ENPP2

Chr 8

ectonucleotide pyrophosphatase/phosphodiesterase 2

Also known as: ATX, ATX-X, AUTOTAXIN, LysoPLD, NPP2, PD-IALPHA, PDNP2

NCBI Gene: 5168 ENSG00000136960 UniProt: Q13822 OMIM: 601060

This gene encodes a secreted lysophospholipase D that hydrolyzes lysophospholipids to produce lysophosphatidic acid (LPA), a signaling molecule involved in cell proliferation, migration, and angiogenesis. Biallelic mutations cause generalized arterial calcification of infancy (GACI), a severe autosomal recessive disorder presenting in early infancy with calcification of large arteries and cardiac complications. The gene shows high tolerance to loss-of-function variants (low pLI score), consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene functions as both a phosphodiesterase, which cleaves phosphodiester bonds at the 5' end of oligonucleotides, and a phospholipase, which catalyzes production of lysophosphatidic acid (LPA) in extracellular fluids. LPA evokes growth factor-like responses including stimulation of cell proliferation and chemotaxis. This gene product stimulates the motility of tumor cells and has angiogenic properties, and its expression is upregulated in several kinds of carcinomas. The gene product is secreted and further processed to make the biologically active form. Several alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2008]

OMIM ResearchGenerating clinical summary…

LOEUF 0.43

Clinical Summary— ENPP2

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.28) despite low pLI — interpret in context.

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ClinVar Variants

122 VUS of 161 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.43LOEUF

pLI 0.003

Z-score 4.98

OE 0.28 (0.19–0.43)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.38Z-score

OE missense 0.83 (0.76–0.90)

425 obs / 513.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.28 (0.19–0.43)

0≤0.351.4

Missense OE?0.83 (0.76–0.90)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 16 / 56.4Missense obs/exp: 425 / 513.1Syn Z: -0.07

ClinVar Variant Classifications

161 submitted variants in ClinVar

ClinVar

Classification Summary

VUS122

Likely Benign5

Benign5

122

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	121	0	1	122
Likely Benign	3	0	2	5
Benign	2	2	1	5
Total	126	2	4	132

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

View in ClinVar →

55 pathogenic / likely-pathogenic (of 66) ClinVar copy-number / structural variants overlap ENPP2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →