PLOD1
Drugs: Sodium Chloride, RAC-3-N-BUTYLPHTHALIDE