PNPLA6

Chr 19

patatin like domain 6, lysophospholipase

Also known as: BNHS, LNMS, NTE, NTEMND, OMCS, SPG39, iPLA2delta, sws

NCBI Gene: 10908 ENSG00000032444 UniProt: Q8IY17

The protein is a phospholipase that deacetylates intracellular phosphatidylcholine to produce glycerophosphocholine and functions in neurite outgrowth and process elongation during neuronal differentiation from its location on the endoplasmic reticulum membrane. Mutations cause autosomal recessive disorders including spastic paraplegia 39, Boucher-Neuhauser syndrome, Oliver-McFarlane syndrome, and possibly Laurence-Moon syndrome. The pathogenic mechanism appears to involve gain-of-function effects.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a phospholipase that deacetylates intracellular phosphatidylcholine to produce glycerophosphocholine. It is thought to function in neurite outgrowth and process elongation during neuronal differentiation. The protein is anchored to the cytoplasmic face of the endoplasmic reticulum in both neurons and non-neuronal cells. Mutations in this gene result in autosomal recessive spastic paraplegia, and the protein is the target for neurodegeneration induced by organophosphorus compounds and chemical warfare agents. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.64

Clinical Summary— PNPLA6

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Gene-Disease Validity (ClinGen)

retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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

126 unique Pathogenic / Likely Pathogenic· 555 VUS of 1523 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — PNPLA6

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.64LOEUF

pLI 0.000

Z-score 4.00

OE 0.48 (0.36–0.64)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

4.35Z-score

OE missense 0.59 (0.55–0.64)

529 obs / 895.8 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.48 (0.36–0.64)

0≤0.351.4

Missense OE?0.59 (0.55–0.64)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 33 / 68.8Missense obs/exp: 529 / 895.8Syn Z: -0.15

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePNPLA6-related retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndromeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7034th %ile

GOF

0.75top 25%

LOF

0.3356th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

1523 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic72

Likely Pathogenic54

VUS555

Likely Benign644

Benign89

Conflicting86

Pathogenic

Likely Pathogenic

555

VUS

644

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	56	12	4	0	72
Likely Pathogenic	32	21	1	0	54
VUS	13	466	51	25	555
Likely Benign	0	9	304	331	644
Benign	0	2	82	5	89
Conflicting	—				86
Total	101	510	442	361	1,500

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

View in ClinVar →

6 pathogenic / likely-pathogenic (of 12) ClinVar copy-number / structural variants overlap PNPLA6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →