ENPP1

ectonucleotide pyrophosphatase/phosphodiesterase 1, the group of Ectonucleotide pyrophosphatase/phosphodiesterase family

Basic information

Region (hg38): 6:131808015-131895155

Previous symbols: [ "NPPS", "M6S1", "PDNP1" ]

Links

ENSG00000197594 ∙ NCBI:5167 ∙ OMIM:173335 ∙ HGNC:3356 ∙ Uniprot:P22413 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• arterial calcification, generalized, of infancy, 1 (Definitive), mode of inheritance: AR
• hypopigmentation-punctate palmoplantar keratoderma syndrome (Strong), mode of inheritance: AD
• autosomal recessive inherited pseudoxanthoma elasticum (Supportive), mode of inheritance: AR
• arterial calcification of infancy (Supportive), mode of inheritance: AD
• autosomal recessive hypophosphatemic rickets (Supportive), mode of inheritance: AR
• hypopigmentation-punctate palmoplantar keratoderma syndrome (Supportive), mode of inheritance: AD
• hypopigmentation-punctate palmoplantar keratoderma syndrome (Limited), mode of inheritance: AD
• arterial calcification, generalized, of infancy, 1 (Strong), mode of inheritance: AR
• hypophosphatemic rickets, autosomal recessive, 2 (Strong), mode of inheritance: AR
• hypopigmentation-punctate palmoplantar keratoderma syndrome (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hypophosphatemic rickets, autosomal recessive 2; Arterial calcification, generalized, of infancy, 1	AR	Renal	For hypophosphatemic rickets, treatment (eg, with phosphates, vitamin D supplements) may be effective; In Arterial calcification, generalized, of infancy, 1, bisphosphonates have been described as beneficial in some	Cardiovascular; Dermatologic; Musculoskeletal; Renal	11159191; 12881724; 15940697; 19380683; 20016754; 19206175; 20137772; 20137773; 21745613; 21932012; 22629037; 22229486; 22209248; 24075184

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ENPP1 gene.

• not provided (372 variants)
• Arterial calcification, generalized, of infancy, 1 (218 variants)
• Hypophosphatemic rickets, autosomal recessive, 2 (178 variants)
• Inborn genetic diseases (29 variants)
• not specified (21 variants)
• Hypophosphatemic Rickets, Recessive (19 variants)
• ENPP1-related condition (8 variants)
• Hypophosphatemic rickets, autosomal recessive, 2;Arterial calcification, generalized, of infancy, 1 (7 variants)
• Type 2 diabetes mellitus (6 variants)
• ENPP1-Related Disorders (4 variants)
• Arterial calcification, generalized, of infancy, 1;Obesity;Type 2 diabetes mellitus;Hypopigmentation-punctate palmoplantar keratoderma syndrome;Hypophosphatemic rickets, autosomal recessive, 2 (4 variants)
• Hypophosphatemic rickets, autosomal recessive, 2;Hypopigmentation-punctate palmoplantar keratoderma syndrome;Obesity;Type 2 diabetes mellitus;Arterial calcification, generalized, of infancy, 1 (3 variants)
• Obesity (3 variants)
• Hypophosphatemic rickets, autosomal recessive, 2;Hypopigmentation-punctate palmoplantar keratoderma syndrome;Arterial calcification, generalized, of infancy, 1;Type 2 diabetes mellitus;Obesity (3 variants)
• Hypopigmentation-punctate palmoplantar keratoderma syndrome (3 variants)
• Hypophosphatemic rickets, autosomal recessive, 2;Type 2 diabetes mellitus;Arterial calcification, generalized, of infancy, 1;Obesity;Hypopigmentation-punctate palmoplantar keratoderma syndrome (2 variants)
• Hypophosphatemic rickets (2 variants)
• Arterial calcification, generalized, of infancy, 1;Hypophosphatemic rickets, autosomal recessive, 2 (2 variants)
• Diabetes mellitus type 2, susceptibility to (2 variants)
• Coronary sclerosis, medial, of infancy (2 variants)
• Hypophosphatemic rickets, autosomal recessive, 2;Arterial calcification, generalized, of infancy, 1;Type 2 diabetes mellitus;Hypopigmentation-punctate palmoplantar keratoderma syndrome;Obesity (2 variants)
• Arterial calcification, generalized, of infancy, 1;Type 2 diabetes mellitus;Hypopigmentation-punctate palmoplantar keratoderma syndrome;Obesity;Hypophosphatemic rickets, autosomal recessive, 2 (2 variants)
• Arterial calcification, generalized, of infancy, 1;Obesity;Hypopigmentation-punctate palmoplantar keratoderma syndrome;Type 2 diabetes mellitus;Hypophosphatemic rickets, autosomal recessive, 2 (1 variants)
• Arterial calcification, generalized, of infancy, 1;Type 2 diabetes mellitus;Hypophosphatemic rickets, autosomal recessive, 2;Hypopigmentation-punctate palmoplantar keratoderma syndrome;Obesity (1 variants)
• Hypopigmentation-punctate palmoplantar keratoderma syndrome;Hypophosphatemic rickets, autosomal recessive, 2;Arterial calcification, generalized, of infancy, 1;Obesity;Type 2 diabetes mellitus (1 variants)
• Hypopigmentation-punctate palmoplantar keratoderma syndrome;Type 2 diabetes mellitus;Arterial calcification, generalized, of infancy, 1;Obesity;Hypophosphatemic rickets, autosomal recessive, 2 (1 variants)
• Type 2 diabetes mellitus;Obesity;Hypophosphatemic rickets, autosomal recessive, 2;Arterial calcification, generalized, of infancy, 1;Hypopigmentation-punctate palmoplantar keratoderma syndrome (1 variants)
• Type 2 diabetes mellitus;Hypophosphatemic rickets, autosomal recessive, 2;Hypopigmentation-punctate palmoplantar keratoderma syndrome;Arterial calcification, generalized, of infancy, 1;Obesity (1 variants)
• Arterial calcification, generalized, of infancy, 1;Obesity;Hypopigmentation-punctate palmoplantar keratoderma syndrome;Hypophosphatemic rickets, autosomal recessive, 2;Type 2 diabetes mellitus (1 variants)
• Type 2 diabetes mellitus;Hypophosphatemic rickets, autosomal recessive, 2;Arterial calcification, generalized, of infancy, 1;Obesity;Hypopigmentation-punctate palmoplantar keratoderma syndrome (1 variants)
• Arterial calcification, generalized, of infancy, 1;Type 2 diabetes mellitus;Obesity;Hypophosphatemic rickets, autosomal recessive, 2;Hypopigmentation-punctate palmoplantar keratoderma syndrome (1 variants)
• Insulin resistance, susceptibility to (1 variants)
• Obesity;Arterial calcification, generalized, of infancy, 1;Hypopigmentation-punctate palmoplantar keratoderma syndrome;Type 2 diabetes mellitus;Hypophosphatemic rickets, autosomal recessive, 2 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ENPP1 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			2	42	4	48
missense	4	7	133	6	1	151
nonsense	10	1	1			12
start loss			1			1
frameshift	12	3			1	16
inframe indel			1			1
splice donor/acceptor (+/-2bp)	5	7	1		1	14
splice region			13	9	3	25
non coding			71	65	121	257
Total	31	18	210	113	128

Highest pathogenic variant AF is 0.000112

Variants in ENPP1

This is a list of pathogenic ClinVar variants found in the ENPP1 region.

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

Position	Type	Phenotype	Significance	ClinVar
6-131808023-G-A		Arterial calcification, generalized, of infancy, 1 • Hypophosphatemic rickets, autosomal recessive, 2 • ENPP1-related disorder	Conflicting classifications of pathogenicity (Apr 11, 2022)
6-131808026-C-T		not specified • Arterial calcification, generalized, of infancy, 1 • Hypophosphatemic rickets, autosomal recessive, 2	Conflicting classifications of pathogenicity (Apr 16, 2019)
6-131808036-A-G		Inborn genetic diseases	Uncertain significance (Sep 23, 2022)
6-131808037-T-C			Uncertain significance (Sep 27, 2023)
6-131808041-G-A			Likely benign (Jun 03, 2023)
6-131808045-G-A		Arterial calcification, generalized, of infancy, 1 • Hypophosphatemic rickets, autosomal recessive, 2	Uncertain significance (Jan 13, 2018)
6-131808048-G-C		Inborn genetic diseases	Uncertain significance (Feb 28, 2024)
6-131808055-C-CG		Hypophosphatemic rickets, autosomal recessive, 2;Arterial calcification, generalized, of infancy, 1	Pathogenic (Mar 16, 2022)
6-131808056-G-T		Arterial calcification, generalized, of infancy, 1 • Hypophosphatemic rickets, autosomal recessive, 2	Uncertain significance (Jan 13, 2018)
6-131808061-G-A			Uncertain significance (Jan 14, 2024)
6-131808062-C-G			Conflicting classifications of pathogenicity (Jan 01, 2023)
6-131808069-C-G			Likely benign (Jan 24, 2023)
6-131808081-G-A		Inborn genetic diseases	Uncertain significance (Jan 16, 2024)
6-131808090-G-A			Uncertain significance (Oct 04, 2022)
6-131808093-C-T			Uncertain significance (May 17, 2023)
6-131808096-C-T			Uncertain significance (Dec 25, 2023)
6-131808122-C-G			Likely benign (Jun 14, 2023)
6-131808123-G-T		ENPP1-related disorder	Uncertain significance (Dec 17, 2023)
6-131808133-G-A			Uncertain significance (Aug 30, 2023)
6-131808138-C-T		Inborn genetic diseases	Uncertain significance (Jun 21, 2023)
6-131808140-C-T			Likely benign (Mar 08, 2023)
6-131808152-G-T			Likely benign (Sep 09, 2023)
6-131808153-C-A			Likely benign (Nov 12, 2023)
6-131808155-C-T			Likely benign (Jun 15, 2023)
6-131808160-A-C			Uncertain significance (Dec 09, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ENPP1	protein_coding	protein_coding	ENST00000360971	25	87140

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
4.99e-8	1.00	125631	0	117	125748	0.000465

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.62	364	462	0.788	0.0000230	6097
Missense in Polyphen		136	193.81	0.7017		2441
Synonymous	0.494	155	163	0.951	0.00000859	1646
Loss of Function	4.00	22	53.6	0.410	0.00000271	696

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000452	0.000391
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.000327	0.000326
Finnish	0.00189	0.00190
European (Non-Finnish)	0.000388	0.000378
Middle Eastern	0.000327	0.000326
South Asian	0.000425	0.000425
Other	0.000654	0.000652

dbNSFP

Source: dbNSFP

• Function: FUNCTION: By generating PPi, plays a role in regulating pyrophosphate levels, and functions in bone mineralization and soft tissue calcification. PPi inhibits mineralization by binding to nascent hydroxyapatite (HA) crystals, thereby preventing further growth of these crystals. Preferentially hydrolyzes ATP, but can also hydrolyze other nucleoside 5' triphosphates such as GTP, CTP, TTP and UTP to their corresponding monophosphates with release of pyrophosphate and diadenosine polyphosphates, and also 3',5'-cAMP to AMP. May also be involved in the regulation of the availability of nucleotide sugars in the endoplasmic reticulum and Golgi, and the regulation of purinergic signaling. Appears to modulate insulin sensitivity and function. {ECO:0000269|PubMed:10615944, ECO:0000269|PubMed:27467858, ECO:0000269|PubMed:8001561}.
• Disease: DISEASE: Ossification of the posterior longitudinal ligament of the spine (OPLL) [MIM:602475]: A calcification of the posterior longitudinal ligament of the spinal column, usually at the level of the cervical spine. Patients with OPLL frequently present with a severe myelopathy that can lead to tetraparesis. {ECO:0000269|PubMed:10453738}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Arterial calcification of infancy, generalized, 1 (GACI1) [MIM:208000]: A severe autosomal recessive disorder characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation. The disorder is often fatal within the first 6 months of life because of myocardial ischemia resulting in refractory heart failure. {ECO:0000269|PubMed:12881724, ECO:0000269|PubMed:15605415, ECO:0000269|PubMed:15940697, ECO:0000269|PubMed:20016754, ECO:0000269|PubMed:22209248, ECO:0000269|PubMed:23430823, ECO:0000269|PubMed:27467858}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:16186408}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Hypophosphatemic rickets, autosomal recessive, 2 (ARHR2) [MIM:613312]: A hereditary form of hypophosphatemic rickets, a disorder of proximal renal tubule function that causes phosphate loss, hypophosphatemia and skeletal deformities, including rickets and osteomalacia unresponsive to vitamin D. Symptoms are bone pain, fractures and growth abnormalities. {ECO:0000269|PubMed:20137772, ECO:0000269|PubMed:20137773, ECO:0000269|PubMed:25741938}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cole disease (COLED) [MIM:615522]: A rare autosomal dominant genodermatosis characterized by punctate keratoderma associated with irregularly shaped hypopigmented macules, which are typically found over the arms and legs but not the trunk or acral regions. Skin biopsies of palmoplantar lesions show hyperorthokeratosis, hypergranulosis, and acanthosis. Hypopigmented areas of skin, however, reveal a reduction in melanin content in keratinocytes but not in melanocytes, as well as hyperkeratosis and a normal number of melanocytes. Ultrastructurally, melanocytes show a disproportionately large number of melanosomes in the cytoplasm and dendrites, whereas keratinocytes show a paucity of these organelles, suggestive of impaired melanosome transfer. Some patients also exhibit calcinosis cutis or calcific tendinopathy. {ECO:0000269|PubMed:24075184, ECO:0000269|PubMed:26617416}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Pyrimidine metabolism - Homo sapiens (human);Nicotinate and nicotinamide metabolism - Homo sapiens (human);Starch and sucrose metabolism - Homo sapiens (human);Pantothenate and CoA biosynthesis - Homo sapiens (human);Riboflavin metabolism - Homo sapiens (human);Purine metabolism - Homo sapiens (human);Nicotinate and Nicotinamide Metabolism;Pantothenate and CoA Biosynthesis;Riboflavin Metabolism;Pyrimidine metabolism;Endochondral Ossification;Insulin Signaling;Vitamin B2 (riboflavin) metabolism;regulators of bone mineralization;Vitamin B3 (nicotinate and nicotinamide) metabolism;Vitamin B5 - CoA biosynthesis from pantothenate;Metabolism;Vitamin B2 (riboflavin) metabolism;Nicotinate Nicotinamide metabolism;Metabolism of water-soluble vitamins and cofactors;Pyrimidine metabolism;Metabolism of vitamins and cofactors (Consensus)

Recessive Scores

• pRec: 0.471

Intolerance Scores

• loftool: 0.783
• rvis_EVS: -0.4
• rvis_percentile_EVS: 26.98

Haploinsufficiency Scores

• pHI: 0.541
• hipred: Y
• hipred_score: 0.747
• ghis: 0.509

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.825

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Enpp1
• Phenotype: muscle phenotype; craniofacial phenotype; cellular phenotype; homeostasis/metabolism phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); limbs/digits/tail phenotype; 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); vision/eye phenotype; immune system phenotype; skeleton phenotype; renal/urinary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; 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); 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)

Zebrafish Information Network

• Gene name: enpp1
• Affected structure: notochord outer sheath cell
• Phenotype tag: abnormal
• Phenotype quality: mineralized

Gene ontology

• Biological process: generation of precursor metabolites and energy;riboflavin metabolic process;phosphate-containing compound metabolic process;receptor-mediated endocytosis;immune response;nucleoside triphosphate catabolic process;negative regulation of cell growth;regulation of bone mineralization;inorganic diphosphate transport;cellular phosphate ion homeostasis;sequestering of triglyceride;biomineral tissue development;negative regulation of protein autophosphorylation;cellular response to insulin stimulus;negative regulation of fat cell differentiation;negative regulation of glycogen biosynthetic process;ATP metabolic process;negative regulation of glucose import;negative regulation of insulin receptor signaling pathway;3'-phosphoadenosine 5'-phosphosulfate metabolic process;nucleic acid phosphodiester bond hydrolysis
• Cellular component: extracellular space;lysosomal membrane;plasma membrane;integral component of plasma membrane;cell surface;integral component of membrane;basolateral plasma membrane
• Molecular function: nucleic acid binding;exonuclease activity;phosphodiesterase I activity;nucleotide diphosphatase activity;scavenger receptor activity;insulin receptor binding;calcium ion binding;protein binding;ATP binding;zinc ion binding;polysaccharide binding;NADH pyrophosphatase activity;protein homodimerization activity;nucleoside-triphosphate diphosphatase activity;3'-phosphoadenosine 5'-phosphosulfate binding