TPP2

Chr 13AR

tripeptidyl peptidase 2

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

NCBI Gene: 7174 ENSG00000134900 UniProt: P29144 OMIM: 190470

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.

OMIM 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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Immunodeficiency 78 with autoimmunity and developmental delayMIM #619220

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · immunodeficiency 78 with autoimmunity and developmental delay · AR · ClinGen 2025

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.26

LOEUF· LoF intol.

LOF

Mechanism· G2P

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

Background carrier burden — how many people carry a rare variant somewhere in TPP2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 66

1,117 rare PASS variants

Rare truncating (LoF)

1 in 3,700

72 rare PASS variants

Rare synonymous (reference)

1 in 130

541 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TPP2. 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 86	1 in 3,300
South Asian	~43k	1 in 77	1 in 4,600
Remaining (unassigned)	~30k	1 in 60	≈ 1 in 9,800
European (Finnish)	~27k	1 in 110	1 in 2,200
Admixed American	~22k	1 in 72	≈ 1 in 8,600
African / African American	~21k	1 in 78	≈ 1 in 6,400
East Asian	~20k	1 in 92	≈ 1 in 6,400
Ashkenazi Jewish	~13k	1 in 110	1 in 1,400
Middle Eastern	~2,884	1 in 69	≈ 1 in 2,600

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 30 coding exons well covered in gnomAD exomes and genomes.? see exons ↓