Hypophosphatemia

Summary

Hypophosphatemia (MONDO:0000313) is a disease with 4 cohort genes and 25 clinical trials. Top therapeutic interventions include cinacalcet, burosumab, and calcitonin.

At a glance

• Cohort genes: 4
• ClinVar variants: 4
• Clinical trials: 25

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypophosphatemia
Mondo ID	MONDO:0000313
MeSH	D017674
DOID	DOID:0050336
NCIT	C37977
SNOMED CT	4996001
UMLS	C0085682
MedGen	39327
Is cancer (heuristic)	no

Also known as: hypophosphatemia · hypophosphatemia (disease)

Data availability: 4 ClinVar variants · 1 HPO phenotype.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › mineral metabolism disease › phosphorus metabolism disease › hypophosphatemia

Related subtypes (1): hyperphosphatemia

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

4 retrieved; paginated sample, class counts are floors:

1 pathogenic, 1 pathogenic/likely pathogenic, 1 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
188877	NM_000478.6(ALPL):c.400_401delinsCA (p.Thr134His)	ALPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1684630	NC_000017.11:g.8117792_8126946del	TRG-GCC2-6	Pathogenic	criteria provided, single submitter
3381204	NM_000444.6(PHEX):c.1182_1189del (p.Gln394fs)	PHEX	Likely pathogenic	no assertion criteria provided
5272	NM_004252.5(NHERF1):c.673G>A (p.Glu225Lys)	NHERF1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NHERF1	Orphanet:244305	Dominant hypophosphatemia with nephrolithiasis or osteoporosis
ALPL	Orphanet:247623	Perinatal lethal hypophosphatasia
ALPL	Orphanet:247638	Prenatal benign hypophosphatasia
ALPL	Orphanet:247651	Infantile hypophosphatasia
ALPL	Orphanet:247667	Childhood-onset hypophosphatasia
ALPL	Orphanet:247676	Adult hypophosphatasia
ALPL	Orphanet:247685	Odontohypophosphatasia
PHEX	Orphanet:89936	X-linked hypophosphatemia

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NHERF1	HGNC:11075	ENSG00000109062	O14745	Na(+)/H(+) exchange regulatory cofactor NHE-RF1	clinvar
TRG-GCC2-6	HGNC:12273			tRNA-Gly (anticodon GCC) 2-6	clinvar
ALPL	HGNC:438	ENSG00000162551	P05186	Alkaline phosphatase, tissue-nonspecific isozyme	clinvar
PHEX	HGNC:8918	ENSG00000102174	P78562	Phosphate-regulating neutral endopeptidase PHEX	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NHERF1	Na(+)/H(+) exchange regulatory cofactor NHE-RF1	Scaffold protein that connects plasma membrane proteins with members of the ezrin/moesin/radixin family and thereby helps to link them to the actin cytoskeleton and to regulate their surface expression.
ALPL	Alkaline phosphatase, tissue-nonspecific isozyme	Alkaline phosphatase that metabolizes various phosphate compounds and plays a key role in skeletal mineralization and adaptive thermogenesis.
PHEX	Phosphate-regulating neutral endopeptidase PHEX	Peptidase that cleaves SIBLING (small integrin-binding ligand, N-linked glycoprotein)-derived ASARM peptides, thus regulating their biological activity.

Protein-family classification

Druggable: 2 · Difficult: 1 · 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
Phosphatase	1	21.0×	0.187
Protease	1	9.2×	0.210
Scaffold/PPI	1	4.3×	0.283
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NHERF1	Scaffold/PPI	no		PDZ, EBP50_C, NHERF-1/NHERF-2
TRG-GCC2-6	Other/Unknown	no
ALPL	Phosphatase	yes	3.1.3.1	Alkaline_phosphatase, Alkaline_phosphatase_core_sf, Alkaline_phosphatase_AS
PHEX	Protease	yes	3.4.24.B15	Peptidase_M13, Peptidase_M13_N, Peptidase_M13_C

Expression context

Cohort genes with no expression data: 1.

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	1

Top tissues across cohort

Tissue	Cohort genes
esophagus mucosa	1
granulocyte	1
lower esophagus mucosa	1
left adrenal gland cortex	1
right adrenal gland	1
right adrenal gland cortex	1
oocyte	1
secondary oocyte	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NHERF1	284	ubiquitous	marker	granulocyte, lower esophagus mucosa, esophagus mucosa
TRG-GCC2-6
ALPL	200	broad	marker	right adrenal gland, right adrenal gland cortex, left adrenal gland cortex
PHEX	139	tissue_specific	marker	secondary oocyte, tibia, oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NHERF1	2,599
ALPL	2,146
PHEX	856
TRG-GCC2-6	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NHERF1	O14745	22
ALPL	P05186	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PHEX	P78562	94.58

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 4 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
Post-translational modification: synthesis of GPI-anchored proteins	1	167.9×	0.006	ALPL

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to sodium phosphate	2	1123.5×	7e-05	ALPL, PHEX
bone mineralization	2	181.2×	0.001	ALPL, PHEX
organophosphate metabolic process	1	5617.3×	0.002	PHEX
pyridoxal 5’-phosphate metabolic process	1	5617.3×	0.002	ALPL
renal phosphate ion absorption	1	5617.3×	0.002	NHERF1
regulation of renal phosphate excretion	1	5617.3×	0.002	NHERF1
skeletal system development	2	83.8×	0.002	ALPL, PHEX
response to vitamin B6	1	2808.7×	0.003	ALPL
futile creatine cycle	1	2808.7×	0.003	ALPL
glutathione transport	1	1872.4×	0.004	NHERF1
renal sodium ion transport	1	1404.3×	0.004	NHERF1
response to macrophage colony-stimulating factor	1	1404.3×	0.004	ALPL
import across plasma membrane	1	1404.3×	0.004	NHERF1
inhibition of non-skeletal tissue mineralization	1	1404.3×	0.004	ALPL
developmental process involved in reproduction	1	1123.5×	0.004	ALPL
bile acid secretion	1	1123.5×	0.004	NHERF1
negative regulation of sodium ion transport	1	936.2×	0.004	NHERF1
gamma-aminobutyric acid import	1	936.2×	0.004	NHERF1
response to insulin-like growth factor stimulus	1	936.2×	0.004	PHEX
gland morphogenesis	1	802.5×	0.004	NHERF1
maintenance of epithelial cell apical/basal polarity	1	802.5×	0.004	NHERF1
regulation of protein kinase activity	1	802.5×	0.004	NHERF1
cementum mineralization	1	802.5×	0.004	ALPL
phospholipase C-activating dopamine receptor signaling pathway	1	702.2×	0.004	NHERF1
negative regulation of platelet-derived growth factor receptor signaling pathway	1	624.1×	0.004	NHERF1
microvillus assembly	1	624.1×	0.004	NHERF1
establishment of Golgi localization	1	624.1×	0.004	NHERF1
renal absorption	1	561.7×	0.005	NHERF1
adenylate cyclase-activating dopamine receptor signaling pathway	1	510.7×	0.005	NHERF1
negative regulation of fibroblast migration	1	510.7×	0.005	NHERF1

Therapeutics

Drugs indicated for this disease

1 approved. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Burosumab	Approved (phase 4)

Drug target analysis

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

Druggability breadth: 2 of 4 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
ALPL	SULCONAZOLE NITRATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ALPL	7	4
NHERF1	0	0
TRG-GCC2-6	0	0
PHEX	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SULCONAZOLE NITRATE	4	ALPL
THEOPHYLLINE	4	ALPL
LEVAMISOLE	4	ALPL
MICONAZOLE NITRATE	4	ALPL
LEVAMISOLE HYDROCHLORIDE	4	ALPL
ISOQUERCETIN	2	ALPL
(-)-EPICATECHIN	2	ALPL

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
ALPL	58	Binding:50, Functional:4, ADMET:3, Toxicity:1
NHERF1	5	Binding:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALPL	3.1.3.1	alkaline phosphatase
PHEX	3.4.24.B15

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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)
SULCONAZOLE NITRATE	4	ALPL
THEOPHYLLINE	4	ALPL
LEVAMISOLE	4	ALPL
MICONAZOLE NITRATE	4	ALPL
LEVAMISOLE HYDROCHLORIDE	4	ALPL
ISOQUERCETIN	2	ALPL
(-)-EPICATECHIN	2	ALPL

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ALPL
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	PHEX
E	Difficult family or no structure, no drug	2	NHERF1, TRG-GCC2-6

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NHERF1	5	—
TRG-GCC2-6	0	—
PHEX	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 25.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	17
PHASE4	3
PHASE3	2
PHASE2/PHASE3	1
PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06350955	PHASE4	RECRUITING	IV Iron-induced Hypophosphatemia After RYGB
NCT04519762	PHASE4	UNKNOWN	Levels of ‘Hypophosphatemia Affect Outcome of Septic Patients in ICU
NCT05098249	PHASE4	COMPLETED	Ferric Carboxymaltose With or Without Phosphate Substitution for the Treatment of Iron Deficiency or Iron Deficiency Anemia
NCT00975000	PHASE3	COMPLETED	Treatment of Autonomous Hyperparathyroidism in Post Renal Transplant Recipients
NCT03581591	PHASE3	COMPLETED	Open Label Trial Assessing Safety and Efficacy of Burosumab (KRN23), in a Patient With ENS and Hypophosphatemic Rickets
NCT06651892	PHASE2/PHASE3	COMPLETED	The Efficacy and Safety of Diluted Oral Phosphate Enema Versus Intravenous Sodium Glycerophosphate in The Treatment of Hypophosphatemia in ICU Patients
NCT06824454	PHASE2	NOT_YET_RECRUITING	Evaluation of Dipyridamole in Preventing Post-Transplant Hypophosphatemia in Kidney Transplant Recipients
NCT03771105	EARLY_PHASE1	RECRUITING	The Impact of Phosphate Metabolism on Healthy Aging
NCT06112236	Not specified	ACTIVE_NOT_RECRUITING	Effects of Treatments for Anemia and Iron Deficiency on the Electrolyte Balance in Lung Transplant Recipients: A Special Focus on Hypophosphatemia
NCT06754670	Not specified	RECRUITING	Effect of Hypophosphatemia on Neuro-excursion Efficiency During Mechanical Ventilator Weaning
NCT07233889	Not specified	RECRUITING	Enteral Supplementation With Sodium Dihydrogen Phosphate and Disodium Hydrogen Phosphate Granules for the Treatment of Hypophosphatemia.
NCT07288944	Not specified	NOT_YET_RECRUITING	Protocolised Management of Phosphate Replacement Trial
NCT00688077	Not specified	COMPLETED	FGF-23 Suppressibility by Calcitonin
NCT01011114	Not specified	TERMINATED	Using Cinacalcet to Treat the Hypophosphatemia of Early Kidney Transplant
NCT01660308	Not specified	UNKNOWN	Observing the Changes of Fibroblast Growth Factor 23 in Patients of Tumor Induced Osteomalacia
NCT02837523	Not specified	WITHDRAWN	Biomarker for Cystinosis Disease: BioCystinosis (BioCystinosis)
NCT03489993	Not specified	COMPLETED	FGF23 and Angiotensin-(1-7) in Hypophosphatemia (GAP)
NCT03529058	Not specified	COMPLETED	Hypophosphatemia as a Predictive Marker of Mortality During Sepsis in ICU
NCT03740802	Not specified	COMPLETED	Hypophosphatemia as a Predictor in Surgical Resuscitation Sepsis
NCT03976440	Not specified	UNKNOWN	Simplified Regional Citrate Anticoagulation Protocols for CVVH, CVVHDF and SLED: a Pilot Study
NCT04273490	Not specified	COMPLETED	Characterising Pain, QoL, Body Composition, Arterial Stiffness, Muscles and Bones in Adult Persons With XLH and Healthy Controls
NCT04502784	Not specified	UNKNOWN	Investigation of Hypophosphataemia Following Intravenous Iron
NCT04814641	Not specified	UNKNOWN	Hypophosphatemia and Bronchiolitis
NCT05909722	Not specified	COMPLETED	Validation of the GIDS and Description of Phosphate Disorders
NCT06344546	Not specified	COMPLETED	Metabolic Pathway Analysis in Intensive Care Unit Patients With Refeeding Syndrome

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CINACALCET	4	6
BUROSUMAB	4	1
CALCITONIN	4	1
DIPYRIDAMOLE	4	1
SODIUM GLYCEROPHOSPHATE	4	1
SODIUM PHOSPHATE, MONOBASIC	4	1
TALFIRASTIDE	2	1