ENPP1

Chr 6

ectonucleotide pyrophosphatase/phosphodiesterase 1

Also known as: ARHR2, COLED, M6S1, NPP1, NPPS, PC-1, PCA1, PDNP1

NCBI Gene: 5167ENSG00000197594UniProt: P22413

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]

GeneReviewsResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtOssification of the posterior longitudinal ligament of the spine
UniProtArterial calcification of infancy, generalized, 1
UniProtType 2 diabetes mellitus
UniProtHypophosphatemic rickets, autosomal recessive, 2

Clinical highlights

Gene-disease validity (ClinGen)
hypopigmentation-punctate palmoplantar keratoderma syndrome · ADLimitednot for standalone diagnostic reporting2 gene-disease associations curated in total
Interpreting a novel variant
Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.
3
Active trials
114
Pubs (1 yr)
—
P/LP submissions
—
P/LP missense
0.59
LOEUF
LOF
Mechanism· G2P
📖
GeneReview available — ENPP1
Authoritative clinical overview · Recommended first read
Open GeneReview ↗
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?
0.59LOEUF
pLI 0.000
Z-score 4.00
OE 0.41 (0.29–0.59)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?
1.62Z-score
OE missense 0.79 (0.72–0.86)
364 obs / 462.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?
LoF OE?0.41 (0.29–0.59)
0≤0.351.4
Missense OE?0.79 (0.72–0.86)
0≤0.61.4
Synonymous OE?0.95
0≤1.21.6
LoF obs/exp: 22 / 53.6Missense obs/exp: 364 / 462.0Syn Z: 0.49

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

ENPP1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients