Alternating hemiplegia of childhood 1

Summary

Alternating hemiplegia of childhood 1 (MONDO:0007087) is a disease caused by ATP1A2 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: ATP1A2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 197

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	alternating hemiplegia of childhood 1
Mondo ID	MONDO:0007087
OMIM	104290
UMLS	C3549447
MedGen	762361
GARD	0015036
Is cancer (heuristic)	no

Also known as: AHC1 · alternating hemiplegia of childhood 1 · alternating hemiplegia of childhood caused by mutation in ATP1A2 · alternating hemiplegia of childhood type 1 · ATP1A2 alternating hemiplegia of childhood

Data availability: 197 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › palsy › hemiplegia › alternating hemiplegia of childhood › alternating hemiplegia of childhood 1

Related subtypes (2): X-linked adrenal hypoplasia congenita, alternating hemiplegia of childhood 2

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

197 retrieved; paginated sample, class counts are floors:

67 uncertain significance, 57 benign, 32 benign/likely benign, 27 conflicting classifications of pathogenicity, 5 pathogenic, 4 pathogenic/likely pathogenic, 4 likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1029935	NM_000702.4(ATP1A2):c.1843G>A (p.Gly615Arg)	ATP1A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12921	NM_000702.4(ATP1A2):c.1133C>A (p.Thr378Asn)	ATP1A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12925	NM_000702.4(ATP1A2):c.2936C>T (p.Pro979Leu)	ATP1A2	Pathogenic	criteria provided, multiple submitters, no conflicts
204886	NM_000702.4(ATP1A2):c.1148G>A (p.Arg383His)	ATP1A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3598996	NM_000702.4(ATP1A2):c.36dup (p.Ala13fs)	ATP1A2	Pathogenic	criteria provided, single submitter
430293	NM_000702.4(ATP1A2):c.889G>A (p.Ala297Thr)	ATP1A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
446871	NM_000702.4(ATP1A2):c.2563G>A (p.Gly855Arg)	ATP1A2	Pathogenic	criteria provided, multiple submitters, no conflicts
520908	NM_000702.4(ATP1A2):c.879C>G (p.Ile293Met)	ATP1A2	Pathogenic	criteria provided, multiple submitters, no conflicts
3385388	NM_001127222.2(CACNA1A):c.1914-2A>C	CACNA1A	Pathogenic	criteria provided, single submitter
1315281	NM_000702.4(ATP1A2):c.2809C>T (p.Arg937Cys)	ATP1A2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1321203	NM_000702.4(ATP1A2):c.2336G>A (p.Ser779Asn)	ATP1A2	Likely pathogenic	criteria provided, single submitter
3382567	NM_000702.4(ATP1A2):c.2444C>G (p.Pro815Arg)	ATP1A2	Likely pathogenic	criteria provided, single submitter
3598997	NM_000702.4(ATP1A2):c.2935_2936delinsAA (p.Pro979Lys)	ATP1A2	Likely pathogenic	criteria provided, single submitter
194183	NM_000702.4(ATP1A2):c.1666A>T (p.Asn556Tyr)	ATP1A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
194713	NM_000702.4(ATP1A2):c.2412C>T (p.Ile804=)	ATP1A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
195466	NM_000702.4(ATP1A2):c.2751G>A (p.Thr917=)	ATP1A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
197162	NM_000702.4(ATP1A2):c.194G>T (p.Arg65Leu)	ATP1A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
204869	NM_000702.4(ATP1A2):c.1092G>A (p.Thr364=)	ATP1A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
204881	NM_000702.4(ATP1A2):c.25T>A (p.Tyr9Asn)	ATP1A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
204888	NM_000702.4(ATP1A2):c.1474G>A (p.Glu492Lys)	ATP1A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
204892	NM_000702.4(ATP1A2):c.1821C>T (p.Gly607=)	ATP1A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293125	NM_000702.4(ATP1A2):c.285C>T (p.Phe95=)	ATP1A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293127	NM_000702.4(ATP1A2):c.360G>A (p.Glu120=)	ATP1A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293129	NM_000702.4(ATP1A2):c.627T>C (p.Cys209=)	ATP1A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293133	NM_000702.4(ATP1A2):c.1674A>G (p.Pro558=)	ATP1A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
293157	NM_000702.4(ATP1A2):c.*932T>C	ATP1A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
387509	NM_000702.4(ATP1A2):c.1578G>A (p.Pro526=)	ATP1A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
406194	NM_000702.4(ATP1A2):c.1262G>A (p.Arg421Gln)	ATP1A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
432411	NM_000702.4(ATP1A2):c.1582G>A (p.Asp528Asn)	ATP1A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
570135	NM_000702.4(ATP1A2):c.1550C>A (p.Thr517Asn)	ATP1A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 19 · Orphanet: 10 · 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
ATP1A2	Strong	Autosomal dominant	alternating hemiplegia of childhood 1	19

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATP1A2	Orphanet:2131	Alternating hemiplegia of childhood
ATP1A2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
ATP1A2	Orphanet:569	Familial or sporadic hemiplegic migraine
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

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
ATP1A2	HGNC:800	ENSG00000018625	P50993	Sodium/potassium-transporting ATPase subunit alpha-2	gencc,clinvar
CACNA1A	HGNC:1388	ENSG00000141837	O00555	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATP1A2	Sodium/potassium-transporting ATPase subunit alpha-2	This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane.
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…

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
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATP1A2	Transcription factor	no		P_typ_ATPase, ATPase_P-typ_cation-transptr_N, P-type_ATPase_IIC
CACNA1A	Ion channel	yes		VDCCAlpha1, CACNA1A, Ion_trans_dom

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
lateral globus pallidus	1
superior vestibular nucleus	1
trigeminal ganglion	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP1A2	262	broad	marker	lateral globus pallidus, trigeminal ganglion, superior vestibular nucleus
CACNA1A	237	broad	marker	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP1A2	2,679
CACNA1A	346

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CACNA1A	O00555	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATP1A2	P50993	88.25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. 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×	0.036	CACNA1A
Regulation of insulin secretion	1	109.8×	0.039	CACNA1A
Ion transport by P-type ATPases	1	103.8×	0.039	ATP1A2
Ion homeostasis	1	102.0×	0.039	ATP1A2
Integration of energy metabolism	1	87.8×	0.039	CACNA1A
Potential therapeutics for SARS	1	57.1×	0.044	ATP1A2
Cardiac conduction	1	54.4×	0.044	ATP1A2
Ion channel transport	1	48.0×	0.044	ATP1A2
Muscle contraction	1	38.6×	0.044	ATP1A2
Transmission across Chemical Synapses	1	38.1×	0.044	CACNA1A
SARS-CoV Infections	1	27.7×	0.055	ATP1A2
Neuronal System	1	22.1×	0.063	CACNA1A
Viral Infection Pathways	1	15.4×	0.084	ATP1A2
Transport of small molecules	1	12.6×	0.089	ATP1A2
Infectious disease	1	12.4×	0.089	ATP1A2
Disease	1	6.5×	0.156	ATP1A2
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
olfactory cortex development	1	8426.0×	0.004	ATP1A2
regulation of glutamate uptake involved in transmission of nerve impulse	1	4213.0×	0.004	ATP1A2
negative regulation of calcium ion transmembrane transport	1	4213.0×	0.004	ATP1A2
negative regulation of striated muscle contraction	1	2808.7×	0.004	ATP1A2
negative regulation of heart contraction	1	2106.5×	0.004	ATP1A2
amygdala development	1	1404.3×	0.004	ATP1A2
response to glycoside	1	1203.7×	0.004	ATP1A2
regulation of striated muscle contraction	1	1053.2×	0.004	ATP1A2
response to potassium ion	1	1053.2×	0.004	ATP1A2
positive regulation of heart contraction	1	1053.2×	0.004	ATP1A2
regulation of muscle contraction	1	842.6×	0.004	ATP1A2
L-ascorbic acid metabolic process	1	766.0×	0.004	ATP1A2
locomotion	1	766.0×	0.004	ATP1A2
neurotransmitter uptake	1	702.2×	0.004	ATP1A2
neuronal action potential propagation	1	702.2×	0.004	ATP1A2
membrane depolarization during cardiac muscle cell action potential	1	702.2×	0.004	ATP1A2
cell communication by electrical coupling involved in cardiac conduction	1	702.2×	0.004	ATP1A2
regulation of respiratory gaseous exchange by nervous system process	1	648.1×	0.004	ATP1A2
negative regulation of cytosolic calcium ion concentration	1	648.1×	0.004	ATP1A2
relaxation of cardiac muscle	1	648.1×	0.004	ATP1A2
membrane repolarization	1	648.1×	0.004	ATP1A2
regulation of smooth muscle contraction	1	601.9×	0.004	ATP1A2
regulation of cardiac muscle cell contraction	1	561.7×	0.004	ATP1A2
sodium ion export across plasma membrane	1	526.6×	0.004	ATP1A2
cellular response to steroid hormone stimulus	1	526.6×	0.004	ATP1A2
regulation of the force of heart contraction	1	495.6×	0.004	ATP1A2
intracellular potassium ion homeostasis	1	495.6×	0.004	ATP1A2
locomotory exploration behavior	1	495.6×	0.004	ATP1A2
response to amyloid-beta	1	495.6×	0.004	CACNA1A
regulation of vasoconstriction	1	401.2×	0.005	ATP1A2

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 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
ATP1A2	OMEPRAZOLE
CACNA1A	NIMODIPINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATP1A2	5	4
CACNA1A	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
OMEPRAZOLE	4	ATP1A2
DIGOXIN	4	ATP1A2
DIGITOXIN	4	ATP1A2
LANSOPRAZOLE	4	ATP1A2
NIMODIPINE	4	CACNA1A
TACRINE	4	CACNA1A
ROSTAFUROXIN	2	ATP1A2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ATP1A2	49	Binding:49
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

7 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)
OMEPRAZOLE	4	ATP1A2
DIGOXIN	4	ATP1A2
DIGITOXIN	4	ATP1A2
LANSOPRAZOLE	4	ATP1A2
NIMODIPINE	4	CACNA1A
TACRINE	4	CACNA1A
ROSTAFUROXIN	2	ATP1A2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	ATP1A2, 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	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.