TPP2

Chr 13

tripeptidyl peptidase 2

Also known as: IMD78, TPP-2, TPP-II, TPPII

NCBI Gene: 7174 ENSG00000134900 UniProt: P29144

This cytosolic tripeptidyl-peptidase removes N-terminal tripeptides from polypeptides as part of the proteolytic cascade downstream of the 26S proteasome and plays an important role in MHC class I antigen presentation and intracellular amino acid homeostasis. Biallelic mutations cause autosomal recessive immunodeficiency 78 with autoimmunity and developmental delay. The gene is highly constrained against loss-of-function variants (pLI 0.999, LOEUF 0.263), indicating intolerance to protein-truncating mutations.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a mammalian peptidase that, at neutral pH, removes tripeptides from the N terminus of longer peptides. The protein has a specialized function that is essential for some MHC class I antigen presentation. The protein is a high molecular mass serine exopeptidase; the amino acid sequence surrounding the serine residue at the active site is similar to the peptidases of the subtilisin class rather than the trypsin class. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.26

Clinical Summary— TPP2

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Gene-Disease Validity (ClinGen)

immunodeficiency 78 with autoimmunity and developmental delay · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

21 unique Pathogenic / Likely Pathogenic· 344 VUS of 861 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.26LOEUF

pLI 0.999

Z-score 6.28

OE 0.16 (0.10–0.26)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.86Z-score

OE missense 0.57 (0.53–0.63)

374 obs / 651.3 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.16 (0.10–0.26)

0≤0.351.4

Missense OE?0.57 (0.53–0.63)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 10 / 64.4Missense obs/exp: 374 / 651.3Syn Z: -0.39

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTPP2-related immune deficiency, autoimmune disease and intellectual disabilityLOFAR

This gene — mechanism propensity

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

0.3594th %ile

GOF

0.2597th %ile

LOF

0.67top 25%

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

861 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17

Likely Pathogenic4

VUS344

Likely Benign417

Benign41

Conflicting5

Pathogenic

Likely Pathogenic

344

VUS

417

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	14	1	2	0	17
Likely Pathogenic	4	0	0	0	4
VUS	1	311	25	7	344
Likely Benign	0	3	177	237	417
Benign	0	2	32	7	41
Conflicting	—				5
Total	19	317	236	251	828

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

View in ClinVar →

101 pathogenic / likely-pathogenic (of 107) ClinVar copy-number / structural variants overlap TPP2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →