Familial primary hypomagnesemia

Summary

Familial primary hypomagnesemia (MONDO:0018100) is a disease (an umbrella term covering 5 Mondo subtypes) caused by TRPM7 (GenCC Strong), with 5 cohort genes and 19 clinical trials. Top therapeutic interventions include magnesium citrate, magnesium oxide, and magnesium chloride.

At a glance

• Causal gene: TRPM7 (GenCC Strong)
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 5
• ClinVar variants: 6
• Clinical trials: 19

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	familial primary hypomagnesemia
Mondo ID	MONDO:0018100
OMIM	602014
Orphanet	34526
DOID	DOID:0060879
NCIT	C123263
SNOMED CT	80710001
UMLS	C0151723
MedGen	57481
GARD	0025126
Is cancer (heuristic)	no

Also known as: familial primary hypomagnesemia · hypomagnesemia

Data availability: 6 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › 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

Related subtypes (8): familial periodic paralysis, hereditary hemochromatosis, acrodermatitis enteropathica, atransferrinemia, Wilson disease, Menkes disease, pseudohypoparathyroidism, sulfite oxidase deficiency due to molybdenum cofactor deficiency

Subtypes (5): familial primary hypomagnesemia with hypercalciuria and nephrocalcinosis, familial primary hypomagnesemia with hypocalcuria, familial primary hypomagnesemia with normocalcuria, EGF-related primary hypomagnesemia with intellectual disability, hypomagnesemia 7, renal, with or without dilated cardiomyopathy

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

6 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 2 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1013600	NM_017649.5(CNNM2):c.1147A>G (p.Met383Val)	CNNM2	Pathogenic	no assertion criteria provided
1177637	NC_012920.1(MT-TF):m.591C>T	MT-TF	Likely pathogenic	reviewed by expert panel
438256	NM_017662.5(TRPM6):c.2920-806_3404-1965del	TRPM6	Likely pathogenic	no assertion criteria provided
694635	NM_006984.5(CLDN10):c.431C>T (p.Thr144Met)	CLDN10	Uncertain significance	criteria provided, multiple submitters, no conflicts
689830	NC_012920.1(MT-TF):m.643A>G	MT-TF	Uncertain significance	criteria provided, multiple submitters, no conflicts
1916073	NM_017662.5(TRPM6):c.1402C>T (p.Arg468Cys)	TRPM6	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 8 · 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
TRPM7	Strong	Autosomal dominant	familial primary hypomagnesemia	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TRPM7	Orphanet:140957	Autosomal dominant macrothrombocytopenia
TRPM7	Orphanet:90020	Parkinson-dementia complex of Guam
CNNM2	Orphanet:620363	Primary hypomagnesemia-generalized seizures-intellectual disability-obesity syndrome
TRPM6	Orphanet:30924	Primary hypomagnesemia with secondary hypocalcemia
CLDN10	Orphanet:528105	Hypohidrosis-electrolyte imbalance-lacrimal gland dysfunction-ichthyosis-xerostomia syndrome
MT-TF	Orphanet:550	MELAS
MT-TF	Orphanet:551	MERRF
MT-TF	Orphanet:620371	Gitelman-like kidney tubulopathy due to mitochondrial DNA mutation

Cohort genes → proteins

5 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TRPM7	HGNC:17994	ENSG00000092439	Q96QT4	Transient receptor potential cation channel subfamily M member 7	gencc
CNNM2	HGNC:103	ENSG00000148842	Q9H8M5	Metal transporter CNNM2	clinvar
TRPM6	HGNC:17995	ENSG00000119121	Q9BX84	Transient receptor potential cation channel subfamily M member 6	clinvar
CLDN10	HGNC:2033	ENSG00000134873	P78369	Claudin-10	clinvar
MT-TF	HGNC:7481	ENSG00000210049		mitochondrially encoded tRNA-Phe (UUU/C)	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TRPM7	Transient receptor potential cation channel subfamily M member 7	Bifunctional protein that combines an ion channel with an intrinsic kinase domain, enabling it to modulate cellular functions either by conducting ions through the pore or by phosphorylating downstream proteins via its kinase domain.
CNNM2	Metal transporter CNNM2	Divalent metal cation transporter.
TRPM6	Transient receptor potential cation channel subfamily M member 6	Bifunctional protein that combines an ion channel with an intrinsic kinase domain, enabling it to modulate cellular functions either by conducting ions through the pore or by phosphorylating downstream proteins via its kinase domain.
CLDN10	Claudin-10	Forms paracellular channels: polymerizes in tight junction strands with cation- and anion-selective channels through the strands, conveying epithelial permeability in a process known as paracellular tight junction permeability.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.4

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
Kinase	2	11.1×	0.024
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TRPM7	Kinase	yes		a-kinase_dom, Kinase-like_dom_sf, TRPM7_a-kinase_dom
CNNM2	Other/Unknown	no		CBS_dom, CNNM, RmlC-like_jellyroll
TRPM6	Kinase	yes		a-kinase_dom, Ion_trans_dom, Kinase-like_dom_sf
CLDN10	Other/Unknown	no		Claudin10, PMP22/EMP/MP20/Claudin, Claudin
MT-TF	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
cardiac muscle of right atrium	1
left ventricle myocardium	1
oocyte	1
right adrenal gland	1
secondary oocyte	1
colonic mucosa	1
jejunal mucosa	1
mucosa of sigmoid colon	1
body of pancreas	1
pancreatic ductal cell	1
parotid gland	1
amygdala	1
prefrontal cortex	1
skeletal muscle tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TRPM7	247	ubiquitous	marker	left ventricle myocardium, calcaneal tendon, cardiac muscle of right atrium
CNNM2	234	ubiquitous	marker	secondary oocyte, oocyte, right adrenal gland
TRPM6	178	tissue_specific	marker	colonic mucosa, mucosa of sigmoid colon, jejunal mucosa
CLDN10	220	broad	marker	parotid gland, pancreatic ductal cell, body of pancreas
MT-TF	118	ubiquitous	marker	prefrontal cortex, amygdala, skeletal muscle tissue

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TRPM7	1,995
CLDN10	1,240
CNNM2	1,230
TRPM6	950
MT-TF	0

Intra-cohort edges

A	B	Sources
CNNM2	TRPM6	string_interaction
CNNM2	TRPM7	string_interaction
TRPM6	TRPM7	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 3 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CNNM2	Q9H8M5	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CLDN10	P78369	79.61
TRPM7	Q96QT4	69.90
TRPM6	Q9BX84	65.03

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 5 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
TRP channels	2	271.9×	5e-05	TRPM7, TRPM6
Tight junction interactions	1	122.8×	0.012	CLDN10
Developmental Lineage of Pancreatic Ductal Cells	1	76.1×	0.013	CLDN10

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
magnesium ion homeostasis	2	936.2×	3e-05	CNNM2, TRPM7
monoatomic cation transmembrane transport	2	312.1×	2e-04	TRPM7, TRPM6
calcium ion transmembrane transport	2	105.3×	1e-03	TRPM7, TRPM6
calcium ion transport	2	90.6×	1e-03	TRPM7, TRPM6
regulation of monoatomic ion transport	1	4213.0×	0.001	CLDN10
calcium-dependent cell-matrix adhesion	1	2106.5×	0.002	TRPM7
magnesium ion transmembrane transport	1	1053.2×	0.003	TRPM6
intracellular magnesium ion homeostasis	1	702.2×	0.004	TRPM7
paracellular transport	1	601.9×	0.004	CLDN10
zinc ion transport	1	383.0×	0.006	TRPM7
magnesium ion transport	1	300.9×	0.007	TRPM7
necroptotic process	1	263.3×	0.007	TRPM7
calcium-independent cell-cell adhesion	1	200.6×	0.008	CLDN10
protein tetramerization	1	156.0×	0.010	TRPM6
actomyosin structure organization	1	140.4×	0.010	TRPM7
bicellular tight junction assembly	1	82.6×	0.017	CLDN10
protein homotetramerization	1	59.3×	0.022	TRPM7
response to toxic substance	1	52.7×	0.023	TRPM6
monoatomic ion transport	1	39.0×	0.029	CLDN10
protein autophosphorylation	1	36.3×	0.030	TRPM7
protein phosphorylation	1	17.0×	0.060	TRPM7
cell adhesion	1	9.4×	0.103	CLDN10

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 5 evidence-associated genes (40%) 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
TRPM6	TOFACITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TRPM6	2	4
TRPM7	0	0
CNNM2	0	0
CLDN10	0	0
MT-TF	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TOFACITINIB	4	TRPM6
TG100-115	2	TRPM6

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TRPM6	56	Binding:55, Functional:1
TRPM7	34	Binding:34

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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)
TOFACITINIB	4	TRPM6
TG100-115	2	TRPM6

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TRPM6
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	TRPM7
E	Difficult family or no structure, no drug	3	CNNM2, CLDN10, MT-TF

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CNNM2	0	TRPM6
TRPM7	34	—
CLDN10	0	—
MT-TF	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 19.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	11
PHASE4	4
PHASE3	2
PHASE1/PHASE2	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03088852	PHASE4	RECRUITING	Magnesium Deficiency In Patients Hospitalized in Internal Medicine Wards
NCT00282620	PHASE4	UNKNOWN	Magnesium to Reduce Implantable Cardioverter Defibrillator (ICD) Shocks and Improve Patient’s Quality of Life.
NCT00603499	PHASE4	COMPLETED	Magnesium and Metabolic Syndrome
NCT00994006	PHASE4	COMPLETED	The Absorption of Magnesium Oxide Compared to Citrate in Healthy Subjects
NCT05998863	PHASE3	RECRUITING	EffCaMgCit to Prevent Mineral Metabolism and Renal Complications of Chronic PPI Therapy
NCT03812380	PHASE3	TERMINATED	Averting Complications of Proton Pump Inhibitor Therapy by Effervescent Calcium Magnesium Citrate
NCT02216877	PHASE1/PHASE2	COMPLETED	Magnesium Supplementation for Hypomagnesemia in Chronic Kidney Disease
NCT04382157	PHASE1/PHASE2	UNKNOWN	Magnesium Replacement and Hyperglycemia After Kidney Transplantation
NCT07056283	Not specified	RECRUITING	The Study of Urinary Biomarkers in Patients With Hypomagnesemia
NCT01700998	Not specified	COMPLETED	Magnesium Replacement Therapy to Prevent Acute Renal Failure in Critically Ill Patients
NCT02690012	Not specified	COMPLETED	Feasibility of Using an Integrated Consent Model to Compare Two Standard of Care Regimens for the Management of Hypomagnesemia From Anti-Cancer Therapies
NCT03976440	Not specified	UNKNOWN	Simplified Regional Citrate Anticoagulation Protocols for CVVH, CVVHDF and SLED: a Pilot Study
NCT04351451	Not specified	COMPLETED	Hypomagnesemia and Hypocalcemia Association Following Thyroidectomy
NCT04426994	Not specified	COMPLETED	Hypomagnesemia Associated With Proton-Pump Inhibitor Use
NCT06353750	Not specified	UNKNOWN	Intracellular Magnesium and Heart Failure
NCT06855550	Not specified	COMPLETED	Postoperative Incidence of Atrial Fibrillation Following Cardiac Surgery
NCT07089004	Not specified	COMPLETED	Hypomagnesemia and Its Clinical Outcome
NCT07380542	Not specified	COMPLETED	Dynamic Magnesium Replacement Strategies and 28-Day Mortality in Non-Cardiac Critically Ill Patients With Hypomagnesemia: A Target Trial Emulation
NCT07576621	Not specified	COMPLETED	Association Between Hypomagnesemia and Coagulopathy in Sepsis

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
MAGNESIUM CITRATE	4	3
MAGNESIUM OXIDE	4	2
MAGNESIUM CHLORIDE	4	1
MAGNESIUM	3	2
MAGNESIUM LACTATE, L-	2	1