Hypomagnesemia, seizures, and intellectual disability 2

Summary

Hypomagnesemia, seizures, and intellectual disability 2 (MONDO:0020788) is a disease caused by ATP1A1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: ATP1A1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 35

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypomagnesemia, seizures, and intellectual disability 2
Mondo ID	MONDO:0020788
OMIM	618314
UMLS	C5193023
MedGen	1675904
GARD	0025249
Is cancer (heuristic)	no

Also known as: HOMGSMR2

Data availability: 35 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn metal metabolism disorder › familial primary hypomagnesemia › familial primary hypomagnesemia with normocalcuria › familial primary hypomagnesemia with normocalciuria and normocalcemia › hypomagnesemia, seizures, and intellectual disability › hypomagnesemia, seizures, and intellectual disability 2

Related subtypes (1): hypomagnesemia, seizures, and intellectual disability 1

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

35 retrieved; paginated sample, class counts are floors:

13 uncertain significance, 12 benign, 4 pathogenic, 3 likely pathogenic, 2 conflicting classifications of pathogenicity, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1687398	NM_000701.8(ATP1A1):c.905T>G (p.Leu302Arg)	ATP1A1	Pathogenic	criteria provided, single submitter
617641	NM_000701.8(ATP1A1):c.905T>C (p.Leu302Pro)	ATP1A1	Pathogenic	no assertion criteria provided
617642	NM_000701.8(ATP1A1):c.907G>C (p.Gly303Arg)	ATP1A1	Pathogenic	no assertion criteria provided
619298	NM_000701.8(ATP1A1):c.2791T>C (p.Trp931Arg)	ATP1A1	Pathogenic	no assertion criteria provided
3237519	NM_000701.8(ATP1A1):c.821C>G (p.Ala274Gly)	ATP1A1	Likely pathogenic	criteria provided, single submitter
3775372	NM_000701.8(ATP1A1):c.2590G>A (p.Gly864Arg)	ATP1A1	Likely pathogenic	criteria provided, single submitter
617643	NM_000701.8(ATP1A1):c.2576T>G (p.Met859Arg)	ATP1A1	Likely pathogenic	criteria provided, single submitter
1700229	NM_000701.8(ATP1A1):c.2660G>A (p.Arg887Gln)	ATP1A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1704508	NM_000701.8(ATP1A1):c.12+3G>T	ATP1A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1334984	NM_000701.8(ATP1A1):c.158G>A (p.Arg53His)	ATP1A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1941986	NM_000701.8(ATP1A1):c.1939C>T (p.Arg647Cys)	ATP1A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2665056	NM_000701.8(ATP1A1):c.518G>A (p.Arg173Gln)	ATP1A1	Uncertain significance	criteria provided, single submitter
2828830	NM_000701.8(ATP1A1):c.2956_2959dup (p.Trp987fs)	ATP1A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2986874	NM_000701.8(ATP1A1):c.1538G>A (p.Arg513Lys)	ATP1A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2995966	NM_000701.8(ATP1A1):c.676A>C (p.Thr226Pro)	ATP1A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3236059	NM_000701.8(ATP1A1):c.1144A>G (p.Thr382Ala)	ATP1A1	Uncertain significance	criteria provided, single submitter
3774566	NM_000701.8(ATP1A1):c.2305T>G (p.Phe769Val)	ATP1A1	Uncertain significance	criteria provided, single submitter
3906857	NM_000701.8(ATP1A1):c.2462C>T (p.Ser821Phe)	ATP1A1	Uncertain significance	no assertion criteria provided
4531861	NM_000701.8(ATP1A1):c.2789A>C (p.Gln930Pro)	ATP1A1	Uncertain significance	criteria provided, single submitter
931627	NM_000701.8(ATP1A1):c.2542C>T (p.Arg848Trp)	ATP1A1	Uncertain significance	criteria provided, multiple submitters, no conflicts
931678	NM_000701.8(ATP1A1):c.12+727T>A	ATP1A1	Uncertain significance	criteria provided, single submitter
992402	NM_000701.8(ATP1A1):c.1866C>G (p.Ile622Met)	ATP1A1-AS1	Uncertain significance	no assertion criteria provided
1181423	NM_000701.8(ATP1A1):c.3043+38T>C	ATP1A1	Benign	criteria provided, multiple submitters, no conflicts
1225564	NM_000701.8(ATP1A1):c.2952-37C>T	ATP1A1	Benign	criteria provided, multiple submitters, no conflicts
1227676	NM_000701.8(ATP1A1):c.1024-100T>G	ATP1A1	Benign	criteria provided, multiple submitters, no conflicts
1261446	NM_000701.8(ATP1A1):c.1223-32G>A	ATP1A1	Benign	criteria provided, multiple submitters, no conflicts
1267145	NM_000701.8(ATP1A1):c.1110G>A (p.Thr370=)	ATP1A1	Benign	criteria provided, multiple submitters, no conflicts
1274903	NM_000701.8(ATP1A1):c.3043+8T>C	ATP1A1	Benign	criteria provided, multiple submitters, no conflicts
1275937	NM_000701.8(ATP1A1):c.741C>A (p.Thr247=)	ATP1A1	Benign	criteria provided, multiple submitters, no conflicts
1286325	NM_000701.8(ATP1A1):c.755-77A>T	ATP1A1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 2 · 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
ATP1A1	Strong	Autosomal dominant	hypomagnesemia, seizures, and intellectual disability 2	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATP1A1	Orphanet:521414	Autosomal dominant Charcot-Marie-Tooth disease type 2DD
ATP1A1	Orphanet:564178	Primary hypomagnesemia-refractory seizures-intellectual disability 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
ATP1A1	HGNC:799	ENSG00000163399	P05023	Sodium/potassium-transporting ATPase subunit alpha-1	gencc,clinvar
ATP1A1-AS1	HGNC:28262	ENSG00000203865	Q5TC04	Putative uncharacterized protein ATP1A1-AS1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATP1A1	Sodium/potassium-transporting ATPase subunit alpha-1	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.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATP1A1	Transcription factor	no	7.2.2.3	P_typ_ATPase, ATPase_P-typ_cation-transptr_N, P-type_ATPase_IIC
ATP1A1-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
left lobe of thyroid gland	2
right lobe of thyroid gland	2
renal medulla	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP1A1	305	ubiquitous	marker	renal medulla, right lobe of thyroid gland, left lobe of thyroid gland
ATP1A1-AS1	178	ubiquitous	marker	tendon of biceps brachii, left lobe of thyroid gland, right lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP1A1	3,520
ATP1A1-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP1A1	P05023	13

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATP1A1-AS1	Q5TC04	65.72

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Ion transport by P-type ATPases	1	207.6×	0.023	ATP1A1
Ion homeostasis	1	203.9×	0.023	ATP1A1
Potential therapeutics for SARS	1	114.2×	0.023	ATP1A1
Cardiac conduction	1	108.8×	0.023	ATP1A1
Ion channel transport	1	96.0×	0.023	ATP1A1
Muscle contraction	1	77.2×	0.024	ATP1A1
SARS-CoV Infections	1	55.4×	0.028	ATP1A1
Viral Infection Pathways	1	30.8×	0.044	ATP1A1
Transport of small molecules	1	25.1×	0.044	ATP1A1
Infectious disease	1	24.8×	0.044	ATP1A1
Disease	1	13.1×	0.076	ATP1A1

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
negative regulation of glucocorticoid biosynthetic process	1	16852.0×	0.001	ATP1A1
positive regulation of striated muscle contraction	1	8426.0×	0.001	ATP1A1
negative regulation of heart contraction	1	4213.0×	0.002	ATP1A1
establishment or maintenance of transmembrane electrochemical gradient	1	2808.7×	0.002	ATP1A1
response to glycoside	1	2407.4×	0.002	ATP1A1
positive regulation of heart contraction	1	2106.5×	0.002	ATP1A1
membrane repolarization during cardiac muscle cell action potential	1	1685.2×	0.002	ATP1A1
osmosensory signaling pathway	1	1532.0×	0.002	ATP1A1
cell communication by electrical coupling involved in cardiac conduction	1	1404.3×	0.002	ATP1A1
relaxation of cardiac muscle	1	1296.3×	0.002	ATP1A1
membrane repolarization	1	1296.3×	0.002	ATP1A1
sodium ion export across plasma membrane	1	1053.2×	0.002	ATP1A1
cellular response to steroid hormone stimulus	1	1053.2×	0.002	ATP1A1
regulation of the force of heart contraction	1	991.3×	0.002	ATP1A1
intracellular potassium ion homeostasis	1	991.3×	0.002	ATP1A1
regulation of sodium ion transport	1	936.2×	0.002	ATP1A1
intracellular sodium ion homeostasis	1	766.0×	0.002	ATP1A1
cardiac muscle cell action potential involved in contraction	1	702.2×	0.002	ATP1A1
potassium ion import across plasma membrane	1	366.4×	0.003	ATP1A1
proton transmembrane transport	1	312.1×	0.004	ATP1A1
regulation of blood pressure	1	221.7×	0.005	ATP1A1
sodium ion transmembrane transport	1	203.0×	0.005	ATP1A1
potassium ion transmembrane transport	1	135.9×	0.008	ATP1A1
response to xenobiotic stimulus	1	69.1×	0.014	ATP1A1

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
ATP1A1	DIGOXIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATP1A1	5	4
ATP1A1-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DIGOXIN	4	ATP1A1
OMEPRAZOLE	4	ATP1A1
DIGITOXIN	4	ATP1A1
LANSOPRAZOLE	4	ATP1A1
ROSTAFUROXIN	2	ATP1A1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ATP1A1	50	Binding:50

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATP1A1	7.2.2.3	P-type Na+ transporter

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

5 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)
DIGOXIN	4	ATP1A1
OMEPRAZOLE	4	ATP1A1
DIGITOXIN	4	ATP1A1
LANSOPRAZOLE	4	ATP1A1
ROSTAFUROXIN	2	ATP1A1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ATP1A1
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	ATP1A1-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)
ATP1A1-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.