Migraine, familial hemiplegic, 3

Summary

Migraine, familial hemiplegic, 3 (MONDO:0012320) is a disease caused by SCN1A (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: SCN1A (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 216

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	migraine, familial hemiplegic, 3
Mondo ID	MONDO:0012320
MeSH	C566500
OMIM	609634
DOID	DOID:0111183
UMLS	C1864987
MedGen	400655
GARD	0010974
Is cancer (heuristic)	no

Also known as: familial or sporadic hemiplegic migraine caused by mutation in SCN1A · FHM3 · migraine, familial hemiplegic, 3 · migraine, familial hemiplegic, type 3 · SCN1A familial or sporadic hemiplegic migraine

Data availability: 216 ClinVar variants · 2 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, 3

Related subtypes (4): migraine, familial hemiplegic, 2, migraine, familial hemiplegic, 1, 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

216 retrieved; paginated sample, class counts are floors:

62 conflicting classifications of pathogenicity, 58 uncertain significance, 39 pathogenic, 21 benign/likely benign, 15 pathogenic/likely pathogenic, 10 likely pathogenic, 7 benign, 4 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
12893	NM_001165963.4(SCN1A):c.4465C>A (p.Gln1489Lys)	LOC102724058	Pathogenic	no assertion criteria provided
12902	NM_001165963.4(SCN1A):c.4495T>C (p.Phe1499Leu)	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
12903	NM_001165963.4(SCN1A):c.4467G>C (p.Gln1489His)	LOC102724058	Pathogenic	no assertion criteria provided
1454054	NM_001165963.4(SCN1A):c.4322C>T (p.Ala1441Val)	LOC102724058	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
167639	NM_001165963.4(SCN1A):c.3733C>T (p.Arg1245Ter)	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
189861	NM_001165963.4(SCN1A):c.3637C>T (p.Arg1213Ter)	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
189896	NM_001165963.4(SCN1A):c.5674C>T (p.Arg1892Ter)	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
189911	NM_001165963.4(SCN1A):c.4573C>T (p.Arg1525Ter)	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
189921	NM_001165963.4(SCN1A):c.4933C>T (p.Arg1645Ter)	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
206837	NM_001165963.4(SCN1A):c.4547C>A (p.Ser1516Ter)	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
206920	NM_001165963.4(SCN1A):c.4554dup (p.Pro1519fs)	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
496124	NM_001165963.4(SCN1A):c.5734C>T (p.Arg1912Ter)	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
68533	NM_001165963.4(SCN1A):c.3734G>A (p.Arg1245Gln)	LOC102724058	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
68551	NM_001165963.4(SCN1A):c.4633A>G (p.Ile1545Val)	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
68558	NM_001165963.4(SCN1A):c.4934G>A (p.Arg1645Gln)	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
68570	NM_001165963.4(SCN1A):c.5347G>A (p.Ala1783Thr)	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
930321	NM_001165963.4(SCN1A):c.5341T>C (p.Tyr1781His)	LOC102724058	Pathogenic	criteria provided, multiple submitters, no conflicts
931824	NM_001165963.4(SCN1A):c.4772A>T (p.Lys1591Ile)	LOC102724058	Pathogenic	criteria provided, single submitter
1057080	NM_001165963.4(SCN1A):c.1169T>C (p.Leu390Pro)	SCN1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12889	NM_001165963.4(SCN1A):c.664C>T (p.Arg222Ter)	SCN1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12896	NM_001165963.4(SCN1A):c.434T>C (p.Met145Thr)	SCN1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1323556	NM_001165963.4(SCN1A):c.840G>A (p.Trp280Ter)	SCN1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1418113	NM_001165963.4(SCN1A):c.811G>A (p.Gly271Ser)	SCN1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1515913	NM_001165963.4(SCN1A):c.602+1del	SCN1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1704263	NM_001165963.4(SCN1A):c.2854T>A (p.Trp952Arg)	SCN1A	Pathogenic	no assertion criteria provided
1704264	NM_001165963.4(SCN1A):c.2946+2T>C	SCN1A	Pathogenic	no assertion criteria provided
1704265	NM_001165963.4(SCN1A):c.659T>A (p.Val220Asp)	SCN1A	Pathogenic	no assertion criteria provided
1704267	NM_001165963.4(SCN1A):c.828A>C (p.Lys276Asn)	SCN1A	Pathogenic	no assertion criteria provided
189869	NM_001165963.4(SCN1A):c.2792G>A (p.Arg931His)	SCN1A	Pathogenic	reviewed by expert panel
189938	NM_001165963.4(SCN1A):c.2589+3A>T	SCN1A	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 20 · Orphanet: 7 · 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
SCN1A	Strong	Autosomal dominant	migraine, familial hemiplegic, 3	20

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCN1A	Orphanet:1942	Epilepsy with myoclonic-atonic seizures
SCN1A	Orphanet:2382	Lennox-Gastaut syndrome
SCN1A	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
SCN1A	Orphanet:33069	Dravet syndrome
SCN1A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN1A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SCN1A	Orphanet:569	Familial or sporadic hemiplegic migraine

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
SCN1A	HGNC:10585	ENSG00000144285	P35498	Sodium channel protein type 1 subunit alpha	gencc,clinvar
SCN1A-AS1	HGNC:54069	ENSG00000236107		SCN1A and SCN9A antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCN1A	Sodium channel protein type 1 subunit alpha	Pore-forming subunit of Nav1.1, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN1A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a1su
SCN1A-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
Brodmann (1909) area 23	1
lateral nuclear group of thalamus	1
primary visual cortex	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCN1A	154	tissue_specific	marker	Brodmann (1909) area 23, lateral nuclear group of thalamus, primary visual cortex
SCN1A-AS1	129	tissue_specific	marker	sural nerve, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SCN1A	2,287
SCN1A-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCN1A	P35498	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
Interaction between L1 and Ankyrins	1	368.4×	0.012	SCN1A
Phase 0 - rapid depolarisation	1	346.1×	0.012	SCN1A
L1CAM interactions	1	120.2×	0.018	SCN1A
Cardiac conduction	1	108.8×	0.018	SCN1A
Muscle contraction	1	77.2×	0.021	SCN1A
Axon guidance	1	45.1×	0.027	SCN1A
Nervous system development	1	42.9×	0.027	SCN1A
Developmental Biology	1	14.5×	0.069	SCN1A

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
membrane depolarization during action potential	1	1685.2×	0.003	SCN1A
neuronal action potential propagation	1	1404.3×	0.003	SCN1A
detection of mechanical stimulus involved in sensory perception of pain	1	1123.5×	0.003	SCN1A
neuromuscular process controlling posture	1	1053.2×	0.003	SCN1A
nerve development	1	936.2×	0.003	SCN1A
cardiac muscle cell action potential involved in contraction	1	702.2×	0.003	SCN1A
adult walking behavior	1	495.6×	0.003	SCN1A
neuronal action potential	1	481.5×	0.003	SCN1A
determination of adult lifespan	1	432.1×	0.003	SCN1A
sodium ion transport	1	271.8×	0.004	SCN1A
sodium ion transmembrane transport	1	203.0×	0.005	SCN1A
establishment of localization in cell	1	160.5×	0.006	SCN1A

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
SCN1A	MEXILETINE HYDROCHLORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN1A	94	4
SCN1A-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MEXILETINE HYDROCHLORIDE	4	SCN1A
BEPRIDIL	4	SCN1A
DIBUCAINE	4	SCN1A
ARTICAINE	4	SCN1A
BUPIVACAINE	4	SCN1A
IMIPRAMINE	4	SCN1A
DROPERIDOL	4	SCN1A
DICYCLOMINE	4	SCN1A
TETRABENAZINE	4	SCN1A
PHENIRAMINE	4	SCN1A
PRILOCAINE	4	SCN1A
PROPOXYCAINE	4	SCN1A
PROPARACAINE	4	SCN1A
HEXYLCAINE	4	SCN1A
PRAMOXINE	4	SCN1A
BENOXINATE	4	SCN1A
QUINIDINE	4	SCN1A
FELODIPINE	4	SCN1A
PHENYTOIN	4	SCN1A
QUININE	4	SCN1A
NISOLDIPINE	4	SCN1A
NIFEDIPINE	4	SCN1A
PRAZOSIN	4	SCN1A
DILTIAZEM	4	SCN1A
PRENYLAMINE	4	SCN1A
COCAINE	4	SCN1A
TRIFLUOPERAZINE	4	SCN1A
CINNARIZINE	4	SCN1A
THIORIDAZINE	4	SCN1A
ETIDOCAINE	4	SCN1A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SCN1A	149	Binding:115, Functional:18, ADMET:14, Toxicity:2

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN1A	149

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

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)
MEXILETINE HYDROCHLORIDE	4	SCN1A
BEPRIDIL	4	SCN1A
DIBUCAINE	4	SCN1A
ARTICAINE	4	SCN1A
BUPIVACAINE	4	SCN1A
IMIPRAMINE	4	SCN1A
DROPERIDOL	4	SCN1A
DICYCLOMINE	4	SCN1A
TETRABENAZINE	4	SCN1A
PHENIRAMINE	4	SCN1A
PRILOCAINE	4	SCN1A
PROPOXYCAINE	4	SCN1A
PROPARACAINE	4	SCN1A
HEXYLCAINE	4	SCN1A
PRAMOXINE	4	SCN1A
BENOXINATE	4	SCN1A
QUINIDINE	4	SCN1A
FELODIPINE	4	SCN1A
PHENYTOIN	4	SCN1A
QUININE	4	SCN1A
NISOLDIPINE	4	SCN1A
NIFEDIPINE	4	SCN1A
PRAZOSIN	4	SCN1A
DILTIAZEM	4	SCN1A
PRENYLAMINE	4	SCN1A
COCAINE	4	SCN1A
TRIFLUOPERAZINE	4	SCN1A
CINNARIZINE	4	SCN1A
THIORIDAZINE	4	SCN1A
ETIDOCAINE	4	SCN1A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SCN1A
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	SCN1A-AS1

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)
SCN1A-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.