PLPP6

Chr 9

phospholipid phosphatase 6

Also known as: LPRP-B, PA-PSP, PDP1, PPAPDC2, PSDP, bA6J24.6

NCBI Gene: 403313 ENSG00000205808 UniProt: Q8IY26 OMIM: 611666

The protein is a magnesium-independent polyisoprenoid diphosphatase that catalyzes dephosphorylation of presqualene, farnesyl, geranyl and geranylgeranyl diphosphates, functioning in cholesterol biosynthesis, protein prenylation, and innate immune response through neutrophil activation regulation. PLPP6 mutations cause autosomal recessive hypomyelinating leukodystrophy-15, a severe early-onset disorder affecting white matter development in the central nervous system. The gene shows low constraint against loss-of-function variants, consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

Enables isoprenoid diphosphate phosphatase activity and phosphatase activity. Involved in several processes, including phospholipid dephosphorylation; phospholipid metabolic process; and positive regulation of neutrophil activation. Located in endoplasmic reticulum membrane and nuclear membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.74

Clinical Summary— PLPP6

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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

54 VUS of 63 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.74LOEUF

pLI 0.001

Z-score 0.21

OE 0.91 (0.47–1.74)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.62Z-score

OE missense 1.13 (1.01–1.28)

190 obs / 167.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.91 (0.47–1.74)

0≤0.351.4

Missense OE?1.13 (1.01–1.28)

0≤0.61.4

Synonymous OE?1.26

0≤1.21.6

LoF obs/exp: 5 / 5.5Missense obs/exp: 190 / 167.6Syn Z: -1.86

This gene — mechanism propensity

0.7034th %ile

GOF

0.6735th %ile

LOF

0.4331th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-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

GOFprediction above median

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.

ClinVar Variant Classifications

63 submitted variants in ClinVar

ClinVar

Classification Summary

VUS54

Likely Benign5

Benign4

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	54	0	0	54
Likely Benign	3	0	2	5
Benign	3	1	0	4
Total	60	1	2	63

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

View in ClinVar →

170 pathogenic / likely-pathogenic (of 188) ClinVar copy-number / structural variants overlap PLPP6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →