Migraine, familial hemiplegic, 1

Summary

Migraine, familial hemiplegic, 1 (MONDO:0020756) is a disease caused by CACNA1A (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: CACNA1A (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 186

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	migraine, familial hemiplegic, 1
Mondo ID	MONDO:0020756
MeSH	C536890
OMIM	141500
DOID	DOID:0111181
ICD-11	1583236457
UMLS	C1832884
MedGen	331388
GARD	0002638
Is cancer (heuristic)	no

Also known as: familial hemiplegic migraine type 1 · FHM1 · hemiplegic migraine, familial type 1 · MHP1 · migraine, familial hemiplegic 1, with progressive cerebellar ataxia · migraine, familial hemiplegic, 1 · migraine, familial hemiplegic, 1, with progressive cerebellar ataxia · migraine, familial hemiplegic, type 1 · migraine, sporadic hemiplegic

Data availability: 186 ClinVar variants · 3 GenCC gene-disease records.

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 with aura › familial or sporadic hemiplegic migraine › familial hemiplegic migraine › migraine, familial hemiplegic, 1

Related subtypes (4): migraine, familial hemiplegic, 2, migraine, familial hemiplegic, 3, hemiplegic migraine-developmental and epileptic encephalopathy spectrum, migraine, familial hemiplegic, 4

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

186 retrieved; paginated sample, class counts are floors:

40 uncertain significance, 35 conflicting classifications of pathogenicity, 25 pathogenic/likely pathogenic, 21 benign, 20 pathogenic, 16 benign/likely benign, 15 likely pathogenic, 10 not provided, 4 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1338921	NM_001127222.2(CACNA1A):c.5335C>T (p.Arg1779Ter)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1398258	NM_001127222.2(CACNA1A):c.841del (p.Cys281fs)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1421109	NM_001127222.2(CACNA1A):c.5422G>A (p.Val1808Ile)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1441063	NM_001127222.2(CACNA1A):c.2311A>T (p.Lys771Ter)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1679523	NM_001127222.2(CACNA1A):c.4519G>A (p.Ala1507Thr)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1679524	NM_001127222.2(CACNA1A):c.4031T>C (p.Leu1344Pro)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1679527	NM_001127222.2(CACNA1A):c.2137G>A (p.Val713Met)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1679533	NM_001127222.2(CACNA1A):c.5015dup (p.Gln1673fs)	CACNA1A	Pathogenic	criteria provided, single submitter
1707523	NM_001127222.2(CACNA1A):c.3990-2A>C	CACNA1A	Pathogenic	criteria provided, single submitter
195935	NM_001127222.2(CACNA1A):c.4174G>A (p.Val1392Met)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2079579	NM_001127222.2(CACNA1A):c.4089+1G>A	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2502284	NM_001127222.2(CACNA1A):c.1237C>T (p.Gln413Ter)	CACNA1A	Pathogenic	criteria provided, single submitter
254268	NM_001127222.2(CACNA1A):c.2134G>A (p.Ala712Thr)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
279951	NM_001127222.2(CACNA1A):c.4494CTT[2] (p.Phe1501del)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
380972	NM_001127222.2(CACNA1A):c.4043G>A (p.Arg1348Gln)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
420055	NM_001127222.2(CACNA1A):c.5393C>T (p.Ser1798Leu)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
420945	NM_001127222.2(CACNA1A):c.4055C>T (p.Pro1352Leu)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
422063	NM_001127222.2(CACNA1A):c.4927G>A (p.Asp1643Asn)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
449943	NM_001127222.2(CACNA1A):c.4897G>A (p.Asp1633Asn)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
450171	NM_001127222.2(CACNA1A):c.2133C>G (p.Ile711Met)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
453193	NM_001127222.2(CACNA1A):c.6397C>T (p.Arg2133Ter)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
476244	NM_001127222.2(CACNA1A):c.2904_2929del (p.Pro969fs)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
545691	NM_001127222.2(CACNA1A):c.835C>T (p.Arg279Cys)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
585567	NM_001127222.2(CACNA1A):c.3692+1G>A	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
638582	NM_001127222.2(CACNA1A):c.4997G>C (p.Arg1666Pro)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
68432	NM_001127222.2(CACNA1A):c.4988G>A (p.Arg1663Gln)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
68433	NM_001127222.2(CACNA1A):c.4996C>T (p.Arg1666Trp)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
68439	NM_001127222.2(CACNA1A):c.584G>A (p.Arg195Lys)	CACNA1A	Pathogenic	criteria provided, single submitter
835237	NM_001127222.2(CACNA1A):c.1635C>A (p.Tyr545Ter)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
837522	NM_001127222.2(CACNA1A):c.1647del (p.Phe550fs)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 23 · Orphanet: 9 · 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
CACNA1A	Strong	Autosomal dominant	migraine, familial hemiplegic, 1	23

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CACNA1A	Orphanet:2131	Alternating hemiplegia of childhood
CACNA1A	Orphanet:2382	Lennox-Gastaut syndrome
CACNA1A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
CACNA1A	Orphanet:569	Familial or sporadic hemiplegic migraine
CACNA1A	Orphanet:71518	Benign paroxysmal torticollis of infancy
CACNA1A	Orphanet:97	Familial paroxysmal ataxia
CACNA1A	Orphanet:98758	Spinocerebellar ataxia type 6
WDR45	Orphanet:329284	Beta-propeller protein-associated neurodegeneration
WDR45	Orphanet:697160	Infantile epileptic spasms syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CACNA1A	HGNC:1388	ENSG00000141837	O00555	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	gencc,clinvar
WDR45	HGNC:28912	ENSG00000196998	Q9Y484	WD repeat domain phosphoinositide-interacting protein 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CACNA1A	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp…
WDR45	WD repeat domain phosphoinositide-interacting protein 4	Component of the autophagy machinery that controls the major intracellular degradation process by which cytoplasmic materials are packaged into autophagosomes and delivered to lysosomes for degradation.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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
Ion channel	1	55.8×	0.036
Scaffold/PPI	1	8.6×	0.112

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CACNA1A	Ion channel	yes		VDCCAlpha1, CACNA1A, Ion_trans_dom
WDR45	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf

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
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
apex of heart	1
granulocyte	1
mucosa of stomach	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CACNA1A	237	broad	marker	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex
WDR45	293	ubiquitous	marker	apex of heart, mucosa of stomach, granulocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WDR45	1,233
CACNA1A	346

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CACNA1A	O00555	4
WDR45	Q9Y484	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Presynaptic depolarization and calcium channel opening	1	475.8×	0.015	CACNA1A
Regulation of insulin secretion	1	109.8×	0.026	CACNA1A
Integration of energy metabolism	1	87.8×	0.026	CACNA1A
Macroautophagy	1	57.7×	0.030	WDR45
Transmission across Chemical Synapses	1	38.1×	0.037	CACNA1A
Neuronal System	1	22.1×	0.052	CACNA1A
Metabolism	1	5.8×	0.165	CACNA1A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
nucleophagy	1	1685.2×	0.006	WDR45
glycophagy	1	702.2×	0.006	WDR45
pexophagy	1	526.6×	0.006	WDR45
protein localization to phagophore assembly site	1	495.6×	0.006	WDR45
response to amyloid-beta	1	495.6×	0.006	CACNA1A
positive regulation of autophagosome assembly	1	401.2×	0.006	WDR45
autophagy of mitochondrion	1	366.4×	0.006	WDR45
calcium ion import across plasma membrane	1	271.8×	0.007	CACNA1A
cellular response to amyloid-beta	1	195.9×	0.009	CACNA1A
autophagosome assembly	1	112.3×	0.013	WDR45
calcium ion transmembrane transport	1	105.3×	0.013	CACNA1A
cellular response to starvation	1	96.8×	0.013	WDR45
modulation of chemical synaptic transmission	1	91.6×	0.013	CACNA1A
positive regulation of cytosolic calcium ion concentration	1	58.5×	0.019	CACNA1A
autophagy	1	55.1×	0.019	WDR45
chemical synaptic transmission	1	38.6×	0.026	CACNA1A

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
CACNA1A	NIMODIPINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA1A	2	4
WDR45	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIMODIPINE	4	CACNA1A
TACRINE	4	CACNA1A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CACNA1A	19	Binding:18, Functional:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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)
NIMODIPINE	4	CACNA1A
TACRINE	4	CACNA1A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CACNA1A
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	1	WDR45

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
WDR45	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.