Migraine without aura

Summary

Migraine without aura (MONDO:0100431) is a disease with 1 cohort gene (3 GWAS associations across 1 studies) and 94 clinical trials. Top therapeutic interventions include dihydroergotamine, sumatriptan, and propranolol.

At a glance

• Cohort genes: 1
• GWAS associations: 3
• ClinVar variants: 1
• Clinical trials: 94

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	migraine without aura
Mondo ID	MONDO:0100431
MeSH	D020326
DOID	DOID:12783
ICD-10-CM	G43.0
ICD-11	2048783472
NCIT	C117004
SNOMED CT	56097005
UMLS	C0338480
MedGen	137899
Is cancer (heuristic)	no

Also known as: common migraine

Data availability: 1 ClinVar variant · 3 GWAS associations (1 study).

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › migraine disorder › migraine without aura

Related subtypes (1): migraine with aura

Genetics & variants

GWAS landscape

3 GWAS associations across 1 studies. Top hits map to 3 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs11172113	1e-19	LRP1	?	0.03
rs9486725	5e-15	FHL5	?	0.03
rs9349379	1e-12	PHACTR1	?	0.03

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90103793	Daghals I	2022	8,348	154,038	Migraine, Stroke, and Cervical Arterial Dissection: Shared Genetics for a Triad of Brain Disorders With Vascular Involvement.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	3

MAF distribution

Bucket	Variants
common (>=0.05)	3
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	3

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs11172113	12	57133500	T>C,G	0.05	intron_variant	LRP1	1e-19	Tier 4: intronic/intergenic
rs9486725	6	96613283	C>G,T	0.05	intron_variant	FHL5	5e-15	Tier 4: intronic/intergenic
rs9349379	6	12903725	A>C,G,T	0.05	intron_variant	PHACTR1	1e-12	Tier 4: intronic/intergenic

ClinVar germline variants

1 retrieved; paginated sample, class counts are floors:

1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
9219	NM_000435.3(NOTCH3):c.505C>T (p.Arg169Cys)	NOTCH3	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NOTCH3	Orphanet:136	Cerebral autosomal dominant arteriopathy-subcortical infarcts-leukoencephalopathy
NOTCH3	Orphanet:2591	Infantile myofibromatosis
NOTCH3	Orphanet:2789	Lateral meningocele syndrome

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
NOTCH3	HGNC:7883	ENSG00000074181	Q9UM47	Neurogenic locus notch homolog protein 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NOTCH3	Neurogenic locus notch homolog protein 3	Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Scaffold/PPI	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NOTCH3	Scaffold/PPI	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom

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
popliteal artery	1
right coronary artery	1
tibial artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NOTCH3	273	ubiquitous	marker	popliteal artery, tibial artery, right coronary artery

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NOTCH3	4,403

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NOTCH3	Q9UM47	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
Defective LFNG causes SCDO3	1	2284.0×	0.002	NOTCH3
Pre-NOTCH Processing in the Endoplasmic Reticulum	1	1903.3×	0.002	NOTCH3
Noncanonical activation of NOTCH3	1	1427.5×	0.002	NOTCH3
Pre-NOTCH Processing in Golgi	1	634.4×	0.003	NOTCH3
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	475.8×	0.003	NOTCH3
NOTCH3 Intracellular Domain Regulates Transcription	1	439.2×	0.003	NOTCH3
Notch-HLH transcription pathway	1	407.9×	0.003	NOTCH3
Pre-NOTCH Transcription and Translation	1	122.8×	0.008	NOTCH3

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
glomerular capillary formation	1	5617.3×	0.002	NOTCH3
neuroblast differentiation	1	2106.5×	0.003	NOTCH3
neuron fate commitment	1	802.5×	0.004	NOTCH3
artery morphogenesis	1	674.1×	0.004	NOTCH3
forebrain development	1	351.1×	0.006	NOTCH3
positive regulation of smooth muscle cell proliferation	1	330.4×	0.006	NOTCH3
positive regulation of miRNA transcription	1	290.6×	0.006	NOTCH3
negative regulation of neuron differentiation	1	271.8×	0.006	NOTCH3
Notch signaling pathway	1	141.6×	0.009	NOTCH3
axon guidance	1	90.6×	0.013	NOTCH3
negative regulation of transcription by RNA polymerase II	1	17.7×	0.062	NOTCH3
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	NOTCH3

Therapeutics

Drugs indicated for this disease

0 approved, 7 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Anisodine Hydrobromide	Phase 3 (in late-stage trials)
Caffeine	Phase 3 (in late-stage trials)
Dihydroergotamine	Phase 3 (in late-stage trials)
Eletriptan	Phase 3 (in late-stage trials)
Promethazine	Phase 3 (in late-stage trials)
Rizatriptan	Phase 3 (in late-stage trials)
Sumatriptan	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Candesartan, Dronabinol, Propranolol, Ramelteon.

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · 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).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NOTCH3	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VAREGACESTAT	2	NOTCH3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NOTCH3	3	Binding:3

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

1 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)
VAREGACESTAT	2	NOTCH3

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	1	NOTCH3
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: 94.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	61
PHASE3	13
PHASE4	8
PHASE2	8
PHASE1	3
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00210496	PHASE4	COMPLETED	Potential Impact (Benefit) of Preventative Treatment With Topamax on the Effectiveness of Axert in the Acute Treatment of Migraine
NCT00212810	PHASE4	COMPLETED	Evaluation of the Effectiveness of Topiramate in Preventing the Transformation From Episodic Migraine to Chronic Daily Headache.
NCT01319825	PHASE4	UNKNOWN	Preventive Treatment of Episodic and Chronic Migraine
NCT01596166	PHASE4	COMPLETED	Intravenous Ketorolac and Metoclopramide for Pediatric Migraine in the Emergency Department
NCT04533568	PHASE4	COMPLETED	Ibuprofen in Migraine Patients
NCT05211154	PHASE4	TERMINATED	Evaluation of the Efficacy of Diclofenac Potassium and Rimegepant for the Acute Treatment of Migraine
NCT05214001	PHASE4	TERMINATED	Evaluation of the Efficacy of Almotriptan and Ubrogepant for the Acute Treatment of Migraine
NCT06244823	PHASE4	UNKNOWN	The FreMRI Study: Advanced MRI on Migraine Patients Treated With Fremanezumab
NCT05484349	PHASE3	RECRUITING	TIzanidine for the Preventive Treatment of Episodic MigrainE （TIME）
NCT00231595	PHASE3	COMPLETED	A Study of the Efficacy and Safety of Topiramate in the Prevention of Migraine
NCT00236509	PHASE3	COMPLETED	A Study of the Efficacy and Safety of Topiramate in the Prevention of Migraine
NCT00236561	PHASE3	COMPLETED	A Study of the Efficacy and Safety of Two Doses of Topiramate Compared to Placebo and Propranolol in the Prevention of Migraine
NCT00334178	PHASE3	COMPLETED	Evaluation of the Efficacy and Safety of Laxymig® as Prophylactic Treatment in Patients With Migraine
NCT00471952	PHASE3	COMPLETED	Maxalt 10mg Plus Caffeine 75mg in the Acute Treatment of Migraine Headache
NCT00884663	PHASE2/PHASE3	COMPLETED	Candesartan Versus Propranolol for Migraine Prevention
NCT01814189	PHASE3	COMPLETED	Efficacy and Safety of Oral Sumatriptan Plus Oral Promethazine in Migraine Treatment
NCT01859481	PHASE3	COMPLETED	Eletriptan Provides Consistent Migraine Relief: Results Of A Within-Patient Multiple-Dose Study
NCT03901482	PHASE3	COMPLETED	A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate STS101 in the Acute Treatment of Migraine
NCT04406649	PHASE3	COMPLETED	A Study to Evaluate the Safety of STS101 in the Acute Treatment of Migraine
NCT04726592	PHASE3	TERMINATED	Efficacy of CLORazepate for the Treatment of MIGraine Attack in the Emergency Room
NCT04940390	PHASE3	COMPLETED	A Randomized, Double-Blind, Parallel Group, Placebo-Controlled Study to Assess STS101 in the Acute Treatment of Migraine
NCT05416476	PHASE3	UNKNOWN	Anisodine Hydrobromide For The Preventive Treatment Of Episodic Migraine
NCT00123201	PHASE2	COMPLETED	Study to Evaluate the Efficacy and Safety of Dronabinol Metered Dose Inhaler (MDI) in Acute Treatment of Migraine Headache
NCT00285402	PHASE2	UNKNOWN	Efficacy and Safety Clinical Trial of Intranasal AST-726 for the Prevention of Migraine
NCT00311662	PHASE2	COMPLETED	Efficacy and Tolerability of Tonabersat in the Prophylaxis of Migraine Headache
NCT00534560	PHASE2	COMPLETED	Dose Ranging Study of the Efficacy and Tolerability of Tonabersat in the Prophylaxis of Migraine Headache
NCT00739024	PHASE2	TERMINATED	A Study of a Melatonin Receptor Agonist to Prevent Migraine
NCT00959751	PHASE2	COMPLETED	Study of the Safety and Effectiveness of NXN-188 for the Treatment of Migraine Headache Without Aura
NCT03472378	PHASE2	COMPLETED	Can DFN-15 Terminate Migraine With Allodynia?
NCT05679908	PHASE2	COMPLETED	A Study to Evaluate the Efficacy and Safety of TNX-1900 in Patients With Chronic Migraine
NCT07068815	PHASE1	NOT_YET_RECRUITING	Efficacy and Mechanism of Fu’s Subcutaneous Needling Treatment for Migraine Without Aura
NCT03874832	PHASE1	COMPLETED	A Phase I Study to Study the PK and Safety of Single Doses of STS101, DHE Injection and Nasal Spray in Healthy Subjects
NCT05337254	PHASE1	COMPLETED	A Study of the PK and Safety of Single Doses of STS101, DHE Injection and Nasal Spray in Healthy Subjects
NCT04715685	Not specified	RECRUITING	Mind Body Balance for Pediatric Migraine
NCT05889624	Not specified	RECRUITING	Responding With Evidence and Access for Childhood Headaches
NCT05903027	Not specified	RECRUITING	Gepant treAtments: EffectIveNess and tolERability (GAINER)
NCT06409832	Not specified	RECRUITING	RimegepAnt effectIvenesS and tolErability as Migraine Preventive Treatment
NCT06409845	Not specified	RECRUITING	Effectiveness and Tolerability of Eptinezumab
NCT06414044	Not specified	ACTIVE_NOT_RECRUITING	Italian Real-life obServational Study on the effecTiveness, sAfety and Tolerability of Atogepant in Migraine Patients
NCT06459635	Not specified	RECRUITING	Migraine Attack Pain Phase Prediction Study

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DIHYDROERGOTAMINE	4	15
SUMATRIPTAN	4	7
PROPRANOLOL	4	6
TOPIRAMATE	4	4
AMITRIPTYLINE	4	3
ERENUMAB	4	2
KETOPROFEN	4	2
METOCLOPRAMIDE	4	2
RIMEGEPANT	4	2
TIZANIDINE	4	2
ATOGEPANT	4	1
CLORAZEPATE DIPOTASSIUM	4	1
DEXKETOPROFEN	4	1
DICLOFENAC	4	1
ELETRIPTAN HYDROBROMIDE	4	1
FERUMOXYTOL	4	1
FREMANEZUMAB	4	1
GALCANEZUMAB	4	1
IVABRADINE	4	1
KETOROLAC TROMETHAMINE	4	1
LASMIDITAN	4	1
MILNACIPRAN	4	1
NITROGLYCERIN	4	1
RAMELTEON	4	1
ANISODINE HYDROBROMIDE	3	1
CANDESARTAN	3	1
VASOACTIVE INTESTINAL PEPTIDE	3	1
LEVCROMAKALIM	2	4
DEXPROPRANOLOL	2	2
TONABERSAT	2	2