PPT1

Chr 1AR

palmitoyl-protein thioesterase 1

Also known as: CLN1, INCL, PPT

NCBI Gene: 5538ENSG00000131238UniProt: P50897

The protein encoded by this gene is a small glycoprotein involved in the catabolism of lipid-modified proteins during lysosomal degradation. The encoded enzyme removes thioester-linked fatty acyl groups such as palmitate from cysteine residues. Defects in this gene are a cause of infantile neuronal ceroid lipofuscinosis 1 (CLN1, or INCL) and neuronal ceroid lipofuscinosis 4 (CLN4). Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Dec 2008]

Primary Disease Associations & Inheritance

Ceroid lipofuscinosis, neuronal, 1MIM #256730
AR
592
ClinVar variants
115
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— PPT1
🧬
Gene-Disease Validity (ClinGen)
neuronal ceroid lipofuscinosis · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
115 Pathogenic / Likely Pathogenic· 195 VUS of 592 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.89LOEUF
pLI 0.000
Z-score 1.94
OE 0.52 (0.32–0.89)
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.
0.03Z-score
OE missense 0.99 (0.87–1.13)
163 obs / 164.2 exp
Tolerant

Mild missense constraint

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.0.52 (0.32–0.89)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.99 (0.87–1.13)
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.1.18
0≤1.21.6
LoF obs/exp: 10 / 19.2Missense obs/exp: 163 / 164.2Syn Z: -1.10

ClinVar Variant Classifications

592 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic51
Likely Pathogenic64
VUS195
Likely Benign238
Benign32
Conflicting12
51
Pathogenic
64
Likely Pathogenic
195
VUS
238
Likely Benign
32
Benign
12
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
26
2
23
0
51
Likely Pathogenic
38
15
11
0
64
VUS
1
141
46
7
195
Likely Benign
1
0
125
112
238
Benign
0
0
32
0
32
Conflicting
—12
Total66158237119592

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

View in ClinVar →

Protein Context — Lollipop Plot

PPT1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

PPT1-related neuronal ceroid lipofuscinosis

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

Ceroid lipofuscinosis, neuronal, 1

MIM #256730

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — PPT1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Targeting phenylpyruvate restrains excessive NLRP3 inflammasome activation and pathological inflammation in diabetic wound healing.
Lv D et al.·Cell Rep Med
2023
Emerging dimensions of autophagy in melanoma.
Pangilinan C et al.·Autophagy
2024Review
The palmitoylation of AEG-1 dynamically modulates the progression of hepatocellular carcinoma.
Zhou B et al.·Theranostics
2022
Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses.
Kousi M et al.·Hum Mutat
2012Review
GNS561, a clinical-stage PPT1 inhibitor, is efficient against hepatocellular carcinoma via modulation of lysosomal functions.
Brun S et al.·Autophagy
2022
Divergent effects of acute and chronic PPT1 inhibition in melanoma.
Crissey MAS et al.·Autophagy
2025
FBXW8-mediated degradation of PPT1 suppresses epithelial-mesenchymal transition and metastasis in hepatocellular carcinoma.
He J et al.·Biochim Biophys Acta Mol Basis Dis
2025
Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations.
Huang M et al.·Acta Neuropathol Commun
2020Functional
Deacylases-structure, function, and relationship to diseases.
Wang S et al.·FEBS Lett
2024Review
Human pathology in NCL.
Anderson GW et al.·Biochim Biophys Acta
2013Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Dysfunction of GABAergic interneurons underlies altered neural network oscillations associated with epileptiform activity in PPT1-deficient mice.
Tong J et al.·Transl Psychiatry
2026🔓 Open Access
PIK3CA Mutations Downregulate PPT1 to Promote Adipogenesis by Suppressing P300 Depalmitoylation and Phase Separation.
Chen H et al.·Adv Sci (Weinh)
2026
Palmitoyl-Protein Thioesterase 1 (PPT1) Protein, Linked to Neuronal Ceroid Lipofuscinosis 1, Is a Major Constituent of Ageing-Related Human Neuronal Lipofuscin.
Anstötz M et al.·Neuropathol Appl Neurobiol
2025🔓 Open Access
PPT1 is a negative regulator of STING signaling in cancer cells and its inhibition reactivates immune surveillance in cold tumors.
Chowdhury SR et al.·Proc Natl Acad Sci U S A
2025
AAV-delivered PPT1 provides long-term neurological benefits in CLN1 mice and achieves therapeutic levels in sheep brain.
Alam MS et al.·Mol Ther
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Neuronal Ceroid LipofuscinosisBatten DiseaseCLN1 Disease

Natural History and Longitudinal Clinical Assessments in NCL / Batten Disease, the International DEM-CHILD Database

RECRUITING
NCT04613089Universitätsklinikum Hamburg-EppendorfStarted 2020-04-08
Natural History

External Resources

Links to major genomics databases and tools