TPP1

Chr 11AR

tripeptidyl peptidase 1

NCBI Gene: 1200 ENSG00000166340 UniProt: O14773

Lysosomal serine protease with tripeptidyl-peptidase I activity (PubMed:11054422, PubMed:19038966, PubMed:19038967). May act as a non-specific lysosomal peptidase which generates tripeptides from the breakdown products produced by lysosomal proteinases (PubMed:11054422, PubMed:19038966, PubMed:19038967). Requires substrates with an unsubstituted N-terminus (PubMed:19038966)

Primary Disease Associations & Inheritance

Ceroid lipofuscinosis, neuronal, 2MIM #204500

Spinocerebellar ataxia, autosomal recessive 7MIM #609270

1300

ClinVar variants

Pathogenic / LP

0.00

pLI score

Active trials

Clinical Summary— TPP1

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

88 Pathogenic / Likely Pathogenic· 150 VUS of 1300 total submissions

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Clinical Trials

3 active or recruiting trials — 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.

0.78LOEUF

pLI 0.000

Z-score 2.48

OE 0.51 (0.34–0.78)

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.

-0.22Z-score

OE missense 1.04 (0.94–1.14)

321 obs / 310.1 exp

Tolerant

Tolerant to missense variation

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.0.51 (0.34–0.78)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.04 (0.94–1.14)

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.1.02

0≤1.21.6

LoF obs/exp: 15 / 29.5Missense obs/exp: 321 / 310.1Syn Z: -0.16

ClinVar Variant Classifications

1300 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic42

Likely Pathogenic46

VUS150

Likely Benign244

Benign1

Conflicting1

Pathogenic

Likely Pathogenic

150

VUS

244

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	21	1	20	0	42
Likely Pathogenic	29	9	8	0	46
VUS	1	134	11	4	150
Likely Benign	0	1	117	126	244
Benign	0	0	1	0	1
Conflicting	—				1
Total	51	145	157	130	484

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

View in ClinVar →

Protein Context — Lollipop Plot

TPP1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

TPP1-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

TRIPEPTIDYL PEPTIDASE I; TPP1

MIM #607998 · *

Ceroid lipofuscinosis, neuronal, 2

MIM #204500

Molecular basis of disorder known

Autosomal recessive

Spinocerebellar ataxia, autosomal recessive 7

MIM #609270

Molecular basis of disorder known

Autosomal recessive

External Resources

Links to major genomics databases and tools

Clinical Literature

Landmark / reviewRecent case evidence

Key Publications

Landmark & review papers · by relevance

PubMed

Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration.

Rusmini P et al.·Autophagy

2019Functional

The clinical and functional effects of TERT variants in myelodysplastic syndrome.

Reilly CR et al.·Blood

2021Clinical trial

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

Safety and efficacy of cerliponase alfa in children with neuronal ceroid lipofuscinosis type 2 (CLN2 disease): an open-label extension study.

Schulz A et al.·Lancet Neurol

2024

C1Q(+) TPP1(+) macrophages promote colon cancer progression through SETD8-driven p53 methylation.

Veschi V et al.·Mol Cancer

2025

An AAV variant selected through NHP screens robustly transduces the brain and drives secreted protein expression in NHPs and mice.

Tecedor L et al.·Sci Transl Med

2025

The neuronal ceroid-lipofuscinoses.

Bennett MJ et al.·Dev Disabil Res Rev

2013Review

Homozygous missense TPP1 mutation associated with mild late infantile neuronal ceroid lipofuscinosis and the genotype-phenotype correlation.

Chen ZR et al.·Seizure

2019Case report

TPP1 Inhibits DNA Damage Response and Chemosensitivity in Esophageal Cancer.

Wen J et al.·Crit Rev Eukaryot Gene Expr

2023

The natural history of progressive myoclonus ataxia.

van der Veen S et al.·Neurobiol Dis

2024Natural history

Top 10 resultsSearch PubMed ↗

Recent Gene-Specific Literature

Gene in title · MEDLINE · newest first

Europe PMC

Shelterin Component TPP1 Drives Tumor Progression and Predicts Poor Prognosis in Hepatocellular Carcinoma.

Jang JE et al.·Biomedicines

2026

Targeting Telomere Shelterin Protein TPP1 with Elbasvir: Induction of Autophagy and Suppression of Esophageal Cancer Tumorigenesis.

Tang M et al.·Anticancer Agents Med Chem

2025

Recreating pathophysiology of CLN2 disease and demonstrating reversion by TPP1 gene therapy in hiPSC-derived retinal organoids and retina-on-chip.

Corti S et al.·Cell Rep Med

2025🔓 Open Access

Tumor Membrane Based Delivery System Encapsulating Metfornin and TPP1 Peptide for Tumor Immune Therapy.

Wang X et al.·ACS Biomater Sci Eng

2025🔓 Open Access

Benchmarking Nanopore Sequencing for CLN2 (TPP1) Mutation Detection: Integrating Rapid Genomics and Orthogonal Validation for Precision Diagnostics.

Teker B et al.·Int J Mol Sci

2025🔓 Open Access

Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Neuronal Ceroid Lipofuscinosis Type 2

A First-in-Human, Open-Label, Dose-Escalation Study to Evaluate the Safety and Tolerability of Gene Therapy With TTX-381 for the Ocular Manifestations Associated With Neuronal Ceroid Lipofuscinosis Type 2 (CLN2) Disease

RECRUITING

NCT05791864Phase PHASE1, PHASE2Tern Therapeutics, LLCStarted 2023-05-17

TTX-381

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

Batten DiseaseCLN2Neuronal Ceroid-Lipofuscinoses

Examining Developmental Outcomes of Children Diagnosed With CLN2 Disease

ENROLLING BY INVITATION

NCT03862274Jessica ScherrStarted 2018-12-01