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GeneE
26 sources retrieved Β· Most recent: April 2026 Β· Index updated 14 days ago
β“˜GeneE is for informational purposes only. It is not a substitute for professional medical advice, diagnosis, or treatment.
TPP1
tripeptidyl peptidase 1
Chromosome 11 Β· 11p15.4
NCBI Gene: 1200Ensembl: ENSG00000166340.19HGNC: HGNC:2073UniProt: O14773
165PubMed Papers
22Diseases
0Drugs
221Pathogenic Variants
FUNCTIONAL ROLE
Protease
RESEARCH IMPACT
TrendingVariant-Rich
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
recycling endosomeprotein bindingmembrane raftpeptidase activityneuronal ceroid lipofuscinosis 2CLN2 diseaseChildhood-onset autosomal recessive slowly progressive spinocerebellar ataxiaautosomal recessive spinocerebellar ataxia 7
✦AI Summary

TPP1 (tripeptidyl peptidase 1) serves dual critical functions in human cells: lysosomal protein degradation and telomere maintenance. As a lysosomal serine protease, TPP1 exhibits tripeptidyl-peptidase activity, generating tripeptides from breakdown products of lysosomal proteinases and requiring substrates with unsubstituted N-termini 1. In telomere biology, TPP1 forms part of the shelterin complex, specifically heterodimerizing with POT1 to protect chromosome 11 and recruit telomerase 2. Structural studies reveal that TPP1 creates a structured interface with telomerase components TERT-TEN and TRAP domains, stabilizing DNA and enhancing telomerase processivity 34. TPP1-POT1 binding suppresses ATR-dependent DNA damage responses and is essential for telomere length regulation 5. Disease relevance includes neuronal ceroid lipofuscinosis type 2 (CLN2) caused by TPP1 mutations, leading to progressive neurodegeneration 6. Additionally, TPP1 promoter mutations cooperate with TERT promoter mutations in melanoma to enhance telomere maintenance and cellular immortalization 7. Mendelian randomization studies implicate TPP1 in amyotrophic lateral sclerosis pathogenesis, highlighting its broader neurological significance 8.

Sources cited
1
TPP1 is a lysosomal hydrolase involved in protein degradation
PMID: 30335591
2
TPP1 is part of the shelterin complex that protects telomeres
PMID: 16166375
3
TPP1 forms structured interface with telomerase and stabilizes DNA
PMID: 35201900
4
TPP1 interacts with TERT domains and enhances telomerase processivity
PMID: 35418675
5
TPP1-POT1 complex suppresses DNA damage response and regulates telomere length
PMID: 32774788
6
TPP1 mutations cause neuronal ceroid lipofuscinosis type 2
PMID: 21990111
7
TPP1 promoter mutations cooperate with TERT mutations in melanoma
PMID: 36356143
8
TPP1 implicated in amyotrophic lateral sclerosis pathogenesis
PMID: 40037332
Disease Associationsβ“˜22
neuronal ceroid lipofuscinosis 2Open Targets
0.79Strong
CLN2 diseaseOpen Targets
0.79Strong
Childhood-onset autosomal recessive slowly progressive spinocerebellar ataxiaOpen Targets
0.77Strong
autosomal recessive spinocerebellar ataxia 7Open Targets
0.75Strong
neuronal ceroid lipofuscinosisOpen Targets
0.72Strong
genetic disorderOpen Targets
0.53Moderate
Intellectual disabilityOpen Targets
0.49Moderate
Abnormality of the skeletal systemOpen Targets
0.48Moderate
Rare hereditary ataxiaOpen Targets
0.48Moderate
Abnormality of the nervous systemOpen Targets
0.46Moderate
hereditary ataxiaOpen Targets
0.46Moderate
eye diseaseOpen Targets
0.37Weak
Angelman syndromeOpen Targets
0.34Weak
juvenile neuronal ceroid lipofuscinosisOpen Targets
0.28Weak
SeizureOpen Targets
0.12Weak
poisoningOpen Targets
0.12Weak
response to antihypertensive drugOpen Targets
0.12Weak
neoplasmOpen Targets
0.11Weak
Spinocerebellar ataxia type 40Open Targets
0.08Suggestive
Familial progressive cardiac conduction defectOpen Targets
0.08Suggestive
Ceroid lipofuscinosis, neuronal, 2UniProt
Spinocerebellar ataxia, autosomal recessive, 7UniProt
Pathogenic Variants221
NM_000391.4(TPP1):c.622C>T (p.Arg208Ter)Pathogenic
Neuronal ceroid lipofuscinosis 2|Neuronal ceroid lipofuscinosis|not provided|Inborn genetic diseases|Neuronal ceroid lipofuscinosis 2;Autosomal recessive spinocerebellar ataxia 7|Abnormality of the nervous system|TPP1-related disorder
β˜…β˜…β˜†β˜†2026β†’ Residue 208
NM_000391.4(TPP1):c.827A>T (p.Asp276Val)Pathogenic
not provided|Neuronal ceroid lipofuscinosis 2|Neuronal ceroid lipofuscinosis 2;Autosomal recessive spinocerebellar ataxia 7
β˜…β˜…β˜†β˜†2026β†’ Residue 276
NM_000391.4(TPP1):c.509-1G>CPathogenic
Neuronal ceroid lipofuscinosis 2|not provided|Autosomal recessive spinocerebellar ataxia 7|Inborn genetic diseases|Neuronal ceroid lipofuscinosis|Neuronal ceroid lipofuscinosis 2;Autosomal recessive spinocerebellar ataxia 7|Familial cancer of breast|TPP1-related disorder|Ovarian serous cystadenocarcinoma|Lung cancer|Malignant tumor of urinary bladder|Retinal disorder
β˜…β˜…β˜†β˜†2026
NM_000391.4(TPP1):c.225A>G (p.Gln75=)Pathogenic
Neuronal ceroid lipofuscinosis 2|not provided|Autosomal recessive spinocerebellar ataxia 7|Neuronal ceroid lipofuscinosis 2;Autosomal recessive spinocerebellar ataxia 7
β˜…β˜…β˜†β˜†2026β†’ Residue 75
NM_000391.4(TPP1):c.357dup (p.Leu120fs)Pathogenic
Neuronal ceroid lipofuscinosis 2|not provided|Neuronal ceroid lipofuscinosis 2;Autosomal recessive spinocerebellar ataxia 7
β˜…β˜…β˜†β˜†2026β†’ Residue 120
NM_000391.4(TPP1):c.1094G>A (p.Cys365Tyr)Pathogenic
Neuronal ceroid lipofuscinosis 2|not provided|Neuronal ceroid lipofuscinosis|Neuronal ceroid lipofuscinosis 2;Autosomal recessive spinocerebellar ataxia 7|TPP1-related disorder
β˜…β˜…β˜†β˜†2026β†’ Residue 365
NM_000391.4(TPP1):c.1340G>A (p.Arg447His)Pathogenic
Neuronal ceroid lipofuscinosis 2|not provided|Neuronal ceroid lipofuscinosis 2;Autosomal recessive spinocerebellar ataxia 7|Neuronal ceroid lipofuscinosis
β˜…β˜…β˜†β˜†2026β†’ Residue 447
NM_000391.4(TPP1):c.509-1G>TPathogenic
not provided|Neuronal ceroid lipofuscinosis 2
β˜…β˜…β˜†β˜†2026
NM_000391.4(TPP1):c.229G>A (p.Gly77Arg)Pathogenic
Neuronal ceroid lipofuscinosis 2|Neuronal ceroid lipofuscinosis|not provided
β˜…β˜…β˜†β˜†2026β†’ Residue 77
NM_000391.4(TPP1):c.1027G>A (p.Glu343Lys)Pathogenic
Neuronal ceroid lipofuscinosis 2|not provided|Neuronal ceroid lipofuscinosis
β˜…β˜…β˜†β˜†2026β†’ Residue 343
NM_000391.4(TPP1):c.1015C>T (p.Arg339Trp)Pathogenic
not provided|Neuronal ceroid lipofuscinosis 2|Inborn genetic diseases|Neuronal ceroid lipofuscinosis|Neuronal ceroid lipofuscinosis 2;Autosomal recessive spinocerebellar ataxia 7
β˜…β˜…β˜†β˜†2026β†’ Residue 339
NM_000391.4(TPP1):c.196C>T (p.Gln66Ter)Pathogenic
not provided|Neuronal ceroid lipofuscinosis|Neuronal ceroid lipofuscinosis 2
β˜…β˜…β˜†β˜†2025β†’ Residue 66
NM_000391.4(TPP1):c.89+5G>CPathogenic
not provided|Neuronal ceroid lipofuscinosis
β˜…β˜…β˜†β˜†2025
NM_000391.4(TPP1):c.1266G>C (p.Gln422His)Pathogenic
Neuronal ceroid lipofuscinosis 2|Inborn genetic diseases|not provided|Neuronal ceroid lipofuscinosis|Autosomal recessive spinocerebellar ataxia 7|Neuronal ceroid lipofuscinosis 2;Autosomal recessive spinocerebellar ataxia 7
β˜…β˜…β˜†β˜†2025β†’ Residue 422
NM_000391.4(TPP1):c.857A>G (p.Asn286Ser)Pathogenic
Neuronal ceroid lipofuscinosis 2|not provided|Neuronal ceroid lipofuscinosis
β˜…β˜…β˜†β˜†2025β†’ Residue 286
NM_000391.4(TPP1):c.1012C>G (p.Gln338Glu)Pathogenic
Neuronal ceroid lipofuscinosis 2|not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 338
NM_000391.4(TPP1):c.833A>G (p.Gln278Arg)Pathogenic
not provided|Neuronal ceroid lipofuscinosis 2|Neuronal ceroid lipofuscinosis
β˜…β˜…β˜†β˜†2025β†’ Residue 278
NM_000391.4(TPP1):c.1497del (p.Gly501fs)Pathogenic
Inborn genetic diseases|not provided|Neuronal ceroid lipofuscinosis 2
β˜…β˜…β˜†β˜†2025β†’ Residue 501
NM_000391.4(TPP1):c.1496dup (p.Leu500fs)Pathogenic
not provided|Neuronal ceroid lipofuscinosis 2
β˜…β˜…β˜†β˜†2025β†’ Residue 500
NM_000391.4(TPP1):c.380G>A (p.Arg127Gln)Pathogenic
Neuronal ceroid lipofuscinosis 2|not provided|Neuronal ceroid lipofuscinosis
β˜…β˜…β˜†β˜†2025β†’ Residue 127
View on ClinVar β†—
Related Genes
TERF2IPProtein interaction100%TINF2Protein interaction100%TERF1Protein interaction100%NUPR2Protein interaction99%FLI1Protein interaction94%CTC1Protein interaction86%
Tissue Expression6 tissues
Bone Marrow
100%
Lung
92%
Brain
82%
Liver
60%
Heart
57%
Ovary
47%
Gene Interaction Network
Click a node to explore
TPP1TERF2IPTINF2TERF1NUPR2FLI1CTC1
PROTEIN STRUCTURE
Preparing viewer…
PDB3EDY Β· 1.85 Γ… Β· X-ray
View on RCSB β†—
Constraintβ“˜
LOEUFβ“˜
0.78LoF Tolerant
pLIβ“˜
0.00Tolerant
Observed/Expected LoF0.60 [0.47–0.78]
RankingsWhere TPP1 stands among ~20K protein-coding genes
  • #2,721of 20,598
    Most Researched165 Β· top quartile
  • #298of 5,498
    Most Pathogenic Variants221 Β· top 10%
  • #6,382of 17,882
    Most Constrained (LOEUF)0.78
Genes detectedTPP1
Sources retrieved26 papers
Response timeβ€”
πŸ“„ Sources
26β–Ό
1
Structural basis of human telomerase recruitment by TPP1-POT1.
PMID: 35201900
Science Β· 2022
1.00
2
Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration.
PMID: 30335591
Autophagy Β· 2019
0.90
3
Recreating pathophysiology of CLN2 disease and demonstrating reversion by TPP1 gene therapy in hiPSC-derived retinal organoids and retina-on-chip.
PMID: 40706588
Cell Rep Med Β· 2025
0.80
4
Shelterin: the protein complex that shapes and safeguards human telomeres.
PMID: 16166375
Genes Dev Β· 2005
0.80
5
C1Q
PMID: 40165182
Mol Cancer Β· 2025
0.72