PNPLA6

Chr 19AR

patatin like domain 6, lysophospholipase

NCBI Gene: 10908ENSG00000032444UniProt: Q8IY17

Phospholipase B that deacylates intracellular phosphatidylcholine (PtdCho), generating glycerophosphocholine (GroPtdCho). This deacylation occurs at both sn-2 and sn-1 positions of PtdCho. Catalyzes the hydrolysis of several naturally occurring membrane-associated lipids (PubMed:11927584). Hydrolyzes lysophospholipids and monoacylglycerols, preferring the 1-acyl to the 2-acyl isomer. Does not catalyze hydrolysis of di- or triacylglycerols or fatty acid amides (PubMed:11927584)

Primary Disease Associations & Inheritance

?Laurence-Moon syndromeMIM #245800
AR
Boucher-Neuhauser syndromeMIM #215470
AR
Oliver-McFarlane syndromeMIM #275400
AR
Spastic paraplegia 39, autosomal recessiveMIM #612020
AR
199
ClinVar variants
28
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— PNPLA6
🧬
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

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
28 Pathogenic / Likely Pathogenic· 55 VUS of 199 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Missense constrained — critical functional residues
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.
0.64LOEUF
pLI 0.000
Z-score 4.00
OE 0.48 (0.36–0.64)
Tolerant

Typical tolerance to LoF variation

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.
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?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.0.48 (0.36–0.64)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.59 (0.55–0.64)
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.1.01
0≤1.21.6
LoF obs/exp: 33 / 68.8Missense obs/exp: 529 / 895.8Syn Z: -0.15

ClinVar Variant Classifications

199 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic14
Likely Pathogenic14
VUS55
Likely Benign116
14
Pathogenic
14
Likely Pathogenic
55
VUS
116
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
2
9
0
14
Likely Pathogenic
9
4
1
0
14
VUS
2
51
2
0
55
Likely Benign
0
1
53
62
116
Benign
0
0
0
0
0
Total14586562199

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

View in ClinVar →

Protein Context — Lollipop Plot

PNPLA6 · protein map & ClinVar variants

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

Gene2Phenotype Curations

PNPLA6-related retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Laurence-Moon syndrome

MIM #245800

Molecular basis of disorder known

Autosomal recessive

Boucher-Neuhauser syndrome

MIM #215470

Molecular basis of disorder known

Autosomal recessive

Oliver-McFarlane syndrome

MIM #275400

Molecular basis of disorder known

Autosomal recessive

Spastic paraplegia 39, autosomal recessive

MIM #612020

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — PNPLA6
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Neuropathy target esterase activity defines phenotypes among PNPLA6 disorders.
Liu J et al.·Brain
2024
PNPLA6 disorders: what's in a name?
Liu J et al.·Ophthalmic Genet
2023Review
Hereditary ataxias and paraparesias: clinical and genetic update.
Parodi L et al.·Curr Opin Neurol
2018Review
Proof of Concept for Genome Profiling of the Neurofibroma/Sarcoma Sequence in Neurofibromatosis Type 1.
Cannizzaro IR et al.·Int J Mol Sci
2024
Ataxia and Hypogonadism: a Review of the Associated Genes and Syndromes.
De Michele G et al.·Cerebellum
2024Review
Novel variants in PNPLA6 causing syndromic retinal dystrophy.
Wu S et al.·Exp Eye Res
2021
A de novo hexokinase 1 (HK1) variant presenting as Boucher-Neuhäuser syndrome.
Peretz RH et al.·Am J Med Genet A
2023
Novel phenotype with prominent cerebellar oculomotor dysfunction in spastic paraplegia type 39.
Viertauer S et al.·J Neurol
2022
Inborn errors of metabolism in the biosynthesis and remodelling of phospholipids.
Wortmann SB et al.·J Inherit Metab Dis
2015Review
Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes.
Hufnagel RB et al.·J Med Genet
2015
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Lysophosphatidylethanolamine Degradation Associated with Upregulation of Pnpla6/7 in a Murine Model of Metabolic Dysfunction-Associated Steatohepatitis.
Inoue N et al.·Int J Mol Sci
2026Functional
Novel PNPLA6 Variants: Hypogonadotropic Hypogonadism, Pituitary Hypoplasia, Anosmia, and Cerebellar Atrophy in Siblings.
Hussain MA et al.·JCEM Case Rep
2026🔓 Open Access
Novel variant in PNPLA6 gene causes Oliver-McFarlane syndrome in a Chinese family: 13 years follow-up.
Xiao P et al.·Front Genet
2025🔓 Open AccessNatural history
Case Report: Novel compound heterozygous mutations in PNPLA6 gene associated with Oliver-McFarlane syndrome.
Zheng J et al.·Front Genet
2025🔓 Open AccessCase report
PNPLA6 regulates retinal homeostasis by choline through phospholipid turnover.
Ono T et al.·Nat Commun
2025🔓 Open Access
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