ENPP1

Chr 6q23.2

ectonucleotide pyrophosphatase/phosphodiesterase 1

Aliases:: PC-1, PCA1
MANE:: ENST00000647893.1

OMIM: 173335 ↗NCBI: 5167 ↗Ensembl ↗

Annotations refreshed 1 month ago.

Predicted protein structure

AlphaFold predicted structure

ENPP1 · P22413

v62025-08-01

Predicted Aligned Error matrix for ENPP1 — diagonal shows residue index, colour shows pairwise prediction confidence (lower is better) — Predicted Aligned Error

Mean pLDDT

90.7/ 100

Very high

925 residues

Confidence breakdown

Very high(≥ 90)85%
Confident(70–90)4%
Low(50–70)2%
Very low(< 50)9%

Open interactive 3D viewer

AlphaFold (Jumper et al., 2021) · CC BY 4.0

Clinical relevance (Genomics England PanelApp)

Diagnostic Grade (Green)

DDG2P
BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies
BIALLELIC, autosomal or pseudoautosomal
Generalised arterial calcification in infancy
BIALLELIC, autosomal or pseudoautosomal
Hypophosphataemia or rickets
BIALLELIC, autosomal or pseudoautosomal
Ichthyosis and erythrokeratoderma
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Palmoplantar keratoderma and erythrokeratodermas
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Palmoplantar keratodermas
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Pigmentary skin disorders
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

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Disease associations (Open Targets)

arterial calcification, generalized, of infancy, 1
0.85
Generalized arterial calcification of infancy
0.81
hypopigmentation-punctate palmoplantar keratoderma syndrome
0.81
hypophosphatemic rickets, autosomal recessive, 2
0.76
type 2 diabetes mellitus
0.65
autosomal recessive hypophosphatemic rickets
0.60
ossification of the posterior longitudinal ligament of the spine
0.56
inherited obesity
0.53
Obesity
0.45
arterial calcification of infancy
0.43

Score is the Open Targets composite evidence score (0-1). Higher = stronger gene-disease association.

Protein function (UniProt)

Ectonucleotide pyrophosphatase/phosphodiesterase family member 1

Nucleotide pyrophosphatase that generates diphosphate (PPi) and functions in bone mineralization and soft tissue calcification by regulating pyrophosphate levels (By similarity). PPi inhibits bone mineralization and soft tissue calcification by binding to nascent hydroxyapatite crystals, thereby preventing further growth of these crystals (PubMed:11004006). Preferentially hydrolyzes ATP, but can also hydrolyze other nucleoside 5' triphosphates such as GTP, CTP and UTP to their corresponding monophosphates with release of pyrophosphate, as well as diadenosine polyphosphates, and also 3',5'-cAMP to AMP (PubMed:25344812, PubMed:27467858, PubMed:28011303, PubMed:35147247, PubMed:8001561). 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 (PubMed:27467858, PubMed:8001561). Inhibits ectopic joint calcification and maintains articular chondrocytes by repressing hedgehog signaling; it is however unclear whether hedgehog inhibition is direct or indirect (By similarity). Appears to modulate insulin sensitivity and function (PubMed:10615944). Also involved in melanogenesis (PubMed:28964717). Also able to hydrolyze 2',3'-cGAMP (cyclic GMP-AMP), a second messenger that activates TMEM173/STING and triggers type-I interferon production (PubMed:25344812). 2',3'-cGAMP degradation takes place in the lumen or extracellular space, and not in the cytosol where it is produced; the role of 2',3'-cGAMP hydrolysis is therefore unclear (PubMed:25344812). Not able to hydrolyze the 2',3'-cGAMP linkage isomer 3'-3'-cGAMP (PubMed:25344812)