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

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]

Primary Disease Associations & Inheritance

{Diabetes mellitus, non-insulin-dependent, susceptibility to}MIM #125853

{Obesity, susceptibility to}MIM #601665

ADARMulti

Arterial calcification, generalized, of infancy, 1MIM #208000

Cole diseaseMIM #615522

Hypophosphatemic rickets, autosomal recessive, 2MIM #613312

UniProtOssification of the posterior longitudinal ligament of the spine

UniProtType 2 diabetes mellitus

489

ClinVar variants

Pathogenic / LP

0.00

pLI score

Active trials

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

45 Pathogenic / Likely Pathogenic· 245 VUS of 489 total submissions

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Clinical Trials

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

Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

1.62Z-score

OE missense 0.79 (0.72–0.86)

364 obs / 462.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.41 (0.29–0.59)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.79 (0.72–0.86)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.95

0≤1.21.6

LoF obs/exp: 22 / 53.6Missense obs/exp: 364 / 462.0Syn Z: 0.49

ClinVar Variant Classifications

489 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20

Likely Pathogenic25

VUS245

Likely Benign126

Benign65

Conflicting8

Pathogenic

Likely Pathogenic

245

VUS

126

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	7	3	10	0	20
Likely Pathogenic	16	6	3	0	25
VUS	1	209	24	11	245
Likely Benign	0	0	63	63	126
Benign	0	0	65	0	65
Conflicting	—				8
Total	24	218	165	74	489

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

View in 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.

Gene2Phenotype Curations

ENPP1-related Cole disease

strong

ADUndeterminedAltered Gene Product Structure

Skin

G2P ↗

ENPP1-related generalised arterial calcification of infancy and hypophosphataemic rickets

definitive

ARLoss Of FunctionAbsent Gene Product

Dev. Disorders

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

ECTONUCLEOTIDE PYROPHOSPHATASE/PHOSPHODIESTERASE 1; ENPP1

MIM #173335 · *

{Diabetes mellitus, non-insulin-dependent, susceptibility to}

MIM #125853