TPP1

Chr 11AR

tripeptidyl peptidase 1

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

NCBI Gene: 1200 ENSG00000166340 UniProt: O14773 OMIM: 607998

This gene encodes a lysosomal serine protease that cleaves N-terminal tripeptides from substrates and degrades specific neuropeptides and ATP synthase subunits. Mutations cause late-infantile neuronal ceroid lipofuscinosis (CLN2) and autosomal recessive spinocerebellar ataxia type 7 through autosomal recessive inheritance. The pathogenic mechanism involves failure to degrade lysosomal substrates due to loss of protease function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Ceroid lipofuscinosis, neuronal, 2MIM #204500

Spinocerebellar ataxia, autosomal recessive 7MIM #609270

Clinical highlights

Management implications

TPP1 has an approved disease-modifying therapy

Gene–disease validity (ClinGen · GenCC)

Definitive · neuronal ceroid lipofuscinosis · AR · ClinGen 2020
Definitive · neuronal ceroid lipofuscinosis 2 · AR · Myriad Women's Health
Strong · autosomal recessive spinocerebellar ataxia 7 · AR · PanelApp Australia

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.78

LOEUF

LOF

Mechanism· G2P

cerliponase alfa (Brineura)
enzyme replacementApproved · FDA 2017
Recombinant human TPP1 enzyme replacement.
Delivery: Intracerebroventricular, every 2 weeksEligibility: ≥3 yr with CLN2
Slows motor/language decline

Therapeutic landscape as of 2026-07. Educational only. Investigational ≠ available; not medical advice or eligibility. Approved entries are precise; investigational program names/phases are conservative and move fast. Curated from FDA/EMA approvals and the clinical-trial literature; verify against current labeling + ClinicalTrials.gov.

ClinicalTrials.gov

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

Background carrier burden — how many people carry a rare variant somewhere in TPP1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 51

740 rare PASS variants

Rare truncating (LoF)

1 in 750

120 rare PASS variants

Rare synonymous (reference)

1 in 230

296 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TPP1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 95	1 in 640
South Asian	~43k	1 in 73	1 in 1,400
Remaining (unassigned)	~30k	1 in 60	1 in 440
European (Finnish)	~27k	1 in 120	1 in 860
Admixed American	~22k	1 in 58	1 in 750
African / African American	~21k	1 in 79	1 in 1,000
East Asian	~20k	1 in 96	1 in 1,400
Ashkenazi Jewish	~13k	1 in 350	1 in 1,600
Middle Eastern	~2,884	1 in 69	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 13 coding exons well covered in gnomAD exomes and genomes.? see exons ↓