FGF23

Summary

FGF23 (fibroblast growth factor 23, HGNC:3680) is a protein-coding gene on chromosome 12p13.32, encoding Fibroblast growth factor 23 (Q9GZV9). Regulator of phosphate homeostasis.

This gene encodes a member of the fibroblast growth factor family of proteins, which possess broad mitogenic and cell survival activities and are involved in a variety of biological processes. The product of this gene regulates phosphate homeostasis and transport in the kidney. The full-length, functional protein may be deactivated via cleavage into N-terminal and C-terminal chains. Mutation of this cleavage site causes autosomal dominant hypophosphatemic rickets (ADHR). Mutations in this gene are also associated with hyperphosphatemic familial tumoral calcinosis (HFTC).

Source: NCBI Gene 8074 — RefSeq curated summary.

At a glance

• Gene–disease (curated): tumoral calcinosis, hyperphosphatemic, familial, 2 (Strong, GenCC) — +3 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 256 total — 7 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 28
• Druggable target: yes
• MANE Select transcript: NM_020638

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3680
Approved symbol	FGF23
Name	fibroblast growth factor 23
Location	12p13.32
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000118972
Ensembl biotype	protein_coding
OMIM	605380
Entrez	8074

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 retained_intron

ENST00000237837, ENST00000648269

RefSeq mRNA: 1 — MANE Select: NM_020638 NM_020638

CCDS: CCDS8526

Canonical transcript exons

ENST00000237837 — 3 exons

Exon	Start	End
ENSE00000802844	4372594	4372697
ENSE00000802845	4379372	4379712
ENSE00000997496	4368227	4370783

Expression profiles

Bgee: expression breadth broad, 44 present calls, max score 86.82.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0292 / max 27.2807, expressed in 8 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
129018	0.0292	8

Top tissues by expression

228 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	86.82	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.77	gold quality
hair follicle	UBERON:0002073	80.63	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.21	silver quality
buccal mucosa cell	CL:0002336	70.26	gold quality
decidua	UBERON:0002450	69.71	gold quality
mucosa of paranasal sinus	UBERON:0005030	60.26	gold quality
heart right ventricle	UBERON:0002080	59.31	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	59.13	gold quality
nasal cavity epithelium	UBERON:0005384	58.38	gold quality
superficial temporal artery	UBERON:0001614	56.78	gold quality
right atrium auricular region	UBERON:0006631	56.45	gold quality
esophagus squamous epithelium	UBERON:0006920	56.05	gold quality
cardiac atrium	UBERON:0002081	56.03	gold quality
biceps brachii	UBERON:0001507	55.82	gold quality
epithelium of nasopharynx	UBERON:0001951	54.65	gold quality
sperm	CL:0000019	54.27	gold quality
germinal epithelium of ovary	UBERON:0001304	53.42	gold quality
jejunal mucosa	UBERON:0000399	53.38	gold quality
mammary duct	UBERON:0001765	53.38	gold quality
parotid gland	UBERON:0001831	53.15	gold quality
liver	UBERON:0002107	52.92	gold quality
endothelial cell	CL:0000115	52.90	gold quality
tibia	UBERON:0000979	52.39	gold quality
seminal vesicle	UBERON:0000998	51.93	gold quality
pigmented layer of retina	UBERON:0001782	51.84	gold quality
right lobe of liver	UBERON:0001114	51.64	gold quality
hindlimb stylopod muscle	UBERON:0004252	51.54	gold quality
saphenous vein	UBERON:0007318	49.79	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.10	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-98	yes	3206.19
E-ANND-3	yes	3.42

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): IRF6, POU1F1, TCF3, VDR

miRNA regulators (miRDB)

82 targeting FGF23, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4756-5P	99.84	64.98	1809

Literature-anchored findings (GeneRIF, showing 40)

• FGF23 mutations cause autosomal dominant hypophosphatemic rickets (ADHR) (PMID:11062477)
• Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23 (PMID:11737582)
• Loss of renal phosphate wasting in a child with autosomal dominant hypophosphatemic rickets caused by a FGF23 mutation. (PMID:11805436)
• involved in hypophosphatemia (REVIEW} (PMID:12032180)
• FGF23 plays a role in phosphate uptake in intestine and phosphate reabsorption in kidney (PMID:12419819)
• FGF23 has a role in dissociating parathyroid hormone actions on mineral fluxes and on vitamin D metabolism at the level of the kidney (PMID:12519781)
• Oncogenic hypophosphatemic osteomalacia tumors express FGF-23 protein (PMID:12590648)
• fibroblast growth factor-23 and matrix extracellular phosphoglycoprotein sequences are potential PHEX substrates (PMID:12678920)
• There is evidence for a hormone/enzyme/extracellular matrix protein cascade involving fibroblastic growth factor 23 (FGF23), a phosphate-regulating gene with homologies to (PHEX) and (MEPE)–REVIEW (PMID:12791601)
• The FGF23 R179Q mutant blunts the signalling of Pi deprivation to the renal type-II Na/Pi cotransporter, suggesting that the FGF23 pathway could be involved in the signalling of dietary Pi. (PMID:12851820)
• FGF23 concentrations were not different between control and hypophosphatemic X-linked hypophosphatemic rickets subjects, but were significantly increased in hyperphosphatemic subjects with End-Stage Renal Disease (PMID:12854832)
• regulates fgf23 expression as part of a potential hormonal axis between bone and kidney that controls systemic phosphate homeostasis and mineralization (PMID:12874285)
• Circulating FGF-23 was significantly elevated in patients with chronic kidney disease and its concentration correlated with renal creatinine clearance. (PMID:14633152)
• FGF-23 is an important determinant of phosphate homeostasis and bone mineralization. (PMID:14988389)
• FGF-23 may not play a significant role in regulating phosphate or 1,25(OH)(2)D in pHPT patients, especially in those with normal renal function. (PMID:15248822)
• FGF-23 may be an important determinant in the regulation of mineral metabolism with renal insufficiency. (PMID:15264182)
• FGF23 is processed by proprotein convertases but not by PHEX. (PMID:15268897)
• high circulating levels of FGF23 are associated with profound disturbances in the regulation of phosphate and vitamin D metabolism as well as calcium homeostasis and that elevated PTH levels (PMID:15284207)
• An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia (PMID:15590700)
• An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia (PMID:15590700)
• FGF-23 may be implicated in the physiological regulation of Pi homeostasis in response to dietary phosphate changes, independent of PTH. (PMID:15613425)
• mRNA expression examined by in situ hybridization in whole human embryos at 30 days and 8 weeks of gestation. (PMID:15749088)
• Physiological regulator of phosphate homeostasis. Excessive FGF23 with normal renal function results in hypophosphatemia, low 1,25-dihydroxyvitamin D levels, and rickets/osteomalacia. Contributes to development of hyperparathyroidism. (PMID:15930999)
• FGF23 mutations causing tumoral calcinosis lead to increased intracellular proteolysis of FGF23, most likely by furin-like proteases (PMID:15961556)
• Roles in health and disease. Review. (PMID:16033853)
• seven PHEX mutations were detected in X-linked hypophosphatemic rickets patients: two missense mutations, two nonsense mutations, and three short deletions; no functional FGF23 mutation was detected in any patient (PMID:16055933)
• FGF23 signals through multiple FGF receptors. Unique endocrine actions of FGF23 involve escape from FGF23-producing cells and circulation to kidney, where highly sulfated glycosaminoglycans most likely act as cofactors for FGF23 activity. (PMID:16081635)
• Serum FGF-23 may be regulated by serum 1alpha,25-dihydroxyvitamin D. (PMID:16234967)
• FGF-23 originating from fibrous dysplasia tissue may cause hypophosphatemia not only in isolated fibrous dysplasia patients but also in the patients with McCune-Albright syndrome syndrome (PMID:16337659)
• Renal phosphate leak affected stone formers and was strongly associated with increased serum FGF23 concentration. (PMID:16352682)
• FGF-23 was elevated in parathyroid glands from primary hyperparathyroidism patients compared with controls. FGF-23 levels correlated positively with serum corrected Ca & intact PTH levels. (PMID:16381997)
• a novel posttranslational regulatory model of FGF23 involving competing O-glycosylation and protease processing to produce intact FGF23 (PMID:16638743)
• Excessive FGF-23 exposure in the early post-transplant period appears to be more strongly associated with post-transplant hypophosphatemia than PTH. (PMID:16941023)
• primary defect in hyperostosis-hypophosphatemia syndrome is impairment of glycosylation of FGF23 resulting from mutations in GALNT3 and leading to augmented processing of FGF23 (PMID:17129170)
• carboxyl terminal fragments of FGF-23 are phosphaturic and a short, 26-amino acid fragment of FGF-23 retains significant phosphaturic activity (PMID:17333246)
• persistence of FGF-23 contributes to hypophosphatemia and suboptimal calcitriol levels in renal transplant recipients. (PMID:17359508)
• The plasma half-life of serum FGF-23 is in the range of 46-58 minutes (PMID:17374707)
• Fibroblast growth factor-23 in patients with transient hypoparathyroidism: its important role in serum phosphate regulation. (PMID:17464094)
• There is a discontinuum of hereditary and acquired disorders of phosphate homeostasis that are caused by either high or low circulating levels of the novel phosphaturic hormone fibroblastic growth factor 23 (PMID:17494882)
• Association between FGF23 and parathyroid hormone levels in chronic kidney disease may suggest a co-regulation that remains to be further elucidated. (PMID:17567652)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fgf23	ENSDARG00000045854
mus_musculus	Fgf23	ENSMUSG00000000182
rattus_norvegicus	Fgf23	ENSRNOG00000066556

Paralogs (21): FGF10 (ENSG00000070193), FGF22 (ENSG00000070388), FGF4 (ENSG00000075388), FGF20 (ENSG00000078579), FGF14 (ENSG00000102466), FGF9 (ENSG00000102678), FGF21 (ENSG00000105550), FGF8 (ENSG00000107831), FGF6 (ENSG00000111241), FGF1 (ENSG00000113578), FGF12 (ENSG00000114279), FGF13 (ENSG00000129682), FGF5 (ENSG00000138675), FGF2 (ENSG00000138685), FGF7 (ENSG00000140285), FGF18 (ENSG00000156427), FGF17 (ENSG00000158815), FGF11 (ENSG00000161958), FGF19 (ENSG00000162344), FGF3 (ENSG00000186895), FGF16 (ENSG00000196468)

Protein

Protein identifiers

Fibroblast growth factor 23 — Q9GZV9 (reviewed: Q9GZV9)

Alternative names: Phosphatonin, Tumor-derived hypophosphatemia-inducing factor

All UniProt accessions (1): Q9GZV9

UniProt curated annotations — full annotation on UniProt →

Function. Regulator of phosphate homeostasis. Inhibits renal tubular phosphate transport by reducing SLC34A1 levels. Up-regulates EGR1 expression in the presence of KL. Acts directly on the parathyroid to decrease PTH secretion. Regulator of vitamin-D metabolism. Negatively regulates osteoblast differentiation and matrix mineralization.

Subunit / interactions. Interacts with FGFR1, FGFR2, FGFR3 and FGFR4. Affinity between fibroblast growth factors (FGFs) and their receptors is increased by KL and heparan sulfate glycosaminoglycans that function as coreceptors.

Subcellular location. Secreted.

Tissue specificity. Expressed in osteogenic cells particularly during phases of active bone remodeling. In adult trabecular bone, expressed in osteocytes and flattened bone-lining cells (inactive osteoblasts).

Post-translational modifications. Following secretion this protein is inactivated by cleavage into a N-terminal fragment and a C-terminal fragment. The processing is effected by proprotein convertases. O-glycosylated at Thr-171 and Thr-178 by GALNT3 and glycosylation of Thr-178 requires previous glycosylation at Thr171. Glycosylation is necessary for secretion; it blocks processing by proprotein convertases when the O-glycan is alpha 2,6-sialylated. Competition between proprotein convertase cleavage and block of cleavage by O-glycosylation determines the level of secreted active FGF23. Phosphorylation at Ser-180 mediated by FAM20C slows down glycosylation at Thr-178 notably.

Disease relevance. Hypophosphatemic rickets, autosomal dominant (ADHR) [MIM:193100] A disease characterized by isolated renal phosphate wasting, hypophosphatemia, and inappropriately normal 1,25-dihydroxyvitamin D3 (calcitriol) levels. Patients frequently present with bone pain, rickets, and tooth abscesses. The disease is caused by variants affecting the gene represented in this entry. Tumoral calcinosis, hyperphosphatemic, familial, 2 (HFTC2) [MIM:617993] A form of hyperphosphatemic tumoral calcinosis, a rare autosomal recessive metabolic disorder that manifests with hyperphosphatemia and massive calcium deposits in the skin and subcutaneous tissues. Some patients have recurrent, transient, painful swellings of the long bones associated with the radiographic findings of periosteal reaction and cortical hyperostosis and absence of skin involvement. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the heparin-binding growth factors family.

RefSeq proteins (1): NP_065689* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002209	Fibroblast_GF_fam	Family
IPR008996	IL1/FGF	Homologous_superfamily

Pfam: PF00167

UniProt features (44 total): strand 16, sequence variant 9, turn 4, chain 3, helix 3, glycosylation site 2, signal peptide 1, disulfide bond 1, mutagenesis site 1, region of interest 1, compositionally biased region 1, site 1, modified residue 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
2P39	X-RAY DIFFRACTION	1.5
6S22	X-RAY DIFFRACTION	1.96
7YSH	ELECTRON MICROSCOPY	2.74
5W21	X-RAY DIFFRACTION	3
7YSW	ELECTRON MICROSCOPY	3.03
7YSU	ELECTRON MICROSCOPY	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9GZV9-F1	77.94	0.47

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 179–180 (cleavage; by proprotein convertases)

Post-translational modifications (1): 180

Disulfide bonds (1): 95–113

Glycosylation sites (2): 171, 178

Mutagenesis-validated functional residues (1):

Position	Phenotype
178	loss of glycosylation.

Function

Pathways and Gene Ontology

Reactome pathways

40 pathways

ID	Pathway
R-HSA-109704	PI3K Cascade
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-1839122	Signaling by activated point mutants of FGFR1
R-HSA-1839130	Signaling by activated point mutants of FGFR3
R-HSA-190322	FGFR4 ligand binding and activation
R-HSA-190372	FGFR3c ligand binding and activation
R-HSA-190373	FGFR1c ligand binding and activation
R-HSA-190374	FGFR1c and Klotho ligand binding and activation
R-HSA-190375	FGFR2c ligand binding and activation
R-HSA-2033519	Activated point mutants of FGFR2
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-5654219	Phospholipase C-mediated cascade: FGFR1
R-HSA-5654221	Phospholipase C-mediated cascade; FGFR2
R-HSA-5654227	Phospholipase C-mediated cascade; FGFR3
R-HSA-5654228	Phospholipase C-mediated cascade; FGFR4
R-HSA-5654687	Downstream signaling of activated FGFR1
R-HSA-5654688	SHC-mediated cascade:FGFR1
R-HSA-5654689	PI-3K cascade:FGFR1
R-HSA-5654693	FRS-mediated FGFR1 signaling
R-HSA-5654695	PI-3K cascade:FGFR2
R-HSA-5654699	SHC-mediated cascade:FGFR2
R-HSA-5654700	FRS-mediated FGFR2 signaling
R-HSA-5654704	SHC-mediated cascade:FGFR3
R-HSA-5654706	FRS-mediated FGFR3 signaling
R-HSA-5654710	PI-3K cascade:FGFR3
R-HSA-5654712	FRS-mediated FGFR4 signaling
R-HSA-5654719	SHC-mediated cascade:FGFR4
R-HSA-5654720	PI-3K cascade:FGFR4
R-HSA-5654726	Negative regulation of FGFR1 signaling

MSigDB gene sets: 328 (showing top): RNGTGGGC_UNKNOWN, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GAANYNYGACNY_UNKNOWN, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, KEGG_MAPK_SIGNALING_PATHWAY, REACTOME_FGFR2C_LIGAND_BINDING_AND_ACTIVATION, REACTOME_SIGNALING_BY_FGFR, REACTOME_FGFR1_LIGAND_BINDING_AND_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_OSTEOBLAST_DIFFERENTIATION, GOBP_HORMONE_TRANSPORT, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_NEUROGENESIS

GO Biological Process (28): positive regulation of cell population proliferation (GO:0008284), fibroblast growth factor receptor signaling pathway (GO:0008543), regulation of phosphate transport (GO:0010966), obsolete positive regulation of vitamin D 24-hydroxylase activity (GO:0010980), neurogenesis (GO:0022008), regulation of cell migration (GO:0030334), negative regulation of bone mineralization (GO:0030502), intracellular phosphate ion homeostasis (GO:0030643), response to magnesium ion (GO:0032026), vitamin D catabolic process (GO:0042369), positive regulation of MAPK cascade (GO:0043410), cellular response to leptin stimulus (GO:0044320), negative regulation of osteoblast differentiation (GO:0045668), positive regulation of DNA-templated transcription (GO:0045893), negative regulation of hormone secretion (GO:0046888), phosphate ion homeostasis (GO:0055062), calcium ion homeostasis (GO:0055074), ERK1 and ERK2 cascade (GO:0070371), positive regulation of ERK1 and ERK2 cascade (GO:0070374), cellular response to vitamin D (GO:0071305), cellular response to interleukin-6 (GO:0071354), cellular response to parathyroid hormone stimulus (GO:0071374), positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway (GO:0090080), response to sodium phosphate (GO:1904383), MAPK cascade (GO:0000165), cell differentiation (GO:0030154), regulation of bone mineralization (GO:0030500), vitamin D metabolic process (GO:0042359)

GO Molecular Function (4): type 1 fibroblast growth factor receptor binding (GO:0005105), growth factor activity (GO:0008083), fibroblast growth factor receptor binding (GO:0005104), protein binding (GO:0005515)

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), endoplasmic reticulum lumen (GO:0005788), Golgi lumen (GO:0005796)

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
Downstream signaling of activated FGFR1	4
FGFR1 ligand binding and activation	2
IRS-mediated signalling	1
Intracellular signaling by second messengers	1
FGFR1 mutant receptor activation	1
FGFR3 mutant receptor activation	1
Signaling by FGFR4	1
FGFR3 ligand binding and activation	1
FGFR2 ligand binding and activation	1
FGFR2 mutant receptor activation	1
PI3K/AKT Signaling in Cancer	1
Metabolism of proteins	1
Downstream signaling of activated FGFR2	1
Downstream signaling of activated FGFR3	1
Downstream signaling of activated FGFR4	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
MAPK cascade	2
inorganic ion homeostasis	2
cellular anatomical structure	2
intracellular organelle lumen	2
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to fibroblast growth factor stimulus	1
phosphate ion transport	1
regulation of transport	1
nervous system development	1
cell differentiation	1
cell migration	1
regulation of cell motility	1
negative regulation of ossification	1
bone mineralization	1
regulation of bone mineralization	1
negative regulation of biomineral tissue development	1
phosphate ion homeostasis	1
intracellular chemical homeostasis	1
response to metal ion	1
steroid catabolic process	1
vitamin D metabolic process	1
fat-soluble vitamin catabolic process	1
regulation of MAPK cascade	1
positive regulation of intracellular signal transduction	1
cellular response to hormone stimulus	1
response to leptin	1
osteoblast differentiation	1
negative regulation of cell differentiation	1
regulation of osteoblast differentiation	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
negative regulation of cell communication	1
negative regulation of signaling	1
hormone secretion	1
regulation of hormone secretion	1
negative regulation of secretion by cell	1

Protein interactions and networks

STRING

1499 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FGF23	KL	Q9UEF7	999
FGF23	FGFR1	P11362	997
FGF23	FGFR4	P22455	985
FGF23	PHEX	P78562	981
FGF23	PTH	P01270	976
FGF23	KLB	Q86Z14	966
FGF23	GALNT3	Q14435	952
FGF23	SLC34A3	Q8N130	946
FGF23	FGFR3	P22607	937
FGF23	SLC34A1	Q06495	936
FGF23	CYP27B1	O15528	906
FGF23	DMP1	Q13316	899
FGF23	FGF8	P55075	893
FGF23	FGF9	P31371	863
FGF23	MEPE	Q9NQ76	863

IntAct

28 interactions, top by confidence:

A	B	Type	Score
Kl	FGF23	psi-mi:“MI:0915”(physical association)	0.730
Kl	FGF23	psi-mi:“MI:0407”(direct interaction)	0.730
FGF23	Kl	psi-mi:“MI:0915”(physical association)	0.730
FGF23	Kl	psi-mi:“MI:0407”(direct interaction)	0.730
FGF23	SMAD4	psi-mi:“MI:0915”(physical association)	0.550
SMAD4	FGF23	psi-mi:“MI:2364”(proximity)	0.550
SMAD4	FGF23	psi-mi:“MI:0915”(physical association)	0.550
FGFR1	Kl	psi-mi:“MI:0915”(physical association)	0.540
FGFR1	FGF23	psi-mi:“MI:0407”(direct interaction)	0.540
Fgfr3	Kl	psi-mi:“MI:0914”(association)	0.500
Fgfr1	Kl	psi-mi:“MI:0914”(association)	0.500
Fgfr4	Kl	psi-mi:“MI:0914”(association)	0.500
FGF23	AKT1	psi-mi:“MI:2364”(proximity)	0.470
AKT1	FGF23	psi-mi:“MI:0915”(physical association)	0.470
FBXW7	FGF23	psi-mi:“MI:2364”(proximity)	0.270
SPOP	FGF23	psi-mi:“MI:2364”(proximity)	0.270
FGF23	SPOP	psi-mi:“MI:2364”(proximity)	0.270
FGF23	EGFR	psi-mi:“MI:2364”(proximity)	0.270
FGF23	PTPN11	psi-mi:“MI:2364”(proximity)	0.270
FGF23	TP53	psi-mi:“MI:2364”(proximity)	0.270
FGF23	PTEN	psi-mi:“MI:2364”(proximity)	0.270
FGF23	BRAF	psi-mi:“MI:2364”(proximity)	0.270
FGFR2	FGF23	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (6): FGF23 (Co-localization), FGFR1 (Affinity Capture-Western), KL (Affinity Capture-Western), FGF23 (Affinity Capture-RNA), FGFR1 (Affinity Capture-Western), FGF23 (Affinity Capture-Western)

ESM2 similar proteins: A0MTF4, M3X9S6, O15520, O35565, O42596, O43320, O54769, O60258, O95750, P05524, P08620, P10767, P11403, P12034, P15656, P21658, P31371, P36363, P36364, P36386, P37237, P48802, P48803, P48804, P48805, P48806, P48807, P48808, P54130, P55075, P63075, P63076, P70492, Q02195, Q08C93, Q20FD0, Q2HXK8, Q3ZFI5, Q6UWX4, Q90722

Diamond homologs: A0MTF4, A6P7H6, M3X9S6, O15520, O35565, O43320, O54769, O57341, P03968, P05230, P05524, P10767, P11403, P11487, P12034, P12226, P15656, P19596, P20002, P21658, P21781, P31371, P34004, P36363, P36364, P36386, P37237, P41444, P48801, P48802, P48803, P48804, P48805, P48806, P48807, P48808, P54130, P55075, P61148, P61149

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
FAM20C	“down-regulates activity”	FGF23	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 15 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	5	44.0×	2e-05
PIP3 activates AKT signaling	5	30.4×	5e-05

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of ERK1 and ERK2 cascade	5	38.7×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

256 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	4
Uncertain significance	153
Likely benign	48
Benign	18

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
1072118	NM_020638.3(FGF23):c.526C>T (p.Arg176Trp)	Pathogenic
1179114	GRCh37/hg19 12p13.32(chr12:4477393-4488878)	Pathogenic
36135	NM_020638.3(FGF23):c.536G>A (p.Arg179Gln)	Pathogenic
4709911	NM_020638.3(FGF23):c.471C>A (p.Phe157Leu)	Pathogenic
5025	NM_020638.3(FGF23):c.527G>A (p.Arg176Gln)	Pathogenic
5028	NM_020638.3(FGF23):c.287T>C (p.Met96Thr)	Pathogenic
5029	NM_020638.3(FGF23):c.386C>T (p.Ser129Phe)	Pathogenic
216929	NM_020638.3(FGF23):c.260G>A (p.Gly87Asp)	Likely pathogenic
2681728	NM_020638.3(FGF23):c.515_529del (p.Pro172_Arg176del)	Likely pathogenic
3574584	NM_020638.3(FGF23):c.211+1G>A	Likely pathogenic
36134	NM_020638.3(FGF23):c.162G>C (p.Gln54His)	Likely pathogenic

SpliceAI

190 predictions. Top by Δscore:

Variant	Effect	Δscore
12:4370779:TAGTG:T	acceptor_gain	1.0000
12:4370780:AGTG:A	acceptor_gain	1.0000
12:4370782:TG:T	acceptor_gain	1.0000
12:4370783:GC:G	acceptor_loss	1.0000
12:4370784:C:CC	acceptor_gain	1.0000
12:4370784:C:CG	acceptor_loss	1.0000
12:4370785:T:A	acceptor_loss	1.0000
12:4372590:TCACT:T	donor_loss	1.0000
12:4372591:CACTG:C	donor_loss	1.0000
12:4372592:A:AC	donor_gain	1.0000
12:4372593:C:CA	donor_gain	1.0000
12:4372593:CT:C	donor_gain	1.0000
12:4372593:CTG:C	donor_gain	1.0000
12:4372593:CTGA:C	donor_gain	1.0000
12:4372593:CTGAT:C	donor_gain	1.0000
12:4379370:A:AC	donor_gain	1.0000
12:4379371:C:CC	donor_gain	1.0000
12:4370781:GTG:G	acceptor_gain	0.9900
12:4372585:GAAAC:G	donor_loss	0.9900
12:4372586:AAACT:A	donor_loss	0.9900
12:4372587:AACTC:A	donor_loss	0.9900
12:4372588:ACTCA:A	donor_loss	0.9900
12:4372596:AT:A	donor_gain	0.9900
12:4372597:T:C	donor_gain	0.9900
12:4372609:G:A	donor_gain	0.9900
12:4372695:CAC:C	acceptor_gain	0.9900
12:4372695:CACCT:C	acceptor_loss	0.9900
12:4372697:CCTAT:C	acceptor_loss	0.9900
12:4372698:C:CA	acceptor_loss	0.9900
12:4372699:T:A	acceptor_loss	0.9900

AlphaMissense

1646 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:4370755:A:G	F115S	0.999
12:4370628:G:C	F157L	0.998
12:4370628:G:T	F157L	0.998
12:4370629:A:C	F157C	0.998
12:4370630:A:G	F157L	0.998
12:4370755:A:C	F115C	0.998
12:4370629:A:G	F157S	0.997
12:4372610:C:A	G100V	0.997
12:4372624:G:C	C95W	0.997
12:4372696:A:C	S71R	0.996
12:4372696:A:T	S71R	0.996
12:4379372:T:G	S71R	0.996
12:4370760:G:C	C113W	0.995
12:4370761:C:T	C113Y	0.995
12:4372625:C:T	C95Y	0.995
12:4372628:A:T	L94H	0.995
12:4372697:C:A	S71I	0.995
12:4379419:A:G	I55T	0.995
12:4370720:A:C	Y127D	0.994
12:4370754:G:C	F115L	0.994
12:4370754:G:T	F115L	0.994
12:4370756:A:G	F115L	0.994
12:4370761:C:G	C113S	0.994
12:4370762:A:T	C113S	0.994
12:4379425:A:G	L53P	0.994
12:4370761:C:A	C113F	0.993
12:4372639:G:C	S90R	0.993
12:4372639:G:T	S90R	0.993
12:4372641:T:G	S90R	0.993
12:4372691:A:G	L73P	0.993

dbSNP variants (sampled 300 via entrez): RS1000231781 (12:4369973 T>C), RS1000311800 (12:4370871 A>C), RS1000317348 (12:4377302 G>T), RS1000422264 (12:4376862 A>C,G), RS1000673281 (12:4375980 A>G), RS1000689698 (12:4378481 T>C), RS1000741625 (12:4378243 C>T), RS1001036478 (12:4372460 G>A), RS1001377020 (12:4380741 A>C,T), RS1001440596 (12:4381492 T>C), RS1001701294 (12:4372032 T>C), RS1001829830 (12:4376519 T>C), RS1002085723 (12:4373231 T>G), RS1002895658 (12:4377426 T>C), RS1003196351 (12:4380824 G>A)

Disease associations

OMIM: gene MIM:605380 | disease phenotypes: MIM:193100, MIM:617993, MIM:211900

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant hypophosphatemic rickets	Strong	Autosomal dominant
tumoral calcinosis, hyperphosphatemic, familial, 2	Strong	Autosomal recessive
familial hyperphosphatemic tumoral calcinosis/hyperphosphatemic hyperostosis syndrome	Strong	Autosomal recessive
tumoral calcinosis, hyperphosphatemic, familial, 1	Supportive	Autosomal recessive

Mondo (6): autosomal dominant hypophosphatemic rickets (MONDO:0008660), tumoral calcinosis, hyperphosphatemic, familial, 2 (MONDO:0060714), familial hyperphosphatemic tumoral calcinosis/hyperphosphatemic hyperostosis syndrome (MONDO:0100251), hypophosphatemic rickets (MONDO:0024300), tumoral calcinosis, hyperphosphatemic, familial, 1 (MONDO:0100252), (MONDO:0008897)

Orphanet (3): Autosomal dominant hypophosphatemic rickets (Orphanet:89937), Familial hyperphosphatemic tumoral calcinosis/Hyperphosphatemic hyperostosis syndrome (Orphanet:306661), Familial tumoral calcinosis (Orphanet:53715)

HPO phenotypes

28 total (28 of 28 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000117	Renal phosphate wasting
HP:0000164	Abnormality of the dentition
HP:0001324	Muscle weakness
HP:0001510	Growth delay
HP:0001891	Iron deficiency anemia
HP:0002148	Hypophosphatemia
HP:0002150	Hypercalciuria
HP:0002653	Bone pain
HP:0002748	Rickets
HP:0002749	Osteomalacia
HP:0002814	Abnormality of the lower limb
HP:0002901	Hypocalcemia
HP:0002979	Bowing of the legs
HP:0002986	Radial bowing
HP:0003109	Hyperphosphaturia
HP:0003155	Elevated circulating alkaline phosphatase concentration
HP:0003324	Generalized muscle weakness
HP:0003829	Typified by incomplete penetrance
HP:0004322	Short stature
HP:0004912	Hypophosphatemic rickets
HP:0007618	Subcutaneous calcification
HP:0012378	Fatigue
HP:0012408	Medullary nephrocalcinosis
HP:0020110	Bone fracture
HP:0030757	Tooth abscess
HP:0100512	Decreased circulating vitamin D concentration

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000703_5	Phosphorus levels	4.000000e-09
GCST001792_1	Colorectal cancer	3.000000e-08
GCST001792_2	Colorectal cancer	5.000000e-10
GCST003986_4	Migraine	1.000000e-18
GCST005981_9	Phosphorus levels	3.000000e-18

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004861	phosphorus measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D063730	Rickets, Hypophosphatemic	C05.116.198.816.875; C18.452.104.816.875; C18.452.174.845.875; C18.452.750.400.750; C18.654.521.500.133.770.734.875
C562791	Hypophosphatemic Rickets, Autosomal Dominant (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3713913 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

8 potent at pChembl≥5 of 9 total, top 8 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.85	IC50	140	nM	CHEMBL4755048
6.70	IC50	200	nM	CHEMBL4790497
6.43	IC50	370	nM	CHEMBL4798326
6.41	IC50	390	nM	CHEMBL4749792
6.28	IC50	520	nM	CHEMBL4781167
5.55	IC50	2790	nM	CHEMBL4754240
5.30	IC50	5000	nM	CHEMBL4764072
5.00	IC50	1e+04	nM	CHEMBL4750493

PubChem BioAssay actives

8 with measured affinity, of 45 total; 8 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(NE)-N-[[2-[(E)-2-(4-methylphenyl)ethenyl]phenyl]methylidene]hydroxylamine	1683352: Inhibition of FGF23 (unknown origin)-mediated activation of FGFR/alpha-Klotho transfected in HEK293T cells cotransfected with ERK luciferase reporter measured after 5 hrs by dual-luciferase reporter assay	ic50	0.1400	uM
(NE)-N-[[2-[(E)-2-(4-methylphenyl)ethenyl]cyclopenten-1-yl]methylidene]hydroxylamine	1683352: Inhibition of FGF23 (unknown origin)-mediated activation of FGFR/alpha-Klotho transfected in HEK293T cells cotransfected with ERK luciferase reporter measured after 5 hrs by dual-luciferase reporter assay	ic50	0.2000	uM
(NE)-N-[[2-[(E)-2-(4-fluorophenyl)ethenyl]cyclopenten-1-yl]methylidene]hydroxylamine	1683352: Inhibition of FGF23 (unknown origin)-mediated activation of FGFR/alpha-Klotho transfected in HEK293T cells cotransfected with ERK luciferase reporter measured after 5 hrs by dual-luciferase reporter assay	ic50	0.3700	uM
(NE)-N-[[2-[(E)-2-(4-methylphenyl)ethenyl]-3-pyridinyl]methylidene]hydroxylamine	1683352: Inhibition of FGF23 (unknown origin)-mediated activation of FGFR/alpha-Klotho transfected in HEK293T cells cotransfected with ERK luciferase reporter measured after 5 hrs by dual-luciferase reporter assay	ic50	0.3900	uM
(NE)-N-[[2-[(E)-2-(4-methylphenyl)ethenyl]cyclohexen-1-yl]methylidene]hydroxylamine	1683352: Inhibition of FGF23 (unknown origin)-mediated activation of FGFR/alpha-Klotho transfected in HEK293T cells cotransfected with ERK luciferase reporter measured after 5 hrs by dual-luciferase reporter assay	ic50	0.5200	uM
(NE)-N-[[2-(4-tert-butylphenyl)cyclopenten-1-yl]methylidene]hydroxylamine	1683352: Inhibition of FGF23 (unknown origin)-mediated activation of FGFR/alpha-Klotho transfected in HEK293T cells cotransfected with ERK luciferase reporter measured after 5 hrs by dual-luciferase reporter assay	ic50	2.7900	uM
(NE)-N-[[2-[(E)-2-phenylethenyl]cyclopenten-1-yl]methylidene]hydroxylamine	1683352: Inhibition of FGF23 (unknown origin)-mediated activation of FGFR/alpha-Klotho transfected in HEK293T cells cotransfected with ERK luciferase reporter measured after 5 hrs by dual-luciferase reporter assay	ic50	5.0000	uM
(NE)-N-[(2-phenylcyclopenten-1-yl)methylidene]hydroxylamine	1683352: Inhibition of FGF23 (unknown origin)-mediated activation of FGFR/alpha-Klotho transfected in HEK293T cells cotransfected with ERK luciferase reporter measured after 5 hrs by dual-luciferase reporter assay	ic50	10.0000	uM

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Phosphates	decreases reaction, decreases uptake, affects metabolic processing, affects reaction, affects abundance (+4 more)	18
Calcitriol	increases expression, affects response to substance, decreases abundance	6
Vitamin D	affects reaction, affects metabolic processing, increases metabolic processing, affects abundance	5
Calcium	affects expression	2
Phosphorus	affects abundance, affects transport, increases expression	2
perfluorotetradecanoic acid	increases expression	1
bisphenol A	decreases methylation	1
ethyl-p-hydroxybenzoate	decreases expression	1
perfluorooctanoic acid	increases expression	1
beta-glycerophosphoric acid	increases expression	1
calcium bicarbonate	affects cotreatment, decreases expression	1
sodium chlorate	decreases uptake, decreases reaction	1
perfluorobutyric acid	increases expression	1
perfluorodecanoic acid	decreases expression	1
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases reaction, decreases uptake	1
perfluoro-n-nonanoic acid	decreases expression	1
2-cyclopentyl-4-(5-phenyl-1H-pyrrolo(2,3-b)pyridin-3-yl)-benzoic acid	decreases reaction, decreases uptake	1
perfluoroundecanoic acid	decreases expression	1
Sevelamer	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Pamidronate	decreases expression	1
Arsenic	affects expression	1
Benzo(a)pyrene	increases methylation, affects methylation	1
Cadmium	increases abundance, increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	increases methylation	1
Phosphorus, Dietary	increases expression	1
Cadmium Chloride	increases abundance, increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4678002	Binding	Inhibition of FGF23 (unknown origin)-mediated activation of FGFR/alpha-Klotho transfected in HEK293T cells cotransfected with ERK luciferase reporter at 10 uM measured after 5 hrs by dual-luciferase reporter assay relative to control	Design and development of FGF-23 antagonists: Definition of the pharmacophore and initial structure-activity relationships probed by synthetic analogues. — Bioorg Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B9XY	Abcam THP-1 FGF23 KO	Cancer cell line	Male
CVCL_C6ZS	Abcam PC-3 FGF23 KO	Cancer cell line	Male
CVCL_E0D0	Ubigene HeLa FGF23 KO	Cancer cell line	Female

Clinical trials (associated diseases)

10 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01237288	PHASE3	COMPLETED	Therapeutic Use of Oral Sodium Phosphate (Z-521) in Primary Hypophosphatemic Rickets
NCT03581591	PHASE3	COMPLETED	Open Label Trial Assessing Safety and Efficacy of Burosumab (KRN23), in a Patient With ENS and Hypophosphatemic Rickets
NCT00473187	PHASE1	UNKNOWN	Effects of GH on Body Proportions and Final Height in X-Linked Hypophosphatemic Rickets
NCT02233322	Not specified	COMPLETED	Iron Therapy for Autosomal Dominant Hypophosphatemic Rickets: A Pilot Project.
NCT03748966	EARLY_PHASE1	COMPLETED	Calcitriol Monotherapy for X-Linked Hypophosphatemia
NCT00844740	Not specified	WITHDRAWN	Calcimimetics in Hypophosphatemic Rickets
NCT01578824	Not specified	COMPLETED	Assessment Of Vitamin D Role In The Pathogenesis Of Asthma In Vitamin D Resistent Patients
NCT03348644	Not specified	COMPLETED	Milk Products in the Treatment of Hypophosphatemic Rickets
NCT03651505	Not specified	ACTIVE_NOT_RECRUITING	X-linked Hypophosphatemia Disease Monitoring Program
NCT04184661	Not specified	COMPLETED	Burosumab and 1-25 (OH) Vitamin D on Human Osteoclasts