TPP2

protein-coding

tripeptidyl peptidase 2

Gene summary

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]

MANE transcript

NM_001330588.2

Inheritance

ClinVar variants

P:19U:342B:252

Top phenotype

Immunodeficiency 78 with autoimmunity and developmental delay

gnomAD constraint

pLI —, LoF o/e 0.16

Max pathogenic AF

—

Genomic locus

chr13:102,596,958-102,679,958

External References & Databases

Ensembl (ENSG00000134900)

Transcript & Mutation Effects

hg38 • Region Span ~83.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency 78 with autoimmunity and developmental delayDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0030971

Submitter: G2P

immunodeficiency 78 with autoimmunity and developmental delayMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0030971

Submitter: Ambry Genetics

immunodeficiency 78 with autoimmunity and developmental delayDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0030971

Submitter: ClinGen

*TPP2* was first reported in relation to autosomal recessive immunodeficiency 78 with autoimmunity and developmental delay in 2014 (Wei Lu, et al., PMID 25525876). The condition is characterized by recurrent bacterial, viral and fungal infections since early childhood, autoimmune hemolytic anemia and thrombocytopenia, as well as developmental delay, cerebral vascular accident and bronchiectasis. T (mainly CD8+) and B-cell lymphopenia may be present, as well as decreased naïve lymphocytes, increased levels of differentiated T and B lymphocytes, hypergammaglobulinemia (with increased IgE and decreased IgM) and autoantibodies. At least 7 variants (3 missense, 1 nonsense, 1 frameshift, 1 splice site, 1 large deletions) have been reported in 12 probands in 5 publications (PMIDs: 25525876, 25414442, 33682069, 33586135, 30968598) are included in this curation. A score of 8.2 for genetic evidence has been reached with all reported cases included. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by animal models, biochemical function studies, and in vitro functional assays (PMIDs: 18362329, 25525876, 25414442). Studies show that TPPII controls the balance between intracellular amino acid availability, lysosome number, and glycolysis, essential to produce effector cytokines (including IFNg and IL-1b), which is vital for adaptive and innate immunity and neurodevelopmental health. In summary, there is definitive evidence supporting the relationship between *TPP2* and autosomal recessive immunodeficiency 78 with autoimmunity and developmental delay. This has been repeatedly demonstrated in both research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Primary Immune Regulatory Disorders GCEP on the meeting date 12/16/2025 (SOP Version 11).

autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018636

Submitter: Orphanet

immunodeficiency 78 with autoimmunity and developmental delaySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030971

Submitter: Labcorp Genetics (formerly Invitae)

immunodeficiency 78 with autoimmunity and developmental delaySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030971

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Immunodeficiency 78 with autoimmunity and developmental delayAR

Manifestation: Allergy/Immunology/Infectious; Hematologic; Neurologic

Intervention: Allergy/Immunology/Infectious

Rationale: Among other findings, the condition can involve early-onset immunodeficiency, with severe and recurrent infections, and awareness may allow preventative measures and early and aggressive treatment of infections; BMT has been described

Refs: 25525876; 25414442; 33586135

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TPP2 variants in ClinVar

13 Conditions Cataloged

Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiencyTotal: 731

Inborn genetic diseasesTotal: 108

not providedTotal: 44

not specifiedTotal: 35

Immunodeficiency 78 with autoimmunity and developmental delayTotal: 15

TPP2-related disorderTotal: 14

Recurrent lower respiratory tract infectionsTotal: 1

ThrombocytopeniaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001330588.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			13 clinvar	241 clinvar	2 clinvar	256
missense	1 clinvar		316 clinvar	9 clinvar		326
nonsense	6 clinvar	1 clinvar	2 clinvar			9
start loss						0
frameshift	7 clinvar	1 clinvar	1 clinvar			9
splice donor/acceptor (+/-2bp)	1 clinvar	2 clinvar	10 clinvar			13
Total	15	4	342	250	2	613

Highest pathogenic variant AF is 0.000006571425

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 41 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001330588.2	RefSeq	NP_001317517.1	30	MANE Select
ENST00000376052.5	Ensembl	ENSP00000365220.3	30	MANE Select
NM_001367947.1	RefSeq	NP_001354876.1	30	Standard
NM_003291.4	RefSeq	NP_003282.2	29	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

protein polyubiquitination
proteolysis

Molecular Function

endopeptidase activity
aminopeptidase activity
serine-type endopeptidase activity
protein binding
tripeptidyl-peptidase activity

Cellular Component

nucleoplasm
cytoplasm
cytosol
nuclear body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000376065
Coding exons: 29
Length: 82169
Individuals with no LoFs: 125724
Homozygous LoFs: 0
Heterozygous LoFs: 24
Defined: 125748
p: 0.0000954

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.86	374	651	0.574	0.0000323	8156
Missense (PolyPhen)		76	226.53	0.33549		2790
Synonymous	-0.389	245	237	1.03	0.0000128	2380
Loss of Function	6.28	10	64.4	0.155	0.00000323	841

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.000060	0.000058	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00011	0.00011	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000098	0.000097	rare
South Asian	0.000066	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the proteolytic cascade acting downstream of the 26S proteasome in the ubiquitin-proteasome pathway. May be able to complement the 26S proteasome function to some extent under conditions in which the latter is inhibited. Stimulates adipogenesis (By similarity). {ECO:0000250}.;

Recessive Scores

pRec: 0.176

Intolerance Scores

LoFtool: 0.0666
RVIS EVS: -1.15
RVIS percentile EVS: 6.27

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.463

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium