ENPP3

Chr 6

ectonucleotide pyrophosphatase/phosphodiesterase 3

Also known as: B10, CD203c, NPP3, PD-IBETA, PDNP3

NCBI Gene: 5169ENSG00000154269UniProt: O14638

The protein encoded by this gene belongs to a series of ectoenzymes that are involved in hydrolysis of extracellular nucleotides. These ectoenzymes possess ATPase and ATP pyrophosphatase activities and are type II transmembrane proteins. Expression of the related rat mRNA has been found in a subset of immature glial cells and in the alimentary tract. The corresponding rat protein has been detected in the pancreas, small intestine, colon, and liver. The human mRNA is expressed in glioma cells, prostate, and uterus. Expression of the human protein has been detected in uterus, basophils, and mast cells. Two transcript variants, one protein coding and the other non-protein coding, have been found for this gene. [provided by RefSeq, Oct 2015]

286
ClinVar variants
16
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— ENPP3
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
16 Pathogenic / Likely Pathogenic· 258 VUS of 286 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
1.02LOEUF
pLI 0.000
Z-score 1.40
OE 0.79 (0.61–1.02)
Tolerant

Highly tolerant — LoF variants common in population

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.
0.07Z-score
OE missense 0.99 (0.92–1.07)
463 obs / 467.5 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.0.79 (0.61–1.02)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.99 (0.92–1.07)
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.1.05
0≤1.21.6
LoF obs/exp: 41 / 51.9Missense obs/exp: 463 / 467.5Syn Z: -0.49

ClinVar Variant Classifications

286 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13
Likely Pathogenic3
VUS258
Likely Benign10
Benign2
13
Pathogenic
3
Likely Pathogenic
258
VUS
10
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
13
0
13
Likely Pathogenic
0
0
3
0
3
VUS
0
247
11
0
258
Likely Benign
0
7
2
1
10
Benign
0
2
0
0
2
Total0256291286

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

View in ClinVar →

Protein Context — Lollipop Plot

ENPP3 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Identification of the extracellular membrane protein ENPP3 as a major cGAMP hydrolase and innate immune checkpoint.
Mardjuki R et al.·Cell Rep
2024
AGS16F Is a Novel Antibody Drug Conjugate Directed against ENPP3 for the Treatment of Renal Cell Carcinoma.
Doñate F et al.·Clin Cancer Res
2016
Antibody-Based Therapeutics for the Treatment of Renal Cell Carcinoma: Challenges and Opportunities.
Mahmoud AM et al.·Oncologist
2023Review
Micro-inflammation related gene signatures are associated with clinical features and immune status of fibromyalgia.
Yao M et al.·J Transl Med
2023
The basophil-specific ectoenzyme E-NPP3 (CD203c) as a marker for cell activation and allergy diagnosis.
Bühring HJ et al.·Int Arch Allergy Immunol
2004Review
The antibody-drug conjugate target landscape across a broad range of tumour types.
Moek KL et al.·Ann Oncol
2017
A methodology for gene level omics-WAS integration identifies genes influencing traits associated with cardiovascular risks: the Long Life Family Study.
Acharya S et al.·Hum Genet
2024
Employing a synergistic bioinformatics and machine learning framework to elucidate biomarkers associating asthma with pyrimidine metabolism genes.
Zhang D et al.·Respir Res
2024
ColoGuideEx: a robust gene classifier specific for stage II colorectal cancer prognosis.
Agesen TH et al.·Gut
2012
Quantitative, phenotypic, and functional evaluation of basophils in myelodysplastic syndromes.
Füreder W et al.·Eur J Clin Invest
2001Functional
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
ENPP3 drives ccRCC progression by cGAMP hydrolysis and STING-IFN suppression.
Ma J et al.·Cancer Biol Ther
2026🔓 Open Access
Divergent splicing factor SRSF1 signaling promotes inflammation post-CME: the SRSF1/ENPP3 axis acts via inhibition of BRD4 O-GlcNAcylation to enhance NF-κB activation and accelerate heart failure.
Hu CK et al.·Theranostics
2025🔓 Open Access
Dual targeting of ENPP3 and SIRPα with a bispecific antibody enhances macrophage-mediated immunity in renal cell carcinoma.
Xu L et al.·Biochem Biophys Res Commun
2025
Free amino acids accelerate the time-dependent inactivation of rat liver nucleotide pyrophosphatase/phosphodiesterase Enpp3 elicited by EDTA.
Romero A et al.·Amino Acids
2024🔓 Open Access
miR-34a-5p Predicts the Risk of Diabetic Neuropathic Pain and Mediates Neuroinflammation in Microglia via Targeting ENPP3.
Zhang P et al.·Immunol Invest
2024
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools