PLPP3

Chr 1

phospholipid phosphatase 3

Also known as: Dri42, LPP3, PAP2B, PPAP2B, VCIP

NCBI Gene: 8613 ENSG00000162407 UniProt: O14495 OMIM: 607125

The protein functions as a plasma membrane phospholipid phosphatase that dephosphorylates various bioactive lipid mediators including lysophosphatidic acid and sphingosine 1-phosphate, regulating vascular homeostasis and cerebellar development. Mutations cause autosomal recessive hypomyelinating leukodystrophy with ataxia and intellectual disability, typically presenting in early childhood. This gene is highly constrained against loss-of-function variants, indicating it is essential for normal development.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a member of the phosphatidic acid phosphatase (PAP) family. PAPs convert phosphatidic acid to diacylglycerol, and function in de novo synthesis of glycerolipids as well as in receptor-activated signal transduction mediated by phospholipase D. This protein is a membrane glycoprotein localized at the cell plasma membrane. It has been shown to actively hydrolyze extracellular lysophosphatidic acid and short-chain phosphatidic acid. The expression of this gene is found to be enhanced by epidermal growth factor in Hela cells. [provided by RefSeq, Mar 2010]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.38

Clinical Summary— PLPP3

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.92). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

28 VUS of 37 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.38LOEUF

pLI 0.917

Z-score 3.00

OE 0.08 (0.03–0.38)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.43Z-score

OE missense 0.71 (0.61–0.82)

134 obs / 189.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.08 (0.03–0.38)

0≤0.351.4

Missense OE?0.71 (0.61–0.82)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 1 / 12.4Missense obs/exp: 134 / 189.5Syn Z: 0.86

This gene — mechanism propensity

0.6551th %ile

GOF

0.5955th %ile

LOF

0.4529th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

LOFLOEUF 0.38

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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

ClinVar Variant Classifications

37 submitted variants in ClinVar

ClinVar

Classification Summary

VUS28

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	28	28
Likely Benign	0	0
Benign	0	0
Total	28	28

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap PLPP3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →