TPP1

Chr 11AR

tripeptidyl peptidase 1

Also known as: CLN2, GIG1, LPIC, SCAR7, TPP-1

NCBI Gene: 1200ENSG00000166340UniProt: O14773OMIM: 607998

This gene encodes a member of the sedolisin family of serine proteases. The protease functions in the lysosome to cleave N-terminal tripeptides from substrates, and has weaker endopeptidase activity. It is synthesized as a catalytically-inactive enzyme which is activated and auto-proteolyzed upon acidification. Mutations in this gene result in late-infantile neuronal ceroid lipofuscinosis, which is associated with the failure to degrade specific neuropeptides and a subunit of ATP synthase in the lysosome. [provided by RefSeq, Jul 2008]

GeneReviewsOMIMResearchGenerating clinical summary…
LOFmechanismARLOEUF 0.782 OMIM phenotypes
Clinical Summary— TPP1
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Gene-Disease Validity (ClinGen)
neuronal ceroid lipofuscinosis · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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
221 unique Pathogenic / Likely Pathogenic· 448 VUS of 1290 total submissions
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Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — TPP1
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?
0.78LOEUF
pLI 0.000
Z-score 2.48
OE 0.51 (0.34–0.78)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?
-0.22Z-score
OE missense 1.04 (0.94–1.14)
321 obs / 310.1 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?
LoF OE?0.51 (0.34–0.78)
0≤0.351.4
Missense OE?1.04 (0.94–1.14)
0≤0.61.4
Synonymous OE?1.02
0≤1.21.6
LoF obs/exp: 15 / 29.5Missense obs/exp: 321 / 310.1Syn Z: -0.16
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveTPP1-related neuronal ceroid lipofuscinosisLOFAR

This gene — mechanism propensity

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

DN
0.6162th %ile
GOF
0.4678th %ile
LOF
0.3358th %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

1290 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic97
Likely Pathogenic124
VUS448
Likely Benign515
Benign25
Conflicting61
97
Pathogenic
124
Likely Pathogenic
448
VUS
515
Likely Benign
25
Benign
61
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
81
13
3
0
97
Likely Pathogenic
80
40
3
1
124
VUS
6
385
51
6
448
Likely Benign
0
11
207
297
515
Benign
0
0
23
2
25
Conflicting
—61
Total1674492873061,270

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

View in ClinVar →

18 pathogenic / likely-pathogenic (of 23) ClinVar copy-number / structural variants overlap TPP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

TPP1 · protein map & ClinVar variants

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

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients