Migraine with or without aura, susceptibility to, 1

Summary

Migraine with or without aura, susceptibility to, 1 (MONDO:0008000) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 14

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	migraine with or without aura, susceptibility to, 1
Mondo ID	MONDO:0008000
OMIM	157300
SNOMED CT	37796009
UMLS	C3887485
MedGen	854348
Is cancer (heuristic)	no

Also known as: migraine with or without aura, susceptibility to, 1 · migraine with or without aura, susceptibility to, type 1 · migraine without aura, susceptibility to · migraine, resistance to · migraine, susceptibility to

Data availability: 14 ClinVar variants.

Disease family

Classification path: disease susceptibility › inherited disease susceptibility › migraine with or without aura, susceptibility to › migraine with or without aura, susceptibility to, 1

Related subtypes (12): migraine, familial typical, susceptibility to, 2, migraine with or without aura, susceptibility to, 3, migraine without aura, susceptibility to, 4, migraine with or without aura, susceptibility to, 5, migraine with or without aura, susceptibility to, 6, migraine with aura, susceptibility to, 7, migraine with or without aura, susceptibility to, 8, migraine with aura, susceptibility to, 9, migraine with or without aura, susceptibility to, 10, migraine with or without aura, susceptibility to, 11, migraine with or without aura, susceptibility to, 12, migraine, with or without aura, susceptibility to, 13

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

14 retrieved; paginated sample, class counts are floors:

5 benign/likely benign, 5 uncertain significance, 2 benign, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3893037	NM_001957.4(EDNRA):c.742A>C (p.Met248Leu)	EDNRA	Uncertain significance	criteria provided, single submitter
3891414	NM_000125.4(ESR1):c.433G>A (p.Gly145Ser)	ESR1	Uncertain significance	criteria provided, single submitter
3891418	NM_000125.4(ESR1):c.804G>C (p.Lys268Asn)	ESR1	Uncertain significance	criteria provided, single submitter
1697317	NM_000594.4(TNF):c.17T>A (p.Met6Lys)	TNF	Uncertain significance	criteria provided, single submitter
3892678	NM_000594.4(TNF):c.248C>A (p.Thr83Asn)	TNF	Uncertain significance	criteria provided, single submitter
1166335	NM_001957.4(EDNRA):c.24A>G (p.Ala8=)	EDNRA	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1256683	NM_001957.4(EDNRA):c.748-19_748-18insCT	EDNRA	Benign	criteria provided, multiple submitters, no conflicts
1654745	NM_001957.4(EDNRA):c.1034+19G>A	EDNRA	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
711201	NM_001957.4(EDNRA):c.1146A>G (p.Ser382=)	EDNRA	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
721740	NM_001957.4(EDNRA):c.354G>A (p.Leu118=)	EDNRA	Likely benign	criteria provided, multiple submitters, no conflicts
723006	NM_001957.4(EDNRA):c.549-10T>C	EDNRA	Likely benign	criteria provided, multiple submitters, no conflicts
745811	NM_001957.4(EDNRA):c.1110T>C (p.Tyr370=)	EDNRA	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1250979	NM_000125.4(ESR1):c.30T>C (p.Ser10=)	ESR1	Benign	criteria provided, multiple submitters, no conflicts
1263746	NM_000125.4(ESR1):c.1782G>A (p.Thr594=)	ESR1	Benign/Likely benign	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
EDNRA	Orphanet:443995	Mandibulofacial dysostosis with alopecia
EDNRA	Orphanet:586	Cystic fibrosis
ESR1	Orphanet:785	Estrogen resistance syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TNF	HGNC:11892	ENSG00000232810	P01375	Tumor necrosis factor	clinvar
EDNRA	HGNC:3179	ENSG00000151617	P25101	Endothelin-1 receptor	clinvar
ESR1	HGNC:3467	ENSG00000091831	P03372	Estrogen receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TNF	Tumor necrosis factor	Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR.
EDNRA	Endothelin-1 receptor	Receptor for endothelin-1.
ESR1	Estrogen receptor	Nuclear hormone receptor.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
Nuclear receptor	1	128.6×	0.023
GPCR	1	8.0×	0.180
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TNF	Other/Unknown	no		TNF_alpha, TNF_dom, TNF
EDNRA	GPCR	yes		GPCR_Rhodpsn, Endthln_rcpt, ETA_rcpt
ESR1	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Estr_rcpt, Znf_hrmn_rcpt

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bone marrow	1
granulocyte	1
male germ line stem cell (sensu Vertebrata) in testis	1
cauda epididymis	1
seminal vesicle	1
visceral pleura	1
cervix epithelium	1
mammalian vulva	1
oviduct epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TNF	119	broad	marker	granulocyte, male germ line stem cell (sensu Vertebrata) in testis, bone marrow
EDNRA	253	ubiquitous	marker	cauda epididymis, seminal vesicle, visceral pleura
ESR1	216	broad	marker	oviduct epithelium, cervix epithelium, mammalian vulva

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ESR1	12,382
TNF	11,116
EDNRA	2,013

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ESR1	P03372	478
TNF	P01375	52
EDNRA	P25101	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TNFR1-mediated ceramide production	1	634.4×	0.015	TNF
RUNX1 regulates estrogen receptor mediated transcription	1	634.4×	0.015	ESR1
RUNX1 regulates transcription of genes involved in WNT signaling	1	634.4×	0.015	ESR1
Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)	1	292.8×	0.020	TNF
TFAP2 (AP-2) family regulates transcription of growth factors and their receptors	1	253.8×	0.020	ESR1
Developmental Lineage of Mammary Gland Alveolar Cells	1	211.5×	0.020	ESR1
Mitochondrial unfolded protein response (UPRmt)	1	200.3×	0.020	ESR1
Developmental Lineage of Mammary Gland Luminal Epithelial Cells	1	152.3×	0.020	ESR1
TNFR1-induced proapoptotic signaling	1	146.4×	0.020	TNF
TNF signaling	1	141.0×	0.020	TNF
Nuclear signaling by ERBB4	1	115.3×	0.020	ESR1
SUMOylation of intracellular receptors	1	112.0×	0.020	ESR1
TNFR1-induced NF-kappa-B signaling pathway	1	112.0×	0.020	TNF
Ovarian tumor domain proteases	1	92.8×	0.022	ESR1
Interleukin-10 signaling	1	77.7×	0.024	TNF
Regulation of TNFR1 signaling	1	74.6×	0.024	TNF
Nuclear Receptor transcription pathway	1	66.8×	0.025	ESR1
TNFR2 non-canonical NF-kB pathway	1	60.4×	0.025	TNF
Regulation of RUNX2 expression and activity	1	60.4×	0.025	ESR1
Extra-nuclear estrogen signaling	1	56.8×	0.025	ESR1
Transcriptional regulation of white adipocyte differentiation	1	43.3×	0.030	TNF
ESR-mediated signaling	1	42.8×	0.030	ESR1
Constitutive Signaling by Aberrant PI3K in Cancer	1	42.3×	0.030	ESR1
Interleukin-4 and Interleukin-13 signaling	1	34.3×	0.035	TNF
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	32.3×	0.036	ESR1
Estrogen-dependent gene expression	1	25.2×	0.043	ESR1
Peptide ligand-binding receptors	1	24.7×	0.043	EDNRA
PIP3 activates AKT signaling	1	22.3×	0.046	ESR1
G alpha (q) signalling events	1	19.1×	0.051	EDNRA

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
cellular response to toxic substance	2	936.2×	4e-04	TNF, EDNRA
negative regulation of miRNA transcription	2	416.1×	1e-03	TNF, ESR1
response to amphetamine	2	330.4×	1e-03	TNF, EDNRA
positive regulation of nitric oxide biosynthetic process	2	303.6×	1e-03	TNF, ESR1
positive regulation of translational initiation by iron	1	5617.3×	0.003	TNF
negative regulation of branching involved in lung morphogenesis	1	5617.3×	0.003	TNF
negative regulation of bile acid secretion	1	5617.3×	0.003	TNF
response to Gram-negative bacterium	1	5617.3×	0.003	TNF
positive regulation of interleukin-33 production	1	5617.3×	0.003	TNF
regulation of epithelial cell apoptotic process	1	5617.3×	0.003	ESR1
response to 3,3’,5-triiodo-L-thyronine	1	5617.3×	0.003	TNF
regulation of protein localization to cell leading edge	1	5617.3×	0.003	EDNRA
negative regulation of L-glutamate import across plasma membrane	1	2808.7×	0.003	TNF
chronic inflammatory response to antigenic stimulus	1	2808.7×	0.003	TNF
positive regulation of chronic inflammatory response to antigenic stimulus	1	2808.7×	0.003	TNF
positive regulation of fractalkine production	1	2808.7×	0.003	TNF
cellular response to human chorionic gonadotropin stimulus	1	2808.7×	0.003	EDNRA
positive regulation of protein transport	1	2808.7×	0.003	TNF
positive regulation of vitamin D biosynthetic process	1	2808.7×	0.003	TNF
podocyte apoptotic process	1	2808.7×	0.003	EDNRA
response to hydrogen sulfide	1	2808.7×	0.003	TNF
response to quercetin	1	2808.7×	0.003	TNF
response to gold nanoparticle	1	2808.7×	0.003	TNF
positive regulation of blood microparticle formation	1	2808.7×	0.003	TNF
regulation of endothelial cell apoptotic process	1	2808.7×	0.003	TNF
negative regulation of canonical NF-kappaB signal transduction	2	114.6×	0.003	TNF, ESR1
phospholipase C-activating G protein-coupled receptor signaling pathway	2	87.8×	0.003	EDNRA, ESR1
positive regulation of cytosolic calcium ion concentration	2	78.0×	0.003	EDNRA, ESR1
response to hypoxia	2	63.8×	0.003	TNF, EDNRA
cardiac chamber formation	1	1872.4×	0.004	EDNRA

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 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
TNF	PREDNISOLONE
EDNRA	AMBRISENTAN
ESR1	CANDESARTAN CILEXETIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ESR1	162	4
EDNRA	31	4
TNF	12	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PREDNISOLONE	4	TNF
POMALIDOMIDE	4	TNF
PENTOXIFYLLINE	4	TNF
MESALAMINE	4	TNF
LENALIDOMIDE	4	TNF
AMBRISENTAN	4	EDNRA
GRAMICIDIN	4	EDNRA
NITAZOXANIDE	4	EDNRA
IRBESARTAN	4	EDNRA
ACYCLOVIR	4	EDNRA
MACITENTAN	4	EDNRA
APROCITENTAN	4	EDNRA
SITAXENTAN	4	EDNRA
FLUOXETINE	4	EDNRA
SULFATHIAZOLE	4	EDNRA
SULFISOXAZOLE	4	EDNRA
SUNITINIB	4	EDNRA
SPARSENTAN	4	EDNRA
PIOGLITAZONE	4	EDNRA
MELOXICAM	4	EDNRA
AMIODARONE	4	EDNRA
ENOXACIN	4	EDNRA
BOSENTAN	4	EDNRA
CANDESARTAN CILEXETIL	4	ESR1
DIENESTROL	4	ESR1
BEXAROTENE	4	ESR1
VARENICLINE	4	ESR1
ACETOPHENAZINE	4	ESR1
ARIPIPRAZOLE	4	ESR1
RALOXIFENE HYDROCHLORIDE	4	ESR1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ESR1	2,435	Binding:2037, Functional:363, ADMET:35
EDNRA	418	Binding:342, Functional:73, Toxicity:2, ADMET:1
TNF	193	Binding:162, Functional:31

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TNF	193
EDNRA	418
ESR1	2,435

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

30 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)
PREDNISOLONE	4	TNF
POMALIDOMIDE	4	TNF
PENTOXIFYLLINE	4	TNF
MESALAMINE	4	TNF
LENALIDOMIDE	4	TNF
AMBRISENTAN	4	EDNRA
GRAMICIDIN	4	EDNRA
NITAZOXANIDE	4	EDNRA
IRBESARTAN	4	EDNRA
ACYCLOVIR	4	EDNRA
MACITENTAN	4	EDNRA
APROCITENTAN	4	EDNRA
SITAXENTAN	4	EDNRA
FLUOXETINE	4	EDNRA
SULFATHIAZOLE	4	EDNRA
SULFISOXAZOLE	4	EDNRA
SUNITINIB	4	EDNRA
SPARSENTAN	4	EDNRA
PIOGLITAZONE	4	EDNRA
MELOXICAM	4	EDNRA
AMIODARONE	4	EDNRA
ENOXACIN	4	EDNRA
BOSENTAN	4	EDNRA
CANDESARTAN CILEXETIL	4	ESR1
DIENESTROL	4	ESR1
BEXAROTENE	4	ESR1
VARENICLINE	4	ESR1
ACETOPHENAZINE	4	ESR1
ARIPIPRAZOLE	4	ESR1
RALOXIFENE HYDROCHLORIDE	4	ESR1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	TNF, EDNRA, ESR1
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.