ENPP1
protein-codingectonucleotide pyrophosphatase/phosphodiesterase 1, the group of Ectonucleotide pyrophosphatase/phosphodiesterase family
Gene summary
This gene is a member of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family. The encoded protein is a type II transmembrane glycoprotein comprising two identical disulfide-bonded subunits. This protein has broad specificity and cleaves a variety of substrates, including phosphodiester bonds of nucleotides and nucleotide sugars and pyrophosphate bonds of nucleotides and nucleotide sugars. This protein may function to hydrolyze nucleoside 5' triphosphates to their corresponding monophosphates and may also hydrolyze diadenosine polyphosphates. Mutations in this gene have been associated with 'idiopathic' infantile arterial calcification, ossification of the posterior longitudinal ligament of the spine (OPLL), and insulin resistance. [provided by RefSeq, Jul 2008]
- NPPS
- M6S1
- PDNP1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~87.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014227
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0008817
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013219
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0008817
Submitter: ClinGen
The *ENPP1* gene is located on chromosome 6 at 6q23.2 and encodes the ectonucleotide pyrophosphatase/phosphodiesterase 1 protein, which catalyzes the hydrolysis of ATP to AMP to produce extracellular inorganic pyrophosphate (PPi), which inhibits bone mineralization and soft tissue calcification. *ENPP1* was first reported in relation to autosomal recessive generalized arterial calcification of infancy, hypophosphatemic rickets, and pseudoxanthoma elasticum in 2003 (Rutsch et al., PMID: 12881724). The disorder is characterized by infantile onset of arterial calcification and/or narrowing of medium- and large-sized vessels that cause cardiovascular findings. Additional features can include pseudoxanthoma elasticum, periarticular calcifications, rickets, cervical spine fusion, and hearing loss. *ENPP1* has also been associated with autosomal dominant hypopigmentation-punctate palmoplantar keratoderma syndrome, or Cole disease, by Eytan et al. in 2013 (PMID: 24075184). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we identified differences in inheritance pattern and in clinical phenotype between hypopigmentation-punctate palmoplantar keratoderma syndrome and the remaining disorders, where we found no clear difference in the phenotypic variability or molecular mechanism(s) underlying the disease entities. Therefore, the diseases were split into generalized arterial calcification of infancy 1 (OMIM: 208000), which includes autosomal recessive hypophosphatemic rickets and pseudoxanthoma elasticum, and hypopigmentation-punctate palmoplantar keratoderma syndrome (OMIM: 615522). The split curation for autosomal dominant hypopigmentation-punctate palmoplantar keratoderma syndrome has been curated separately. Evidence supporting the relationship between *ENPP1* and generalized arterial calcification of infancy 1 includes case-level data. Thirteen variants (including 4 nonsense, 3 frameshift, and 6 missense variants in a homozygous or compound heterozygous state) that have been reported in 7 probands from 3 publications (Rutsch et al. 2003, PMID: 12881724; Ruf et al. 2005, Mehta et al. 2012, PMID: 22539483) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is reported to be biallelic loss of function (Ralph et al. 2022, PMID: 35475527). This gene-disease relationship is also supported by several animal models, including zebrafish and mice, that recapitulate many features of the human disease phenotype (Okawa et al. 1998, PMID: 9662402; Takabayashi et al. 2014, PMID: 24770645; Apschner et al. 2014, PMID: 24906371; Li et al. 2014, PMID: 25479107). In summary, *ENPP1* is definitively associated with autosomal recessive generalized arterial calcification of infancy 1. 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 Syndromic Disorders Gene Curation Expert Panel on the meeting date 06.17.2022 (SOP Version 8). In summary, there is a clear prenatal/neonatal phenotype associated with *ENPP1* and arterial calcification, generalized, of infancy, 1, evident in many probands demonstrating the gene-disease association and several animal models. Common prenatal findings include polyhydramnios, hyperechogenicity associated with arterial and cardiac valve calcifications, hydrops, and pericardial effusion between 20 and 38 WGA. Stillbirth and early neonatal demise have also been widely reported (PMIDs: 20016754, 19206175, 21932012, 28276217, 31742715, 31444901, 33005041, 34199854, 36184779, 35482848). The ClinGen Prenatal GCEP perfomed the secondary analysis on meeting date 06.11. 2025 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0008817
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0014227
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0014227
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0014227
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014227
Submitter: ClinGen
The ENPP1 gene is located on chromosome 6 at 6q23.2 and encodes the ectonucleotide pyrophosphatase/phosphodiesterase 1 protein, which catalyzes the hydrolysis of ATP to AMP to produce extracellular inorganic pyrophosphate (PPi), which inhibits bone mineralization and soft tissue calcification. ENPP1 was first reported in relation to autosomal dominant hypopigmentation-punctate palmoplantar keratoderma syndrome, or Cole disease, in 2013 (Eytan et al. 2013, PMID: 24075184). This disorder is characterized by early-onset punctate keratoderma associated with irregularly shaped hypopigmented macules that typically occur on the limbs but not usually on the trunk. Calcinosis cutis and early-onset calcific tendinopathy are also reported. ENPP1 has also been associated with autosomal recessive generalized arterial calcification of infancy 1 by Rutsch et al. in 2003 (PMID: 12881724). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there is a difference in inheritance pattern and in clinical phenotype. Therefore, the diseases were split into hypopigmentation-punctate palmoplantar keratoderma syndrome (OMIM: 615522) and generalized arterial calcification of infancy 1 (OMIM: 208000). The split curation for autosomal recessive generalized arterial calcification of infancy 1, which also includes autosomal recessive hypophosphatemic rickets and pseudoxanthoma elasticum, has been curated separately. Evidence supporting the relationship between ENPP1 and hypopigmentation-punctate palmoplantar keratoderma syndrome includes case-level data. Seven unique missense variants, all impacting conserved cysteine residues within the somatomedin-B-like (SMB) domains that have been reported in 11 families in five publications are included in this curation (PMID: 24075184; Schlipf et al. 2016, PMID: 26617416; Chourabi et al. 2018, PMID: 28964717; Gabaton et al. 2020; PMID: 32598042; Li et al. 2021, PMID: 34297442; Nanda et al. 2022, PMID: 35220637). Reduced penetrance is suggested in one family (PMID: 26617416) and the disorder appears to follow an autosomal recessive inheritance pattern in three families (PMID: 28964717). This gene-disease relationship is not supported by gene-level experimental evidence. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 06.17.2022 (SOP Version 8).
Inheritance Pattern: AD
Disease ID:MONDO:0014227
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0008817
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009925
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0017324
Submitter: Orphanet
Inheritance Pattern: SD
Disease ID:MONDO:0014227
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0018870
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Dermatologic; Musculoskeletal; Renal
Intervention: Renal
Rationale: 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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ENPP1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006208.3. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 14 | 128 | 3 | 145 | ||
| missense | 11 | 26 | 318 | 21 | 1 | 377 |
| nonsense | 13 | 5 | 18 | |||
| start loss | 1 | 2 | 3 | |||
| frameshift | 18 | 15 | 33 | |||
| splice donor/acceptor (+/-2bp) | 8 | 12 | 5 | 25 | ||
| Total | 50 | 59 | 339 | 149 | 4 | 601 |
Highest pathogenic variant AF is 0.00011259278
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_006199.2 | 25 | MANE Select | |
| Ensembl | ENSP00000498074.1 | 25 | MANE Select | |
| Ensembl | ENSP00000422424.1 | 11 | Standard | |
| Ensembl | ENSP00000497519.1 | 3 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| enpp1 | Danio rerio | Structure: notochord outer sheath cell Quality: mineralized abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- 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)
Biological Process
- generation of precursor metabolites and energy
- riboflavin metabolic process
- phosphate-containing compound metabolic process
- receptor-mediated endocytosis
- immune response
Molecular Function
- nucleic acid binding
- exonuclease activity
- phosphodiesterase I activity
- nucleotide diphosphatase activity
- scavenger receptor activity
Cellular Component
- extracellular space
- lysosomal membrane
- plasma membrane
- integral component of plasma membrane
- cell surface
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000360971
- Coding exons
- 25
- Length
- 87140
- Individuals with no LoFs
- 125631
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 117
- Defined
- 125748
- p
- 0.000465
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.62 | 364 | 462 | 0.788 | 0.0000230 | 6097 |
| Missense (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 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00031 | 0.00025 | rare |
| Latino/Admixed American | 0.00014 | 0.00014 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00033 | 0.00033 | rare |
| Finnish | 0.0019 | 0.0019 | notable |
| European (Non-Finnish) | 0.00039 | 0.00038 | rare |
| South Asian | 0.00042 | 0.00042 | rare |
| Other | 0.00065 | 0.00065 | rare |
dbNSFP Gene Annotations
Source:
- 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.;
Recessive Scores
- pRec
- 0.471
Intolerance Scores
- LoFtool
- 0.783
- RVIS EVS
- -0.4
- RVIS percentile EVS
- 26.98
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.825
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |