PHEX

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

Basic information

Region (hg38): X:22032324-22494713

Previous symbols: [ "HYP", "HPDR" ]

Links

ENSG00000102174 ∙ NCBI:5251 ∙ OMIM:300550 ∙ HGNC:8918 ∙ Uniprot:P78562 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• X-linked dominant hypophosphatemic rickets (Definitive), mode of inheritance: XL
• X-linked dominant hypophosphatemic rickets (Strong), mode of inheritance: XL
• X-linked dominant hypophosphatemic rickets (Supportive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hypophosphatemic rickets, X-linked dominant	XL	Cardiovascular; Renal	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	Cardiovascular; Dental; Musculoskeletal; Neurologic; Renal	4305189; 4333173; 188828; 2984933; 3839245; 2571821; 1660099; 1660098; 1414477; 1464657; 7550339; 9106524; 9253316; 9768646; 10874297; 12915641; 14769584; 16055933; 18252791; 21050253; 21524226; 22319799

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PHEX gene.

• not provided (876 variants)
• Familial X-linked hypophosphatemic vitamin D refractory rickets (305 variants)
• not specified (44 variants)
• Hypophosphatemic rickets (24 variants)
• Inborn genetic diseases (21 variants)
• PHEX-related condition (6 variants)
• Hypophosphatemia (2 variants)
• Lower limb pain;Bowing of the legs;Hypophosphatemic rickets (1 variants)
• Autosomal dominant hypophosphatemic rickets (1 variants)
• See cases (1 variants)
• Vitamin D-dependent rickets, type 2 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PHEX gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous		1	7	28	14	50
missense	63	68	82	16	8	237
nonsense	130	6	2		2	140
start loss	4					4
frameshift	215	17			2	234
inframe indel	4	3	11			18
splice donor/acceptor (+/-2bp)	126	26			2	154
splice region	9	18	19	6	7	59
non coding			15	44	68	127
Total	542	121	117	88	96

Highest pathogenic variant AF is 0.0000535

Variants in PHEX

This is a list of pathogenic ClinVar variants found in the PHEX region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
X-22032577-T-C			Uncertain significance (Oct 04, 2023)
X-22032880-C-A		Familial X-linked hypophosphatemic vitamin D refractory rickets	Uncertain significance (Jan 13, 2018)
X-22032880-C-G		Familial X-linked hypophosphatemic vitamin D refractory rickets	Benign (Jan 13, 2018)
X-22032898-A-G		Familial X-linked hypophosphatemic vitamin D refractory rickets	Benign (Jan 13, 2018)
X-22032916-A-G		Familial X-linked hypophosphatemic vitamin D refractory rickets	Benign (Jan 13, 2018)
X-22032973-C-T		Familial X-linked hypophosphatemic vitamin D refractory rickets	Benign (Sep 05, 2021)
X-22032995-C-T			Likely benign (Apr 09, 2022)
X-22032996-G-T		Familial X-linked hypophosphatemic vitamin D refractory rickets	Uncertain significance (Jan 13, 2018)
X-22033006-A-T			Pathogenic (Jul 18, 2022)
X-22033007-T-C			Pathogenic (May 23, 2020)
X-22033008-G-A		Familial X-linked hypophosphatemic vitamin D refractory rickets	Pathogenic (May 04, 2022)
X-22033008-G-T			Pathogenic (Oct 31, 2019)
X-22033011-A-AGC		Familial X-linked hypophosphatemic vitamin D refractory rickets	Pathogenic (May 28, 2019)
X-22033015-G-C		Familial X-linked hypophosphatemic vitamin D refractory rickets • not specified • PHEX-related disorder	Conflicting classifications of pathogenicity (Jan 29, 2024)
X-22033019-CAG-C			Pathogenic (Apr 29, 2021)
X-22033024-AGC-A		Familial X-linked hypophosphatemic vitamin D refractory rickets	Pathogenic (May 28, 2019)
X-22033026-C-ACTGG			Pathogenic (Dec 06, 2019)
X-22033030-GTGGAGAC-G			Pathogenic (Sep 24, 2019)
X-22033032-G-GA			Pathogenic (Oct 23, 2019)
X-22033038-T-C			Uncertain significance (Mar 30, 2016)
X-22033040-GAA-G		Familial X-linked hypophosphatemic vitamin D refractory rickets	Pathogenic (May 04, 2022)
X-22033049-C-G			Likely benign (Aug 30, 2023)
X-22033054-A-T			Pathogenic (Feb 22, 2020)
X-22033061-C-A			Likely benign (Aug 08, 2022)
X-22033063-C-T		Familial X-linked hypophosphatemic vitamin D refractory rickets	Pathogenic (Oct 22, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PHEX	protein_coding	protein_coding	ENST00000379374	22	218869

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.0000370	125711	3	3	125717	0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.71	211	293	0.719	0.0000229	4974
Missense in Polyphen		76	131.25	0.57906		2183
Synonymous	-0.309	110	106	1.04	0.00000846	1341
Loss of Function	5.18	1	33.2	0.0301	0.00000245	561

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000724	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000368	0.0000264
Middle Eastern	0.0000724	0.0000544
South Asian	0.000105	0.0000653
Other	0.00	0.00

dbNSFP

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

Haploinsufficiency Scores

• pHI: 0.618
• hipred: Y
• hipred_score: 0.699
• ghis: 0.507

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.0861

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Phex
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hearing/vestibular/ear phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); limbs/digits/tail phenotype; digestive/alimentary phenotype; immune system phenotype; skeleton phenotype; renal/urinary system phenotype; growth/size/body region phenotype; endocrine/exocrine gland phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); craniofacial phenotype; cellular phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: skeletal system development;cellular protein modification process;proteolysis;cell-cell signaling;organophosphate metabolic process;bone mineralization;lung development;bone development;response to growth hormone;cellular response to vitamin D;cellular response to parathyroid hormone stimulus;response to sodium phosphate;response to insulin-like growth factor stimulus
• Cellular component: endoplasmic reticulum;Golgi apparatus;plasma membrane;integral component of plasma membrane;perinuclear region of cytoplasm
• Molecular function: aminopeptidase activity;metalloendopeptidase activity;zinc ion binding