ENPP1

Chr 6ADARMulti

ectonucleotide pyrophosphatase/phosphodiesterase 1

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

NCBI Gene: 5167 ENSG00000197594 UniProt: P22413 OMIM: 173335

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]

GeneReviews OMIM Research

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAD/AR/MultiLOEUF 0.595 OMIM phenotypes

Clinical Summary— ENPP1

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Gene-Disease Validity (ClinGen)

hypopigmentation-punctate palmoplantar keratoderma syndrome · ADLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

100 unique Pathogenic / Likely Pathogenic· 422 VUS of 936 total submissions

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ENPP1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongENPP1-related Cole diseaseOTHERAD

definitiveENPP1-related generalised arterial calcification of infancy and hypophosphataemic ricketsLOFAR

This gene — mechanism propensity

0.5181th %ile

GOF

0.4972th %ile

LOF

0.3454th %ile

The Badonyi & Marsh model scores dominant-negative highest, but genomic evidence most strongly supports loss-of-function (haploinsufficiency) as the primary mechanism.

LOF1 literature citation · 68% of P/LP variants are LoF

Literature Evidence

LOFLoss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 20137773 ↗

ClinVar Variant Classifications

936 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic55

Likely Pathogenic45

VUS422

Likely Benign221

Benign130

Conflicting52

Pathogenic

Likely Pathogenic

422

VUS

221

Likely Benign

130

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	39	14	2	0	55
Likely Pathogenic	29	16	0	0	45
VUS	4	313	91	14	422
Likely Benign	0	4	117	100	221
Benign	0	1	125	4	130
Conflicting	—				52
Total	72	348	335	118	925

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

16 pathogenic / likely-pathogenic (of 28) ClinVar copy-number / structural variants overlap ENPP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →