PHEX

Summary

PHEX (phosphate regulating endopeptidase X-linked, HGNC:8918) is a protein-coding gene on chromosome Xp22.11, encoding Phosphate-regulating neutral endopeptidase PHEX (P78562). Peptidase that cleaves SIBLING (small integrin-binding ligand, N-linked glycoprotein)-derived ASARM peptides, thus regulating their biological activity. It is haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene is a transmembrane endopeptidase that belongs to the type II integral membrane zinc-dependent endopeptidase family. The protein is thought to be involved in bone and dentin mineralization and renal phosphate reabsorption. Mutations in this gene cause X-linked hypophosphatemic rickets. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 5251 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked dominant hypophosphatemic rickets (Definitive, ClinGen)
• GWAS associations: 5
• Clinical variants (ClinVar): 1,627 total — 733 pathogenic, 143 likely-pathogenic
• Phenotypes (HPO): 71
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000444

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8918
Approved symbol	PHEX
Name	phosphate regulating endopeptidase X-linked
Location	Xp22.11
Locus type	gene with protein product
Status	Approved
Aliases	PEX, HPDR1, HYP1, XLH
Ensembl gene	ENSG00000102174
Ensembl biotype	protein_coding
OMIM	300550
Entrez	5251

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 4 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000379374, ENST00000456621, ENST00000475778, ENST00000682888, ENST00000683162, ENST00000683214, ENST00000683289, ENST00000683917, ENST00000684143, ENST00000684356, ENST00000684745

RefSeq mRNA: 2 — MANE Select: NM_000444 NM_000444, NM_001282754

CCDS: CCDS14204

Canonical transcript exons

ENST00000379374 — 22 exons

Exon	Start	End
ENSE00000666734	22076388	22076474
ENSE00000666735	22077476	22077702
ENSE00000666737	22090429	22090497
ENSE00000666740	22099006	22099151
ENSE00000666741	22111467	22111560
ENSE00000666742	22114458	22114586
ENSE00000666743	22133523	22133624
ENSE00000666744	22168312	22168389
ENSE00000666745	22178273	22178376
ENSE00000666746	22190444	22190502
ENSE00000666747	22212904	22212958
ENSE00000666750	22226443	22226508
ENSE00000666751	22227507	22227611
ENSE00000666752	22245333	22245409
ENSE00000872549	22219036	22219103
ENSE00000872550	22221613	22221743
ENSE00001108643	22038469	22038537
ENSE00001480713	22247851	22251310
ENSE00001480775	22032325	22033123
ENSE00003529093	22047050	22047211
ENSE00003554995	22093983	22094099
ENSE00003670236	22096955	22097038

Expression profiles

Bgee: expression breadth ubiquitous, 139 present calls, max score 92.24.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.6414 / max 198.9794, expressed in 64 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
195738	0.2641	22
195741	0.1932	23
195746	0.0484	3
195744	0.0437	7
195739	0.0302	20
195742	0.0178	6
195745	0.0123	3
195743	0.0120	4
195740	0.0116	4
195737	0.0080	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	92.24	gold quality
tibia	UBERON:0000979	91.01	gold quality
oocyte	CL:0000023	85.48	gold quality
right lung	UBERON:0002167	76.02	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.78	gold quality
jejunal mucosa	UBERON:0000399	71.64	gold quality
upper lobe of left lung	UBERON:0008952	68.14	gold quality
upper lobe of lung	UBERON:0008948	67.22	gold quality
lung	UBERON:0002048	64.35	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	63.26	gold quality
smooth muscle tissue	UBERON:0001135	63.06	gold quality
spinal cord	UBERON:0002240	62.23	gold quality
tibialis anterior	UBERON:0001385	62.21	silver quality
blood vessel layer	UBERON:0004797	61.97	gold quality
body of uterus	UBERON:0009853	61.84	gold quality
sperm	CL:0000019	61.68	gold quality
myometrium	UBERON:0001296	61.48	gold quality
duodenum	UBERON:0002114	61.16	gold quality
ileal mucosa	UBERON:0000331	61.08	silver quality
pancreatic ductal cell	CL:0002079	61.03	silver quality
male germ cell	CL:0000015	60.91	gold quality
medial globus pallidus	UBERON:0002477	60.25	silver quality
gall bladder	UBERON:0002110	60.19	gold quality
stromal cell of endometrium	CL:0002255	59.81	gold quality
lymph node	UBERON:0000029	59.68	gold quality
orbitofrontal cortex	UBERON:0004167	59.51	gold quality
lateral globus pallidus	UBERON:0002476	58.95	gold quality
globus pallidus	UBERON:0001875	58.72	silver quality
decidua	UBERON:0002450	58.43	gold quality
lower lobe of lung	UBERON:0008949	58.41	silver quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.98
E-CURD-112	no	2.81

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CTNNB1, DNMT1, JUN, NFIL3, PARP1, RELA, SOX9, VDR

miRNA regulators (miRDB)

97 targeting PHEX, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548C-3P	99.99	74.01	7587
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-3658	99.96	73.87	4379
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-6715A-3P	99.83	68.05	1473
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-944	99.82	70.85	3042

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• 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)
• regulates fgf23 expression as part of a potential hormonal axis between bone and kidney that controls systemic phosphate homeostasis and mineralization (PMID:12874285)
• Anthropometric characteristics arising from mutations of PHEX were evaluated. (PMID:15057978)
• FGF23 is processed by proprotein convertases but not by PHEX. (PMID:15268897)
• a cis-element is required for PHEX gene transcription that participates in negative feedback control of PHEX expression and thereby modulates the actions of phosphatonin (PMID:15337762)
• In our present study, we found that suppression of PHEX expression by PHEX antisense in human osteoblast cells caused an increase in cathepsin D expression at protein, but not mRNA, levels. (PMID:15896324)
• Overexpression of human PHEX under the human beta-actin promoter in hypophosphatemia mice rescued the bone phenotype almost completely, but did not affect phosphate homeostasis. (PMID:15940367)
• 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)
• XLH is caused by mutations in the PHEX (phosphate regulating gene with homology to endopeptidases) gene, which is located on Xp22.1. (PMID:16437029)
• Our data support previous findings and therefore contribute to the decipherment of the pathogenetic pathways of XLH. (PMID:17406123)
• The results suggest that PHEX gene mutations were responsible for XLH in these patients and these mutations may contribute to a higher serum fibroblast growth factor 23 level. (PMID:18046499)
• Skeletal disease tended to be more severe in the group with a mutation in the C-terminal half of the PHEX gene, but no genotype-phenotype correlation was detected in other comparisons. (PMID:18162710)
• These data provide evidence that aberrant Phex function in osteoblasts and/or osteocytes alone is sufficient to underlie the hyp-mouse phenotype. (PMID:18172553)
• mRNA of PHEX involved in the pathogenesis of hypophosphataemic rickets is highly expressed in cells of the osteoblasts/osteocyte lineage. (PMID:18214537)
• Normal growth and muscle dysfunction in X-linked hypophosphatemic rickets associated with a novel mutation in the PHEX gene. (PMID:18252791)
• U(2)OS cells transfected with wild-type TNAP and polymorphism TNAP cDNA showed PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) induction as in SaOS-2 cells. (PMID:18455459)
• Data indicate that there is no single predominant PHEX mutation responsible for X-linked hypophosphatemic rickets. (PMID:18625346)
• inactivating mutations in PHEX increase, through yet unknown mechanisms, FGF23 synthesis and thus enhance renal phosphate excretion-REVIEW (PMID:18660670)
• missense mutations in X-linked dominant hypophosphatemic rickets (PMID:19219621)
• We conclude that molecular genetic analysis confirms the clinical diagnosis of XLH and should include sequence analysis as well as the search for large deletions, which is facilitated by MLPA. (PMID:19513579)
• Case Report: describe a novel nonsense mutation in exon 3 of the PHEX gene (Glu(96)X (c.286G>T) causing X linked hypophosphatemic rickets in a mother and daughter of Indian ancestry. (PMID:20664300)
• Cooperative role of NF-{kappa}B and poly(ADP-ribose) polymerase 1 (PARP-1) in the TNF-induced inhibition of PHEX expression in osteoblasts. (PMID:20817730)
• M. leprae is capable of inhibiting PHEX expression in osteoblasts in a very similar manner as that observed in Schwann cells, indicating that the bacillus modulates PHEX in both osteogenic and non-osteogenic cells. (PMID:20835608)
• Data show the wide spectrum of genetic variation that can be seen in PHEX, FGF23 and DMP1 when screening a large cohort with hypophosphatemic rickets. (PMID:21050253)
• Three novel mutations in the PHEX gene in Chinese subjects with hypophosphatemic rickets extends genotypic variability. (PMID:21293852)
• Novel PHEX nonsense mutation in a patient with X-linked hypophosphatemic rickets and review of current therapeutic regimens. (PMID:21553362)
• PTHrP(1-34)-mediated repression of the PHEX gene in osteoblastic cells involves the transcriptional repressor E4BP4. (PMID:21826652)
• Hypophosphatemic rickets (HR) is a rare hereditary disease in which dental problems in terms of spontaneous periapical infections are frequently reported (PMID:21902707)
• tubular reabsorption of phosphate and 1,25(OH)2D serum levels are associated with PHEX mutation type in X-linked dominant Hypophosphatemic Rickets (PMID:21902834)
• Analysis of PHEX mRNA from peripheral blood would be appropriate for the first screening step in determining the etiology of FGF23-related hypophosphatemic rickets. (PMID:22577109)
• Mutations in PHEX and DMP1 play a role in causing hypophosphatemic rickets. (PMID:22695891)
• PHEX gene mutations were responsible for X-linked hypophosphatemia in these Chinese families. (PMID:22713460)
• study shows that PHEX mutation is a common cause of either familial or sporadic hypophosphatemic rickets in Turkish population (PMID:23079138)
• 15 PHEX mutations have been reported in Chinese populations with X-linked hypophosphatemic rickets (PMID:23813354)
• The c.732+1G>T mutation of PHEX is associated with hypophosphatasia pedigree. (PMID:24078575)
• Two novel mutations were detected unrelated families with hypophosphatemic rickets. (PMID:24836714)
• exon 22 is the mutation hot spot and missense mutation is the most common type of mutation in the PHEX gene in Chinese X-link dominate hypophosphatemic rickets (XLH) patients (PMID:24857004)
• PHEX c.*231A > G can masquerade as sporadic or X-linked recessive HR. (PMID:25042154)
• A novel de novo nonsense mutation of the PHEX gene has been identified in Chinese family expanding the mutation spectrum of PHEX leading to X-linked hypophosphatemic rickets. (PMID:25839938)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	phex	ENSDARG00000062363
mus_musculus	Phex	ENSMUSG00000057457
rattus_norvegicus	Phex	ENSRNOG00000023440
drosophila_melanogaster	Nepl9	FBGN0032613
caenorhabditis_elegans		WBGENE00022874

Paralogs (6): ECE1 (ENSG00000117298), MMEL1 (ENSG00000142606), ECE2 (ENSG00000145194), ECEL1 (ENSG00000171551), MME (ENSG00000196549), KEL (ENSG00000197993)

Protein

Protein identifiers

Phosphate-regulating neutral endopeptidase PHEX — P78562 (reviewed: P78562)

Alternative names: Metalloendopeptidase homolog PEX, Vitamin D-resistant hypophosphatemic rickets protein, X-linked hypophosphatemia protein

All UniProt accessions (6): P78562, A0A804HJR7, A0A804HKN7, A0A804HKT0, A0A804HL45, A0A804HLA0

UniProt curated annotations — full annotation on UniProt →

Function. Peptidase that cleaves SIBLING (small integrin-binding ligand, N-linked glycoprotein)-derived ASARM peptides, thus regulating their biological activity. Cleaves ASARM peptides between Ser and Glu or Asp residues. Regulates osteogenic cell differentiation and bone mineralization through the cleavage of the MEPE-derived ASARM peptide. Promotes dentin mineralization and renal phosphate reabsorption by cleaving DMP1- and MEPE-derived ASARM peptides. Inhibits the cleavage of MEPE by CTSB/cathepsin B thus preventing MEPE degradation.

Subunit / interactions. Interacts with MEPE; the interaction is zinc-dependent (via ASARM motif).

Subcellular location. Cell membrane.

Tissue specificity. Specifically expressed in ovary. Expressed at low levels in kidney.

Disease relevance. Hypophosphatemic rickets, X-linked dominant (XLHRD) [MIM:307800] A disorder characterized by impaired phosphate uptake in the kidney, which is likely to be caused by abnormal regulation of sodium phosphate cotransport in the proximal tubules. Clinical manifestations include skeletal deformities, growth failure, craniosynostosis, paravertebral calcifications, pseudofractures in lower extremities, and muscular hypotonia with onset in early childhood. X-linked hypophosphatemic rickets is the most common form of hypophosphatemia with an incidence of 1 in 20000. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 zinc ion per subunit.

Similarity. Belongs to the peptidase M13 family.

RefSeq proteins (2): NP_000435, NP_001269683 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000718	Peptidase_M13	Family
IPR008753	Peptidase_M13_N	Domain
IPR018497	Peptidase_M13_C	Domain
IPR024079	MetalloPept_cat_dom_sf	Homologous_superfamily
IPR042089	Peptidase_M13_dom_2	Homologous_superfamily

Pfam: PF01431, PF05649

Enzyme classification (BRENDA):

• EC 3.4.24.B15 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

UniProt features (59 total): sequence variant 33, glycosylation site 8, disulfide bond 5, sequence conflict 3, binding site 3, topological domain 2, active site 2, chain 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P78562-F1	94.58	0.90

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 (2): 581; 646 (proton donor)

Ligand- & substrate-binding residues (3): 580; 584; 642

Disulfide bonds (5): 54–59, 77–733, 85–693, 142–406, 617–746

Glycosylation sites (8): 71, 238, 263, 290, 301, 377, 484, 736

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 309 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, HNF3ALPHA_Q6, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOMF_METALLOPEPTIDASE_ACTIVITY, GOBP_CELLULAR_RESPONSE_TO_LIPID, NKX25_02, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, TAL1ALPHAE47_01, AAAYRNCTG_UNKNOWN, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELL_CELL_SIGNALING, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_BONE_DEVELOPMENT, GOBP_PROTEIN_MATURATION

GO Biological Process (17): skeletal system development (GO:0001501), proteolysis (GO:0006508), cell-cell signaling (GO:0007267), protein processing (GO:0016485), organophosphate metabolic process (GO:0019637), bone mineralization (GO:0030282), lung development (GO:0030324), protein modification process (GO:0036211), odontogenesis (GO:0042476), bone development (GO:0060348), response to growth hormone (GO:0060416), cellular response to vitamin D (GO:0071305), cellular response to parathyroid hormone stimulus (GO:0071374), response to sodium phosphate (GO:1904383), response to insulin-like growth factor stimulus (GO:1990418), biomineral tissue development (GO:0031214), response to vitamin D (GO:0033280)

GO Molecular Function (7): metalloendopeptidase activity (GO:0004222), zinc ion binding (GO:0008270), protein binding (GO:0005515), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (5): endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), perinuclear region of cytoplasm (GO:0048471), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
animal organ development	3
cytoplasm	3
protein metabolic process	2
endomembrane system	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
system development	1
cell communication	1
signaling	1
proteolysis	1
protein maturation	1
phosphorus metabolic process	1
ossification	1
biomineral tissue development	1
respiratory tube development	1
respiratory system development	1
macromolecule modification	1
animal organ morphogenesis	1
skeletal system development	1
response to peptide hormone	1
response to vitamin D	1
cellular response to vitamin	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
cellular response to hormone stimulus	1
response to parathyroid hormone	1
response to salt	1
response to hormone	1
tissue development	1
response to vitamin	1
response to lipid	1
response to oxygen-containing compound	1
endopeptidase activity	1
metallopeptidase activity	1
transition metal ion binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1

Protein interactions and networks

STRING

846 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PHEX	FGF23	Q9GZV9	981
PHEX	SLC34A3	Q8N130	942
PHEX	MEPE	Q9NQ76	924
PHEX	ENPP1	P22413	908
PHEX	SLC34A1	Q06495	907
PHEX	KL	Q9UEF7	882
PHEX	DMP1	Q13316	871
PHEX	PTH	P01270	859
PHEX	GALNT3	Q14435	831
PHEX	SMS	P52788	814
PHEX	CYP27B1	O15528	802
PHEX	BGLAP	P02818	775
PHEX	SOST	Q9BQB4	754
PHEX	CLCN5	P51795	693
PHEX	FAM20C	Q8IXL6	686

IntAct

6 interactions, top by confidence:

A	B	Type	Score
PHEX	MEPE	psi-mi:“MI:0407”(direct interaction)	0.540
MEPE	PHEX	psi-mi:“MI:0915”(physical association)	0.540
PHEX	NAXD	psi-mi:“MI:0915”(physical association)	0.400
PHEX		psi-mi:“MI:0915”(physical association)	0.000

BioGRID (4): CARKD (Affinity Capture-MS), CARKD (Affinity Capture-MS), HNRNPA0 (Cross-Linking-MS (XL-MS)), PHEX (Protein-peptide)

ESM2 similar proteins: A0A1Y9G8H0, A0A452E9Y6, A1A4K5, A1KZ92, A5JUY8, P05164, P07202, P09933, P11247, P11678, P14650, P15396, P22079, P22413, P35419, P43446, P49290, P49340, P57110, P70669, P78562, P80025, Q01603, Q08410, Q13822, Q20616, Q23490, Q2KIY5, Q3TCN2, Q4QQW8, Q5R5M5, Q5SW46, Q64610, Q6DYE8, Q6P9A2, Q801F7, Q8CIY2, Q8HYB7, Q8HZK2, Q8HZK3

Diamond homologs: A0A0B4K692, B2RQR8, F1N476, O16796, O44857, O95672, P07861, P08049, P08473, P0C1T0, P0DPD6, P0DPD8, P0DPD9, P0DPE2, P42891, P42892, P42893, P70669, P78562, P97739, Q18673, Q22523, Q495T6, Q4PZA2, Q5RE69, Q61391, Q8IS64, Q8T062, Q9JHL3, Q9JLI3, Q9JMI0, Q9W436, Q9W5Y0, W4VS99, P23276, Q9EQF2, P19621, A5PK19, A5WVX1, P0DPD7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1627 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	733
Likely pathogenic	143
Uncertain significance	275
Likely benign	121
Benign	108

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1003074	NC_000023.10:g.(?22151640)(22151741_?)dup	Pathogenic
1035780	NM_000444.6(PHEX):c.1412_1417del (p.Ala471_Leu473delinsVal)	Pathogenic
1039336	NM_000444.6(PHEX):c.482G>C (p.Arg161Pro)	Pathogenic
1052063	NM_000444.6(PHEX):c.2179T>C (p.Phe727Leu)	Pathogenic
1058288	NM_000444.6(PHEX):c.819_845del (p.Val274_Ala282del)	Pathogenic
1066718	NM_000444.6(PHEX):c.733-2A>C	Pathogenic
1067659	NM_000444.6(PHEX):c.1600C>A (p.Pro534Thr)	Pathogenic
1068306	NM_000444.6(PHEX):c.437-1G>C	Pathogenic
1068695	NM_000444.6(PHEX):c.1982_1986dup (p.Asp663Ter)	Pathogenic
1068962	NM_000444.6(PHEX):c.552del (p.Lys184fs)	Pathogenic
1069144	NM_000444.6(PHEX):c.468dup (p.Leu157fs)	Pathogenic
1069276	NM_000444.6(PHEX):c.779T>G (p.Leu260Ter)	Pathogenic
1069386	NM_000444.6(PHEX):c.1079+2T>G	Pathogenic
1069401	NM_000444.6(PHEX):c.587del (p.Gly196fs)	Pathogenic
1069459	NM_000444.6(PHEX):c.1398dup (p.Glu467fs)	Pathogenic
1069653	NM_000444.6(PHEX):c.1543_1544del (p.Gln515fs)	Pathogenic
1069836	NC_000023.10:g.(?22237133)(22239880_?)del	Pathogenic
1069837	NC_000023.10:g.(?22237153)(22245728_?)del	Pathogenic
1069838	NC_000023.10:g.(?22263430)(22266301_?)del	Pathogenic
1069839	NC_000023.10:g.(?22094486)(22151761_?)del	Pathogenic
1069840	NC_000023.10:g.(?22094506)(22108615_?)del	Pathogenic
1070064	NM_000444.6(PHEX):c.2030_2031dup (p.Phe678fs)	Pathogenic
1070065	NM_000444.6(PHEX):c.1137_1149del (p.Arg380fs)	Pathogenic
1070073	NM_000444.6(PHEX):c.2165_2184dup (p.Lys729fs)	Pathogenic
1070333	NM_000444.6(PHEX):c.1645+2T>G	Pathogenic
1070366	NM_000444.6(PHEX):c.2116C>T (p.Gln706Ter)	Pathogenic
1070461	NM_000444.6(PHEX):c.1812del (p.Thr605fs)	Pathogenic
1070892	NM_000444.6(PHEX):c.1282C>T (p.Gln428Ter)	Pathogenic
1071085	NM_000444.6(PHEX):c.437-2A>G	Pathogenic
1071087	NM_000444.6(PHEX):c.423del (p.Cys142fs)	Pathogenic

SpliceAI

4258 predictions. Top by Δscore:

Variant	Effect	Δscore
X:22038467:A:AG	acceptor_gain	1.0000
X:22038468:G:GG	acceptor_gain	1.0000
X:22038468:GT:G	acceptor_gain	1.0000
X:22038468:GTGA:G	acceptor_gain	1.0000
X:22047044:A:AG	acceptor_gain	1.0000
X:22047045:A:G	acceptor_gain	1.0000
X:22047046:ATAG:A	acceptor_loss	1.0000
X:22047047:TA:T	acceptor_loss	1.0000
X:22047048:A:AG	acceptor_gain	1.0000
X:22047048:AGC:A	acceptor_loss	1.0000
X:22047048:AGCT:A	acceptor_gain	1.0000
X:22047049:G:GG	acceptor_gain	1.0000
X:22047049:GCT:G	acceptor_gain	1.0000
X:22047049:GCTG:G	acceptor_gain	1.0000
X:22047207:GAAGG:G	donor_gain	1.0000
X:22047208:AAGGG:A	donor_loss	1.0000
X:22047209:AGGGT:A	donor_loss	1.0000
X:22047210:GG:G	donor_gain	1.0000
X:22047211:GG:G	donor_gain	1.0000
X:22047211:GGTA:G	donor_loss	1.0000
X:22047212:G:GA	donor_loss	1.0000
X:22047212:G:GG	donor_gain	1.0000
X:22047213:T:G	donor_loss	1.0000
X:22050808:G:GT	donor_gain	1.0000
X:22076471:GAGA:G	donor_gain	1.0000
X:22076473:GA:G	donor_gain	1.0000
X:22076475:G:GG	donor_gain	1.0000
X:22077474:A:AG	acceptor_gain	1.0000
X:22077475:G:GG	acceptor_gain	1.0000
X:22077475:GAA:G	acceptor_gain	1.0000

AlphaMissense

4984 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:22077538:T:A	W167R	1.000
X:22077538:T:C	W167R	1.000
X:22219073:C:G	H580D	1.000
X:22219074:A:C	H580P	1.000
X:22219085:C:G	H584D	1.000
X:22226480:A:T	D646V	1.000
X:22245409:G:T	R716M	1.000
X:22047115:T:C	C85R	0.999
X:22047116:G:A	C85Y	0.999
X:22047116:G:T	C85F	0.999
X:22047117:T:G	C85W	0.999
X:22047126:G:C	W88C	0.999
X:22047126:G:T	W88C	0.999
X:22094019:G:C	A257P	0.999
X:22111489:T:A	W368R	0.999
X:22111489:T:C	W368R	0.999
X:22133586:T:A	W456R	0.999
X:22133586:T:C	W456R	0.999
X:22133588:G:C	W456C	0.999
X:22133588:G:T	W456C	0.999
X:22190471:T:A	N538K	0.999
X:22190471:T:G	N538K	0.999
X:22190475:T:C	F540L	0.999
X:22190477:C:A	F540L	0.999
X:22190477:C:G	F540L	0.999
X:22190495:C:A	N546K	0.999
X:22190495:C:G	N546K	0.999
X:22212922:T:C	L555P	0.999
X:22219050:G:A	G572D	0.999
X:22219059:G:A	G575E	0.999

dbSNP variants (sampled 300 via entrez): RS1000002506 (X:22149724 A>C), RS1000006276 (X:22199598 C>A), RS1000031206 (X:22172864 G>A), RS1000094522 (X:22196457 T>A), RS1000099497 (X:22175850 A>T), RS1000129252 (X:22141955 G>A), RS1000150169 (X:22129159 G>A), RS1000174265 (X:22221031 A>G), RS1000235256 (X:22200861 G>T), RS1000252867 (X:22063590 G>T), RS1000257107 (X:22174113 T>C), RS1000271964 (X:22231679 C>A), RS1000296561 (X:22069048 C>T), RS1000308958 (X:22077408 C>T), RS1000344996 (X:22040834 A>G)

Disease associations

OMIM: gene MIM:300550 | disease phenotypes: MIM:307800, MIM:193100

GenCC curated gene-disease

Disease	Classification	Inheritance
X-linked dominant hypophosphatemic rickets	Definitive	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
X-linked dominant hypophosphatemic rickets	Definitive	XL

Mondo (6): X-linked dominant hypophosphatemic rickets (MONDO:0010619), hypophosphatemic rickets (MONDO:0024300), vitamin D-dependent rickets, type 2 (MONDO:0019642), autosomal dominant hypophosphatemic rickets (MONDO:0008660), intellectual disability (MONDO:0001071), hypophosphatemia (MONDO:0000313)

Orphanet (4): X-linked hypophosphatemia (Orphanet:89936), Hypocalcemic vitamin D-resistant rickets (Orphanet:93160), Autosomal dominant hypophosphatemic rickets (Orphanet:89937), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

71 total (30 of 71 shown, HPO-id order):

HPO	Term
HP:0000117	Renal phosphate wasting
HP:0000121	Nephrocalcinosis
HP:0000124	Renal tubular dysfunction
HP:0000360	Tinnitus
HP:0000407	Sensorineural hearing impairment
HP:0000694	Odontodysplasia
HP:0000787	Nephrolithiasis
HP:0000867	Secondary hyperparathyroidism
HP:0000897	Rachitic rosary
HP:0000920	Enlargement of the costochondral junction
HP:0001324	Muscle weakness
HP:0001363	Craniosynostosis
HP:0001369	Arthritis
HP:0001376	Limitation of joint mobility
HP:0001423	X-linked dominant inheritance
HP:0001433	Hepatosplenomegaly
HP:0001510	Growth delay
HP:0002007	Frontal bossing
HP:0002015	Dysphagia
HP:0002148	Hypophosphatemia
HP:0002176	Spinal cord compression
HP:0002194	Delayed gross motor development
HP:0002360	Sleep disturbance
HP:0002515	Waddling gait
HP:0002644	Abnormal pelvic girdle bone morphology
HP:0002653	Bone pain
HP:0002748	Rickets
HP:0002749	Osteomalacia
HP:0002758	Osteoarthritis
HP:0002829	Arthralgia

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000982_2	F-cell distribution in sickle cell anaemia	3.000000e-06
GCST001538_9	Immune reponse to smallpox (secreted IFN-alpha)	9.000000e-09
GCST001635_5	Tourette syndrome	6.000000e-06
GCST002324_2	Anger	3.000000e-07
GCST005981_6	Phosphorus levels	4.000000e-13

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004576	fetal hemoglobin measurement
EFO:0004645	response to vaccine
EFO:0004873	cytokine measurement
EFO:0003015	aggressive behavior
EFO:0004861	phosphorus measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D017674	Hypophosphatemia	C18.452.750.400
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
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: no

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

CTD chemical–gene interactions

31 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	3
Benzo(a)pyrene	affects methylation, increases expression	2
Phosphates	affects abundance, increases expression	2
Silicon Dioxide	decreases expression	2
aristolochic acid I	decreases expression	1
sodium arsenate	increases abundance, increases expression	1
butyraldehyde	decreases expression	1
aflatoxin B2	increases methylation	1
beta-glycerophosphoric acid	increases expression, decreases reaction	1
avobenzone	decreases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
NSC 689534	affects binding, increases expression	1
(+)-JQ1 compound	increases expression	1
Aluminum Oxide	increases expression	1
Arsenates	affects cotreatment, increases expression	1
Arsenic	increases abundance, increases expression	1
Atrazine	affects cotreatment, increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Copper	affects binding, increases expression	1
Levamisole	increases expression, decreases reaction	1
Phosphorus	affects uptake	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Aflatoxin B1	increases methylation	1
Aflatoxin M1	decreases expression	1
Foscarnet	decreases reaction, increases expression	1
Cadmium Chloride	increases expression	1
Okadaic Acid	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_CV45	GM20254	Transformed cell line	Female
CVCL_CV46	GM20255	Transformed cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03820518	PHASE4	UNKNOWN	Using Different Doses of Active Vitamin D Combined With Neutral Phosphate in Children With X-linked Hypophosphatemia
NCT04146935	PHASE4	COMPLETED	Examining the Effect of Burosumab on Muscle Function
NCT04419363	PHASE4	UNKNOWN	Burosumab in Children and Adolescents With X-linked Hypophosphatemia
NCT04842019	PHASE4	COMPLETED	Study to Assess the Safety, Pharmacokinetics and Efficacy of KRN23 in Adult Chinese Patients With XLH
NCT04842032	PHASE4	COMPLETED	Study to Assess the Safety, Pharmacokinetics and Efficacy of KRN23 in Pediatric Chinese Patients With XLH
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
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
NCT06350955	PHASE4	RECRUITING	IV Iron-induced Hypophosphatemia After RYGB
NCT02526160	PHASE3	COMPLETED	Study of KRN23 in Adults With X-linked Hypophosphatemia (XLH)
NCT02537431	PHASE3	COMPLETED	Open Label Study of KRN23 on Osteomalacia in Adults With X-linked Hypophosphatemia (XLH)
NCT02915705	PHASE3	COMPLETED	Efficacy and Safety of Burosumab Versus Oral Phosphate and Active Vitamin D Treatment in Pediatric Patients With XLH
NCT03233126	PHASE3	COMPLETED	A Study of KRN23 in Pediatric Patients With X-linked Hypophosphatemic Rickets/Osteomalacia
NCT03920072	PHASE3	COMPLETED	Study of the Anti-FGF23 Antibody, Burosumab, in Adults With XLH
NCT04308096	PHASE3	COMPLETED	A Study of KRN23 in Adult and Pediatric Patients With X-linked Hypophosphatemic Rickets/Osteomalacia
NCT04695860	PHASE3	COMPLETED	Anti-FGF23 (Burosumab) in Adult Patients With XLH
NCT04872907	PHASE3	UNKNOWN	Prevention of Spontaneous Dental Abscesses in Children With X-linked Hypophosphatemia : a RCT
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
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00975000	PHASE3	COMPLETED	Treatment of Autonomous Hyperparathyroidism in Post Renal Transplant Recipients
NCT02163577	PHASE2	COMPLETED	Study of KRN23 (Burosumab), a Recombinant Fully Human Monoclonal Antibody Against Fibroblast Growth Factor 23 (FGF23), in Pediatric Subjects With X-linked Hypophosphatemia (XLH)
NCT02312687	PHASE2	COMPLETED	Long-Term Extension Study of KRN23 in Adult Subjects With X-Linked Hypophosphatemia (XLH)
NCT02750618	PHASE2	COMPLETED	Study of the Safety, Pharmacodynamics (PD) and Efficacy of KRN23 in Children From 1 to 4 Years Old With X-linked Hypophosphatemia (XLH)
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00195936	PHASE1	COMPLETED	Effect of Cinacalcet on Parathyroid Hormone Secretion in Children and Adolescents With Hypophosphatemic Rickets
NCT00830674	PHASE1	COMPLETED	A Study of KRN23 in X-linked Hypophosphatemia
NCT02181764	PHASE1	COMPLETED	A Study of KRN23 in Subjects With X-linked Hypophosphatemic Rickets/Osteomalacia
NCT00473187	PHASE1	UNKNOWN	Effects of GH on Body Proportions and Final Height in X-Linked Hypophosphatemic Rickets
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)