Renal hypomagnesemia 2

Summary

Renal hypomagnesemia 2 (MONDO:0007937) is a disease caused by FXYD2 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FXYD2 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 35

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		28	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	renal hypomagnesemia 2
Mondo ID	MONDO:0007937
MeSH	C537152
OMIM	154020
Orphanet	34528
DOID	DOID:0060885
SNOMED CT	725393000
UMLS	C1835171
MedGen	320542
GARD	0003350
Is cancer (heuristic)	no

Also known as: familial primary hypomagnesemia caused by mutation in FXYD2 · FXYD2 familial primary hypomagnesemia · FXYD2 primary hypomagnesemia · HOMG2 · hypomagnesemia 2, renal · isolated autosomal dominant hypomagnesemia · isolated renal magnesium wasting · primary hypomagnesemia caused by mutation in FXYD2 · renal hypomagnesemia type 2

Data availability: 35 ClinVar variants · 5 GenCC gene-disease records.

Disease family

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 › familial primary hypomagnesemia with hypocalcuria › renal hypomagnesemia 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

35 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 9 benign, 6 benign/likely benign, 3 likely benign, 2 conflicting classifications of pathogenicity, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
7684	NM_001680.5(FXYD2):c.121G>A (p.Gly41Arg)	FXYD2	Pathogenic	criteria provided, single submitter
2161768	NM_001680.5(FXYD2):c.176+3G>A	FXYD6-FXYD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
302526	NM_001680.5(FXYD2):c.28G>A (p.Gly10Ser)	FXYD6-FXYD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1489687	NM_001680.5(FXYD2):c.176G>A (p.Arg59Lys)	FXYD2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1696692	NM_001680.5(FXYD2):c.25G>T (p.Gly9Cys)	FXYD2	Uncertain significance	criteria provided, single submitter
3599115	NM_001680.5(FXYD2):c.186T>A (p.Asn62Lys)	FXYD2	Uncertain significance	criteria provided, single submitter
3599118	NM_001680.5(FXYD2):c.49G>A (p.Asp17Asn)	FXYD2	Uncertain significance	criteria provided, single submitter
1360349	NM_001680.5(FXYD2):c.176+6C>T	FXYD6-FXYD2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2197713	NM_001680.5(FXYD2):c.173G>A (p.Arg58His)	FXYD6-FXYD2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2414831	NM_001680.5(FXYD2):c.53C>T (p.Pro18Leu)	FXYD6-FXYD2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2984922	NM_001680.5(FXYD2):c.65-1G>A	FXYD6-FXYD2	Uncertain significance	criteria provided, multiple submitters, no conflicts
302516	NM_001680.5(FXYD2):c.*124T>A	FXYD6-FXYD2	Uncertain significance	criteria provided, single submitter
3599116	NM_001680.5(FXYD2):c.52C>T (p.Pro18Ser)	FXYD6-FXYD2	Uncertain significance	criteria provided, single submitter
3599117	NM_001680.5(FXYD2):c.52C>G (p.Pro18Ala)	FXYD6-FXYD2	Uncertain significance	criteria provided, single submitter
3599119	NM_001680.5(FXYD2):c.41G>A (p.Gly14Glu)	FXYD6-FXYD2	Uncertain significance	criteria provided, single submitter
878676	NM_001680.5(FXYD2):c.*149A>G	FXYD6-FXYD2	Uncertain significance	criteria provided, single submitter
880461	NM_001680.5(FXYD2):c.36C>G (p.Pro12=)	FXYD6-FXYD2	Uncertain significance	criteria provided, single submitter
302518	NM_001680.5(FXYD2):c.*78C>A	FXYD2	Benign	criteria provided, single submitter
302520	NM_001680.5(FXYD2):c.*6+6C>A	FXYD2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
302523	NM_001680.5(FXYD2):c.183C>T (p.Ile61=)	FXYD2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
302524	NM_001680.5(FXYD2):c.76G>A (p.Val26Ile)	FXYD2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
302527	NM_001680.5(FXYD2):c.-10A>G	FXYD2	Benign	criteria provided, multiple submitters, no conflicts
736288	NM_001680.5(FXYD2):c.110C>A (p.Ala37Asp)	FXYD2	Likely benign	criteria provided, multiple submitters, no conflicts
755271	NM_001680.5(FXYD2):c.198G>A (p.Pro66=)	FXYD2	Likely benign	criteria provided, multiple submitters, no conflicts
789041	NM_001680.5(FXYD2):c.114C>T (p.Phe38=)	FXYD2	Likely benign	criteria provided, multiple submitters, no conflicts
302513	NM_001680.5(FXYD2):c.*215G>A	FXYD6-FXYD2	Benign	criteria provided, single submitter
302515	NM_001680.5(FXYD2):c.*176T>G	FXYD6-FXYD2	Benign	criteria provided, multiple submitters, no conflicts
302517	NM_001680.5(FXYD2):c.*105C>T	FXYD6-FXYD2	Benign	criteria provided, single submitter
302519	NM_001680.5(FXYD2):c.*71G>A	FXYD6-FXYD2	Benign	criteria provided, single submitter
302521	NM_001680.5(FXYD2):c.*1C>T	FXYD6-FXYD2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · 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
HNF1B	Definitive	Autosomal dominant	renal cysts and diabetes syndrome	13
FXYD2	Strong	Autosomal dominant	renal hypomagnesemia 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FXYD2	Orphanet:34528	Autosomal dominant primary hypomagnesemia with hypocalciuria
HNF1B	Orphanet:1309	Medullary sponge kidney
HNF1B	Orphanet:1331	Familial prostate cancer
HNF1B	Orphanet:2578	Mayer-Rokitansky-Küster-Hauser syndrome type 2
HNF1B	Orphanet:261265	17q12 microdeletion syndrome
HNF1B	Orphanet:93111	HNF1B-related autosomal dominant tubulointerstitial kidney disease
HNF1B	Orphanet:93172	Renal dysplasia, unilateral
HNF1B	Orphanet:93173	Renal dysplasia, bilateral
HNF1B	Orphanet:97363	Unilateral multicystic dysplastic kidney
HNF1B	Orphanet:97364	Bilateral multicystic dysplastic kidney

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FXYD2	HGNC:4026	ENSG00000137731	P54710	Sodium/potassium-transporting ATPase subunit gamma	gencc,clinvar
HNF1B	HGNC:11630	ENSG00000275410	P35680	Hepatocyte nuclear factor 1-beta	gencc
FXYD6-FXYD2	HGNC:39978	ENSG00000255245		FXYD6-FXYD2 readthrough	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FXYD2	Sodium/potassium-transporting ATPase subunit gamma	May be involved in forming the receptor site for cardiac glycoside binding or may modulate the transport function of the sodium ATPase.
HNF1B	Hepatocyte nuclear factor 1-beta	Transcription factor that binds to the inverted palindrome 5’-GTTAATNATTAAC-3'.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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	37.2×	0.080
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FXYD2	Ion channel	yes		Ion-transport_regulator_FXYD, ATNG, FXYD_motif
HNF1B	Transcription factor	no		HD, HNF1b_C, HNF-1_N
FXYD6-FXYD2	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
metanephros cortex	3
adult mammalian kidney	2
body of pancreas	1
gall bladder	1
kidney	1
cortex of kidney	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FXYD2	162	broad	marker	metanephros cortex, body of pancreas, gall bladder
HNF1B	74	broad	marker	metanephros cortex, adult mammalian kidney, kidney
FXYD6-FXYD2	120	broad	marker	adult mammalian kidney, metanephros cortex, cortex of kidney

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HNF1B	1,660
FXYD2	790
FXYD6-FXYD2	0

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FXYD2	P54710	4
HNF1B	P35680	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 3 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
Regulation of gene expression in early pancreatic precursor cells	1	713.8×	0.014	HNF1B
Nephron development	1	439.2×	0.014	HNF1B
Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells	1	356.9×	0.014	HNF1B
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	1	300.5×	0.014	HNF1B
Developmental Lineage of Pancreatic Acinar Cells	1	150.3×	0.021	HNF1B
Developmental Lineage of Pancreatic Ductal Cells	1	114.2×	0.021	HNF1B
Ion transport by P-type ATPases	1	103.8×	0.021	FXYD2
Ion homeostasis	1	102.0×	0.021	FXYD2
Potential therapeutics for SARS	1	57.1×	0.031	FXYD2
Cardiac conduction	1	54.4×	0.031	FXYD2
Ion channel transport	1	48.0×	0.032	FXYD2
Muscle contraction	1	38.6×	0.036	FXYD2
SARS-CoV Infections	1	27.7×	0.047	FXYD2
Viral Infection Pathways	1	15.4×	0.078	FXYD2
Transport of small molecules	1	12.6×	0.084	FXYD2
Infectious disease	1	12.4×	0.084	FXYD2
Disease	1	6.5×	0.147	FXYD2

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
regulation of pronephros size	1	8426.0×	1e-03	HNF1B
pronephric nephron tubule development	1	8426.0×	1e-03	HNF1B
ureteric bud elongation	1	8426.0×	1e-03	HNF1B
obsolete negative regulation of mesenchymal cell apoptotic process involved in mesonephric nephron morphogenesis	1	8426.0×	1e-03	HNF1B
mesenchymal cell apoptotic process involved in metanephros development	1	8426.0×	1e-03	HNF1B
hepatoblast differentiation	1	4213.0×	0.001	HNF1B
mesonephric duct formation	1	4213.0×	0.001	HNF1B
regulation of branch elongation involved in ureteric bud branching	1	2808.7×	0.002	HNF1B
negative regulation of mesenchymal cell apoptotic process involved in metanephros development	1	2808.7×	0.002	HNF1B
endodermal cell fate specification	1	1404.3×	0.002	HNF1B
inner cell mass cell differentiation	1	1404.3×	0.002	HNF1B
establishment or maintenance of transmembrane electrochemical gradient	1	1404.3×	0.002	FXYD2
cellular hyperosmotic salinity response	1	1404.3×	0.002	FXYD2
pronephros development	1	1203.7×	0.002	HNF1B
genitalia development	1	842.6×	0.003	HNF1B
positive regulation of sodium ion export across plasma membrane	1	842.6×	0.003	FXYD2
hindbrain development	1	561.7×	0.004	HNF1B
sodium ion export across plasma membrane	1	526.6×	0.004	FXYD2
intracellular potassium ion homeostasis	1	495.6×	0.004	FXYD2
endocrine pancreas development	1	468.1×	0.004	HNF1B
embryonic digestive tract morphogenesis	1	468.1×	0.004	HNF1B
regulation of Wnt signaling pathway	1	443.5×	0.004	HNF1B
intracellular sodium ion homeostasis	1	383.0×	0.005	FXYD2
branching morphogenesis of an epithelial tube	1	366.4×	0.005	HNF1B
pancreas development	1	337.0×	0.005	HNF1B
insulin secretion	1	216.1×	0.007	HNF1B
potassium ion import across plasma membrane	1	183.2×	0.008	FXYD2
epithelial cell proliferation	1	156.0×	0.009	HNF1B
proton transmembrane transport	1	156.0×	0.009	FXYD2
positive regulation of transcription initiation by RNA polymerase II	1	135.9×	0.010	HNF1B

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
FXYD2	OMEPRAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FXYD2	5	4
HNF1B	0	0
FXYD6-FXYD2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
OMEPRAZOLE	4	FXYD2
DIGOXIN	4	FXYD2
DIGITOXIN	4	FXYD2
LANSOPRAZOLE	4	FXYD2
ROSTAFUROXIN	2	FXYD2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
FXYD2	45	Binding:45

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

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)
OMEPRAZOLE	4	FXYD2
DIGOXIN	4	FXYD2
DIGITOXIN	4	FXYD2
LANSOPRAZOLE	4	FXYD2
ROSTAFUROXIN	2	FXYD2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	FXYD2
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	2	HNF1B, FXYD6-FXYD2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HNF1B	0	—
FXYD6-FXYD2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.