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GeneE
25 sources retrieved · Most recent: April 2026 · Index updated 14 days ago
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ENPP1
ectonucleotide pyrophosphatase/phosphodiesterase 1
Chromosome 6 · 6q23.2
NCBI Gene: 5167Ensembl: ENSG00000197594.15HGNC: HGNC:3356UniProt: P22413
279PubMed Papers
25Diseases
0Drugs
97Pathogenic Variants
FUNCTIONAL ROLE
Hub Gene
RESEARCH IMPACT
TrendingVariant-Rich
CLINICAL
OMIM Disease Gene
DATA QUALITY
✓ Experimental GO Evidence✓ Swiss-Prot Reviewed
negative regulation of insulin receptor signaling pathwayphosphate-containing compound metabolic processnucleoside triphosphate catabolic processgene expressionarterial calcification, generalized, of infancy, 1hypopigmentation-punctate palmoplantar keratoderma syndromeGeneralized arterial calcification of infancyhypophosphatemic rickets, autosomal recessive, 2
✦AI Summary

ENPP1 is an ectonucleotide pyrophosphatase/phosphodiesterase that generates pyrophosphate (PPi) by hydrolyzing extracellular ATP and other nucleotides, with critical roles in mineralization and immune regulation 1. In bone homeostasis, ENPP1-generated PPi inhibits mineralization by preventing hydroxyapatite crystal growth, while also regulating osteoblast differentiation through histone lactylation pathways 2. ENPP1 uniquely hydrolyzes the immunotransmitter 2'3'-cGAMP, suppressing cGAS-STING antitumor immunity—a mechanism exploited by tumor cells through both membrane-bound and exosomal ENPP1 to evade immune surveillance 34. ENPP1 also impairs insulin signaling and blood-brain barrier integrity, promoting brain metastasis in HER2+ breast cancer 5. Loss-of-function mutations cause paradoxical mineralization disorders: osteoporosis with concurrent vascular calcification (arterial calcification of infancy, hypophosphatemic rickets) 61. Conversely, the K121Q polymorphism increases insulin resistance risk and type 2 diabetes susceptibility 7. ENPP1 represents both a disease target (cGAMP hydrolysis inhibition for cancer immunotherapy) and therapeutic ligand (ENPP1 replacement for calcification disorders), making it clinically significant across metabolic, skeletal, vascular, and oncologic domains.

Sources cited
1
ENPP1 hydrolyzes ATP to generate pyrophosphate and is involved in mineralization disorders
PMID: 37871131
2
ENPP1 is regulated by histone lactylation and contributes to osteoblast differentiation
PMID: 37752768
3
Tumor exosomal ENPP1 hydrolyzes cGAMP to inhibit cGAS-STING pathway
PMID: 38498770
4
ENPP1 in cancer and normal tissues dampens cGAMP-STING antitumoral immunity
PMID: 38117852
5
Tumor-secreted ENPP1 impairs blood-brain barrier integrity and promotes brain metastasis through insulin signaling disruption
PMID: 39210244
6
ENPP1 mutations cause arterial calcification of infancy, hypophosphatemic rickets, and Cole disease
PMID: 35475527
7
ENPP1 K121Q polymorphism associates with insulin resistance and type 2 diabetes
PMID: 17563456
Disease Associationsⓘ25
arterial calcification, generalized, of infancy, 1Open Targets
0.84Strong
hypopigmentation-punctate palmoplantar keratoderma syndromeOpen Targets
0.81Strong
Generalized arterial calcification of infancyOpen Targets
0.81Strong
hypophosphatemic rickets, autosomal recessive, 2Open Targets
0.77Strong
type 2 diabetes mellitusOpen Targets
0.65Moderate
ossification of the posterior longitudinal ligament of the spineOpen Targets
0.56Moderate
inherited obesityOpen Targets
0.53Moderate
obesityOpen Targets
0.45Moderate
arterial calcification of infancyOpen Targets
0.43Moderate
autosomal recessive hypophosphatemic ricketsOpen Targets
0.42Moderate
crystal arthropathyOpen Targets
0.42Moderate
osteoarthritis, handOpen Targets
0.41Moderate
chondrocalcinosisOpen Targets
0.40Weak
Pseudoxanthoma elasticumOpen Targets
0.38Weak
pseudoxanthoma elasticum (inherited or acquired)Open Targets
0.38Weak
calcific tendinitisOpen Targets
0.36Weak
hypophosphatemic ricketsOpen Targets
0.35Weak
placenta praeviaOpen Targets
0.31Weak
pericarditisOpen Targets
0.28Weak
dystonia 28, childhood-onsetOpen Targets
0.27Weak
Arterial calcification of infancy, generalized, 1UniProt
Cole diseaseUniProt
Hypophosphatemic rickets, autosomal recessive, 2UniProt
Ossification of the posterior longitudinal ligament of the spineUniProt
Type 2 diabetes mellitusUniProt
Pathogenic Variants97
NM_006208.3(ENPP1):c.1756G>A (p.Gly586Arg)Pathogenic
Arterial calcification, generalized, of infancy, 1|not provided|Type 2 diabetes mellitus;Arterial calcification, generalized, of infancy, 1;Hypopigmentation-punctate palmoplantar keratoderma syndrome;Inherited obesity;Hypophosphatemic rickets, autosomal recessive, 2|Autosomal recessive ENPP1-related disorders
★★☆☆2025→ Residue 586
NM_006208.3(ENPP1):c.1441C>T (p.Arg481Trp)Pathogenic
Hypophosphatemic rickets, autosomal recessive, 2;Arterial calcification, generalized, of infancy, 1|Arterial calcification, generalized, of infancy, 1|Hypophosphatemic rickets, autosomal recessive, 2|not provided|Type 2 diabetes mellitus;Hypophosphatemic rickets, autosomal recessive, 2;Arterial calcification, generalized, of infancy, 1;Hypopigmentation-punctate palmoplantar keratoderma syndrome;Inherited obesity
★★☆☆2025→ Residue 481
NM_006208.3(ENPP1):c.913C>A (p.Pro305Thr)Pathogenic
Arterial calcification, generalized, of infancy, 1|not provided|ENPP1-related disorder|Inherited obesity;Type 2 diabetes mellitus;Arterial calcification, generalized, of infancy, 1;Hypopigmentation-punctate palmoplantar keratoderma syndrome;Hypophosphatemic rickets, autosomal recessive, 2
★★☆☆2025→ Residue 305
NM_006208.3(ENPP1):c.749C>T (p.Pro250Leu)Pathogenic
not provided|ENPP1-related disorder
★★☆☆2025→ Residue 250
NM_006208.3(ENPP1):c.1412A>G (p.Tyr471Cys)Pathogenic
not provided
★★☆☆2025→ Residue 471
NM_006208.3(ENPP1):c.2192del (p.Asn731fs)Pathogenic
Hypophosphatemic rickets, autosomal recessive, 2;Arterial calcification, generalized, of infancy, 1|not provided
★★☆☆2025→ Residue 731
NM_006208.3(ENPP1):c.715+1G>CPathogenic
not provided
★★☆☆2025
NM_006208.3(ENPP1):c.313+1G>APathogenic
Hypopigmentation-punctate palmoplantar keratoderma syndrome;Inherited obesity;Type 2 diabetes mellitus;Arterial calcification, generalized, of infancy, 1;Hypophosphatemic rickets, autosomal recessive, 2|ENPP1-related disorder
★★☆☆2025
NM_006208.3(ENPP1):c.574del (p.Glu192fs)Pathogenic
Hypophosphatemic rickets, autosomal recessive, 2;Arterial calcification, generalized, of infancy, 1|not provided
★★☆☆2025→ Residue 192
NM_006208.3(ENPP1):c.26dup (p.Gly10fs)Pathogenic
Hypophosphatemic rickets, autosomal recessive, 2;Arterial calcification, generalized, of infancy, 1|ENPP1-related disorder
★★☆☆2024→ Residue 10
NM_006208.3(ENPP1):c.2344C>T (p.Arg782Ter)Pathogenic
Type 2 diabetes mellitus;Arterial calcification, generalized, of infancy, 1;Obesity;Hypophosphatemic rickets, autosomal recessive, 2;Hypopigmentation-punctate palmoplantar keratoderma syndrome|ENPP1-related disorder|not provided
★★☆☆2024→ Residue 782
NM_006208.3(ENPP1):c.2596G>A (p.Glu866Lys)Likely pathogenic
Hypopigmentation-punctate palmoplantar keratoderma syndrome;Inherited obesity;Type 2 diabetes mellitus;Arterial calcification, generalized, of infancy, 1;Hypophosphatemic rickets, autosomal recessive, 2|not provided
★★☆☆2024→ Residue 866
NM_006208.3(ENPP1):c.1426C>T (p.Arg476Ter)Pathogenic
Hypopigmentation-punctate palmoplantar keratoderma syndrome;Inherited obesity;Type 2 diabetes mellitus;Arterial calcification, generalized, of infancy, 1;Hypophosphatemic rickets, autosomal recessive, 2|not provided
★★☆☆2024→ Residue 476
NM_006208.3(ENPP1):c.2677G>T (p.Glu893Ter)Pathogenic
Arterial calcification, generalized, of infancy, 1|not provided
★★☆☆2024→ Residue 893
NM_006208.3(ENPP1):c.2375A>G (p.Asn792Ser)Pathogenic
Hypopigmentation-punctate palmoplantar keratoderma syndrome;Inherited obesity;Type 2 diabetes mellitus;Arterial calcification, generalized, of infancy, 1;Hypophosphatemic rickets, autosomal recessive, 2|not provided
★★☆☆2024→ Residue 792
NM_006208.3(ENPP1):c.2631G>A (p.Trp877Ter)Pathogenic
not provided|Arterial calcification, generalized, of infancy, 1;Type 2 diabetes mellitus;Hypopigmentation-punctate palmoplantar keratoderma syndrome;Inherited obesity;Hypophosphatemic rickets, autosomal recessive, 2
★★☆☆2024→ Residue 877
NM_006208.3(ENPP1):c.1366C>T (p.Arg456Ter)Pathogenic
Type 2 diabetes mellitus|Arterial calcification, generalized, of infancy, 1;Type 2 diabetes mellitus;Hypophosphatemic rickets, autosomal recessive, 2;Inherited obesity;Hypopigmentation-punctate palmoplantar keratoderma syndrome
★★☆☆2024→ Residue 456
NM_006208.3(ENPP1):c.2608-1G>ALikely pathogenic
not provided|Arterial calcification, generalized, of infancy, 1;Hypopigmentation-punctate palmoplantar keratoderma syndrome;Inherited obesity;Hypophosphatemic rickets, autosomal recessive, 2;Type 2 diabetes mellitus
★★☆☆2024
NM_006208.3(ENPP1):c.1025G>T (p.Gly342Val)Pathogenic
Arterial calcification, generalized, of infancy, 1|Coronary sclerosis, medial, of infancy|not provided
★★☆☆2021→ Residue 342
NM_006208.3(ENPP1):c.734del (p.Thr245fs)Likely pathogenic
Arterial calcification, generalized, of infancy, 1
★☆☆☆2026→ Residue 245
View on ClinVar ↗
Related Genes
NMNAT1Protein interaction99%ALPLProtein interaction99%PDE7AProtein interaction99%NMNAT2Protein interaction98%NME1-NME2Protein interaction96%PYGBProtein interaction96%
Tissue Expression6 tissues
Liver
100%
Ovary
30%
Heart
7%
Lung
3%
Brain
1%
Bone Marrow
0%
Gene Interaction Network
Click a node to explore
ENPP1NMNAT1ALPLPDE7ANMNAT2NME1-NME2PYGB
PROTEIN STRUCTURE
Preparing viewer…
PDB6WFJ · 2.50 Å · X-ray
View on RCSB ↗
Constraintⓘ
LOEUFⓘ
0.73LoF Tolerant
pLIⓘ
0.00Tolerant
Observed/Expected LoF0.54 [0.41–0.73]
RankingsWhere ENPP1 stands among ~20K protein-coding genes
  • #1,295of 20,598
    Most Researched279 · top 10%
  • #797of 5,498
    Most Pathogenic Variants97 · top quartile
  • #5,670of 17,882
    Most Constrained (LOEUF)0.73
Genes detectedENPP1
Sources retrieved25 papers
Response time—
📄 Sources
25▼
1
Endothelial Cell-Derived Lactate Triggers Bone Mesenchymal Stem Cell Histone Lactylation to Attenuate Osteoporosis.
PMID: 37752768
Adv Sci (Weinh) · 2023
1.00
2
Tumor Exosomal ENPP1 Hydrolyzes cGAMP to Inhibit cGAS-STING Signaling.
PMID: 38498770
Adv Sci (Weinh) · 2024
0.90
3
ENPP1 induces blood-brain barrier dysfunction and promotes brain metastasis formation in human epidermal growth factor receptor 2-positive breast cancer.
PMID: 39210244
Neuro Oncol · 2025
0.80
4
Dual ENPP1/ATM depletion blunts DNA damage repair boosting radioimmune efficacy to abrogate triple-negative breast cancer.
PMID: 40506449
Signal Transduct Target Ther · 2025
0.76
5
Oral ENPP1 inhibitor designed using generative AI as next generation STING modulator for solid tumors.
PMID: 40410143
Nat Commun · 2025
0.72