GeneBe

PHEX

protein-coding

phosphate regulating endopeptidase X-linked, the group of M13 metallopeptidases

Gene summary

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. [provided by RefSeq, Sep 2013]

Previous symbols:
  • HYP
  • HPDR

MANE transcript

NM_000444.6

Inheritance

XL

ClinVar variants

P:849U:316B:137

Top phenotype

Hypophosphatemic rickets, X-linked dominant

gnomAD constraint

pLI —, LoF o/e 0.03

Max pathogenic AF

—

Genomic locus

chrX:22,032,325-22,494,713

External References & Databases

Ensembl (ENSG00000102174)NCBI Gene (5251)OMIM (300550)HGNC:8918GenCCUniProt (P78562)AlphaFoldClinVar (PHEX)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~462.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

X-linked dominant hypophosphatemic ricketsSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010619

Submitter: PanelApp Australia

X-linked dominant hypophosphatemic ricketsDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010619

Submitter: Illumina

The PHEX gene is located on chromosome X at Xp22.11 and encodes the phosphate regulating endopeptidase homolog X-linked protein, which is predominantly expressed in osteoblasts. PHEX degrades small integrin-binding ligand, N-linked glycoproteins (SIBLING proteins) such as osteopontin and suppresses levels of phosphatonin and fibroblast growth factor 23 (FGF23). The PHEX gene was first reported in relation to X-linked hypophosphatemic rickets in 1995 (7550339: HYP Consortium, 1995). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At lease seven loss of function variants have been reported in seven cases from four publications. In three of these cases the variants were confirmed to have occurred de novo. Considerably more case level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism of disease is haploinsufficiency. This gene-disease relationship is supported by evidence that PHEX regulates FGF23 levels, pathogenic variants in PHEX lead to the elevation of FGF23 serum levels which correlate with disease. The elevation of FGF23 serum levels is associated with other forms of non-nutritional diseases of hypophosphatemia (30808384: Back-Nielson et al. 2019). At least four mouse models carrying either a Phex deletion or missense variant fully recapitulate the clinical disease phenotype (22573557:Owen et al. 2012; 30808384: Back-Nielson et al. 2019). In summary, PHEX is definitively associated with X-linked hypophosphatemic rickets. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

X-linked dominant hypophosphatemic ricketsDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010619

Submitter: G2P

X-linked dominant hypophosphatemic ricketsSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010619

Submitter: Orphanet

X-linked dominant hypophosphatemic ricketsDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010619

Submitter: ClinGen

PHEX was first reported in relation to X-linked dominant hypophosphatemic rickets in 1995 (The HYP Consortium, PMID: 7550339). 14 variants (missense, nonsense, frameshift, splicing) that have been reported in at least 15 probands in 5 publications are included in this curation (PMIDs: 19219621, 29460029, 30682568, 32253725, 33639975). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by a mouse model (PMIDs: 188049, 1569185). Mutant mice show delayed growth, hypophosphatemia. and skeletal anomalies. Supplementation with phosphate in the mutant suppressed the phenotype. In summary, there is definitive evidence supporting the relationship between PHEX and X-linked dominant hypophosphatemia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Tubulopathy GCEP on the meeting date 05/15/2025 (SOP Version 11).

X-linked dominant hypophosphatemic ricketsSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010619

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Hypophosphatemic rickets, X-linked dominantXL

Manifestation: Cardiovascular; Dental; Musculoskeletal; Neurologic; Renal

Intervention: Cardiovascular; Renal

Rationale: Frequent oral administration of phosphate and high-dose calcitriol can be beneficial for bowing of long bones during growth and for pain; Diagnosis can help avoid therapies that may result in adverse sequelae; Due to reported cardiovascular manifestations (eg, hypertension, left ventricular hypertrophy), surveillance may allow early diagnosis and management

Refs: 4305189; 4333173; 188828; 2984933; 3839245; 2571821; 1660099; 1660098; 1414477; 1464657; 7550339; 9106524; 9253316; 9768646; 10874297; 12915641; 14769584; 16055933; 18252791; 21050253; 21524226; 22319799Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PHEX variants in ClinVar

15 Conditions Cataloged
not providedTotal: 1090
Familial X-linked hypophosphatemic vitamin D refractory ricketsTotal: 445
PHEX-related disorderTotal: 99
not specifiedTotal: 95
Inborn genetic diseasesTotal: 55
Hypophosphatemic ricketsTotal: 26
Hypophosphataemia or ricketsTotal: 15
See casesTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000444.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
3
clinvar
28
clinvar
70
clinvar
15
clinvar
 116
missense
65
clinvar
103
clinvar
262
clinvar
44
clinvar
8
clinvar
 482
nonsense
138
clinvar
13
clinvar
8
clinvar
 159
start loss
5
clinvar
 5
frameshift
302
clinvar
43
clinvar
 345
splice donor/acceptor (+/-2bp)
130
clinvar
47
clinvar
18
clinvar
 195
Total640209316114231302

Highest pathogenic variant AF is 0.0000029148712

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000444.6RefSeqNP_000435.322MANE Select
ENST00000379374.5EnsemblENSP00000368682.422MANE Select
NM_001282754.2RefSeqNP_001269683.121Standard
ENST00000682888.1EnsemblENSP00000508003.17Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

  • skeletal system development
  • cellular protein modification process
  • proteolysis
  • cell-cell signaling
  • organophosphate metabolic process

Molecular Function

  • aminopeptidase activity
  • metalloendopeptidase activity
  • zinc ion binding

Cellular Component

  • endoplasmic reticulum
  • Golgi apparatus
  • plasma membrane
  • integral component of plasma membrane
  • perinuclear region of cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000379374
Coding exons
22
Length
218869
Individuals with no LoFs
125711
Homozygous LoFs
3
Heterozygous LoFs
3
Defined
125717
p
0.0000239
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.712112930.7190.00002294974
Missense (PolyPhen)76131.250.579062183
Synonymous-0.3091101061.040.000008461341
Loss of Function5.18133.20.03010.00000245561

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian0.0000720.000054rare
Finnish00.0absent
European (Non-Finnish)0.0000370.000026rare
South Asian0.000110.000065rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Probably involved in bone and dentin mineralization and renal phosphate reabsorption.;

Recessive Scores

pRec
0.616

Intolerance Scores

LoFtool
0.0626
RVIS EVS
-1.13
RVIS percentile EVS
6.43

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.0861

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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