TPP2

Summary

TPP2 (tripeptidyl peptidase 2, HGNC:12016) is a protein-coding gene on chromosome 13q33.1, encoding Tripeptidyl-peptidase 2 (P29144). Cytosolic tripeptidyl-peptidase that releases N-terminal tripeptides from polypeptides and is a component of the proteolytic cascade acting downstream of the 26S proteasome in the ubiquitin-proteasome pathway.

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.

Source: NCBI Gene 7174 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 78 with autoimmunity and developmental delay (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 851 total — 17 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 30
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001330588

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12016
Approved symbol	TPP2
Name	tripeptidyl peptidase 2
Location	13q33.1
Locus type	gene with protein product
Status	Approved
Aliases	TPPII
Ensembl gene	ENSG00000134900
Ensembl biotype	protein_coding
OMIM	190470
Entrez	7174

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 15 retained_intron, 10 protein_coding, 4 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000376052, ENST00000376065, ENST00000466153, ENST00000482393, ENST00000490010, ENST00000490420, ENST00000493770, ENST00000496126, ENST00000650757, ENST00000651448, ENST00000651544, ENST00000651748, ENST00000651823, ENST00000651921, ENST00000652033, ENST00000652308, ENST00000698381, ENST00000698382, ENST00000698383, ENST00000698384, ENST00000698385, ENST00000698386, ENST00000698387, ENST00000698388, ENST00000698389, ENST00000698390, ENST00000698391, ENST00000698392, ENST00000698393, ENST00000854161, ENST00000912746, ENST00000959512

RefSeq mRNA: 3 — MANE Select: NM_001330588 NM_001330588, NM_001367947, NM_003291

CCDS: CCDS81777, CCDS9502

Canonical transcript exons

ENST00000376052 — 30 exons

Exon	Start	End
ENSE00000917076	102636224	102636392
ENSE00001469250	102651359	102651397
ENSE00003973486	102649408	102649486
ENSE00003973488	102644557	102644673
ENSE00003973489	102596986	102597203
ENSE00003973490	102643222	102643376
ENSE00003973491	102676296	102676415
ENSE00003973492	102648907	102649151
ENSE00003973495	102604793	102604921
ENSE00003973497	102627848	102627924
ENSE00003973498	102640270	102640376
ENSE00003973499	102616396	102616500
ENSE00003973500	102627012	102627166
ENSE00003973501	102638239	102638315
ENSE00003973504	102678227	102679958
ENSE00003973505	102674283	102674490
ENSE00003973508	102663648	102663744
ENSE00003973509	102664795	102664925
ENSE00003973511	102633950	102634098
ENSE00003973513	102622877	102623040
ENSE00003973516	102629482	102629609
ENSE00003973517	102646294	102646390
ENSE00003973518	102618722	102618846
ENSE00003973519	102647207	102647344
ENSE00003973520	102657056	102657207
ENSE00003973521	102635587	102635702
ENSE00003973523	102637082	102637239
ENSE00003973524	102644909	102645009
ENSE00003973526	102630096	102630195
ENSE00003973527	102614101	102614196

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 97.52.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 45.2460 / max 531.6882, expressed in 1823 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
135919	38.3767	1822
135918	3.4497	1338
135917	2.6065	1129
135920	0.7449	459
135923	0.0408	6
135924	0.0274	3

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	97.52	gold quality
right testis	UBERON:0004534	97.19	gold quality
testis	UBERON:0000473	96.48	gold quality
sperm	CL:0000019	96.44	gold quality
calcaneal tendon	UBERON:0003701	96.35	gold quality
male germ cell	CL:0000015	94.98	gold quality
colonic epithelium	UBERON:0000397	94.52	gold quality
monocyte	CL:0000576	94.41	gold quality
mononuclear cell	CL:0000842	94.24	gold quality
rectum	UBERON:0001052	94.04	gold quality
leukocyte	CL:0000738	94.03	gold quality
adrenal tissue	UBERON:0018303	93.79	gold quality
tendon	UBERON:0000043	93.68	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	93.39	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.22	gold quality
right uterine tube	UBERON:0001302	92.99	gold quality
right lung	UBERON:0002167	92.99	gold quality
gastrocnemius	UBERON:0001388	92.98	gold quality
muscle of leg	UBERON:0001383	92.93	gold quality
right ovary	UBERON:0002118	92.80	gold quality
ventricular zone	UBERON:0003053	92.74	gold quality
right lobe of thyroid gland	UBERON:0001119	92.68	gold quality
left ovary	UBERON:0002119	92.66	gold quality
seminal vesicle	UBERON:0000998	92.65	gold quality
left lobe of thyroid gland	UBERON:0001120	92.52	gold quality
upper lobe of left lung	UBERON:0008952	92.47	gold quality
bone marrow cell	CL:0002092	92.35	gold quality
mucosa of stomach	UBERON:0001199	92.35	gold quality
tibial nerve	UBERON:0001323	92.32	gold quality
thyroid gland	UBERON:0002046	92.22	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	27.56
E-ANND-3	yes	10.13
E-GEOD-93593	yes	5.07
E-GEOD-110499	no	378.94

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 20)

• the promoter could be localized to a 215 bp fragment upstream of the initiation codon. (PMID:15716107)
• TPPII appears to promote malignant cell growth by allowing exit from mitosis and the survival of cells with severe mitotic spindle damage. (PMID:16762321)
• TPP2 plays a specialized role in antigen processing and one that is not essential for the generation of most presented peptides. (PMID:16849449)
• This investigation reveals that TPP II expression could be regulated through both positive and negative regulatory elements. (PMID:17343995)
• Expression of mRNA for MuRF-1 increased approximately 3-fold at 10 days without changes in MAFbx or tripeptidyl peptidase II mRNA, but all decreased between 10 and 21 days of muscle disuse. (PMID:17901116)
• Results indicate that TPPII is dispensable for the generation of proteasome-dependent HLA class I ligands and, the enzyme is not involved significantly in generating the proteasome-independent HLA-B27-bound peptide repertoire. (PMID:18286573)
• Cross-presentation of NY-ESO-1/ISCOMATRIX cancer vaccine was proteasome independent and requires the cytosolic protease tripeptidyl peptidase II. (PMID:19155470)
• MHC class I-restricted LMP1 epitopes studied in this work are two of very few epitopes known to date to be processed proteasome independently by tripeptidyl peptidase II. (PMID:19587004)
• Results suggest an important function of TPPII in the maintenance of viral growth and may have implications for anti-viral therapy. (PMID:21134372)
• Current knowledge about TPPII with a focus on structural aspects. (PMID:21771670)
• Previously unknown differences between TPP II orthologues and subtilisin as well as features that might be conserved within the entire family of subtilisin-like serine peptidases. (PMID:22266401)
• obtained a 3D structure of the human TPPII (PMID:22483107)
• Study showed that overexpression of Tripeptidyl peptidase II (TPP2) occurs frequently during oral carcinogenesis and might be associated with the progression of Oral Squamous Cell Carcinoma (OSCC) via Spindle Assembly Checkpoint(SAC) activation. (PMID:22986808)
• TPPII, MYBBP1A and CDK2 form a protein-protein interaction network. (PMID:25303791)
• Early-onset Evans syndrome, immunodeficiency, and premature immunosenescence associated with TPP2 deficiency have been described in two consanguineous siblings. (PMID:25414442)
• Study found that autosomal recessive TPP2 mutations cause recurrent infections, autoimmunity, and neurodevelopmental delay in humans. (PMID:25525876)
• TPP2 mediates many important cellular functions by controlling ERK1 and ERK2 phosphorylation. (PMID:26041847)
• Novel interactions of TPPII, p53, and SIRT7 presented in this study might contribute to the knowledge of the regulatory effects of these proteins on apoptotic pathways and to the understanding mechanisms of aging and lifespan regulation. (PMID:26169984)
• Immune deficiency, autoimmune disease and intellectual disability: A pleiotropic disorder caused by biallelic variants in the TPP2 gene. (PMID:33586135)
• Unveiling a novel serpinB2-tripeptidyl peptidase II signaling axis during senescence. (PMID:35466366)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tpp2	ENSDARG00000078751
mus_musculus	Tpp2	ENSMUSG00000041763
rattus_norvegicus	Tpp2	ENSRNOG00000011194
drosophila_melanogaster	TppII	FBGN0020370
caenorhabditis_elegans		WBGENE00017686

Paralogs (9): PCSK5 (ENSG00000099139), PCSK4 (ENSG00000115257), PCSK2 (ENSG00000125851), PCSK6 (ENSG00000140479), FURIN (ENSG00000140564), MBTPS1 (ENSG00000140943), PCSK7 (ENSG00000160613), PCSK9 (ENSG00000169174), PCSK1 (ENSG00000175426)

Protein

Protein identifiers

Tripeptidyl-peptidase 2 — P29144 (reviewed: P29144)

Alternative names: Tripeptidyl aminopeptidase, Tripeptidyl-peptidase II

All UniProt accessions (10): A0A494C0A3, A0A494C0U1, A0A494C0X4, A0A494C159, A0A494C1B8, A0A494C1L2, A0A494C1S4, A0A494C1S6, P29144, Q5VZU9

UniProt curated annotations — full annotation on UniProt →

Function. Cytosolic tripeptidyl-peptidase that releases N-terminal tripeptides from polypeptides and is a component of the proteolytic cascade acting downstream of the 26S proteasome in the ubiquitin-proteasome pathway. It plays an important role in intracellular amino acid homeostasis. Stimulates adipogenesis.

Subcellular location. Cytoplasm. Nucleus.

Disease relevance. Immunodeficiency 78 with autoimmunity and developmental delay (IMD78) [MIM:619220] An autosomal recessive disorder characterized by immune dysregulation, increased susceptibility to bacterial, viral and fungal infections, recurrent sinopulmonary or skin infections, and autoimmune abnormalities including hemolytic anemia and autoimmune cytopenias. Patients also have global developmental delay with speech delay and variable intellectual disability. Disease onset is in infancy or early childhood. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. The limitation of proteolytic products to tripeptides is achieved by tailoring the size of the substrate-binding cleft: the two negatively charged residues Glu-305 and Glu-331 that are blocking position P4 limit the number of residues that can be accommodated in the binding cleft and thus create a molecular ruler. At the same time, they orient substrates so that the tripeptides are removed exclusively from the N-terminus.

Similarity. Belongs to the peptidase S8 family.

RefSeq proteins (3): NP_001317517, NP_001354876, NP_003282 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000209	Peptidase_S8/S53_dom	Domain
IPR015500	Peptidase_S8_subtilisin-rel	Family
IPR022229	TPPII_Ig-like-2	Domain
IPR022232	TPPII_C_art	Domain
IPR022398	Peptidase_S8_His-AS	Active_site
IPR023828	Peptidase_S8_Ser-AS	Active_site
IPR034051	TPP_II_domain	Domain
IPR036852	Peptidase_S8/S53_dom_sf	Homologous_superfamily
IPR046939	TPPII_C_sf	Homologous_superfamily
IPR046940	TPPII_Ig-like_sf	Homologous_superfamily
IPR048383	TPPII_Ig-like-1	Domain
IPR048384	TPPII_GBD	Domain
IPR050131	Peptidase_S8_subtilisin-like	Family

Pfam: PF00082, PF12580, PF12583, PF21223, PF21316

Enzyme classification (BRENDA):

• EC 3.4.14.10 — tripeptidyl-peptidase II (BRENDA: 16 organisms, 80 substrates, 143 inhibitors, 120 Km, 111 kcat entries)

Substrate kinetics (BRENDA)

9 substrates with measured Km, best-characterized 9. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
L-ALA-L-ALA-L-ALA 4-NITROANILIDE	0.008–20	30
L-ALA-L-ALA-L-PHE 4-NITROANILIDE	0.017–30	30
ALA-ALA-PHE-4-NITROANILIDE	0.012–0.88	25
ALA-ALA-ALA-4-NITROANILIDE	0.0036–0.13	24
ALA-ALA-PHE-7-AMIDO-4-METHYLCOUMARIN	0.11–0.47	3
ARG-ARG-ALA-(PHOSPHO)SER-VAL-ALA	0.008–0.015	3
L-ALA-L-ALA-L-PHE-P-NITROANILIDE	0.013–1	3
ALA-ALA-PHE 4-METHYLCOUMARIN 7-AMIDE	0.016	1
ALA-ALA-PHE-P-NITROANILIDE	0.02	1

UniProt features (16 total): sequence variant 4, modified residue 3, active site 3, initiator methionine 1, chain 1, sequence conflict 1, domain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P29144-F1	91.98	0.80

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3): 44 (charge relay system); 264 (charge relay system); 449 (charge relay system)

Post-translational modifications (3): 915, 2, 401

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 249 (showing top): FREAC2_01, HNF3ALPHA_Q6, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, MORF_BRCA1, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, PUJANA_CHEK2_PCC_NETWORK, MARTINEZ_RB1_TARGETS_UP, MCBRYAN_PUBERTAL_BREAST_4_5WK_DN, ONKEN_UVEAL_MELANOMA_UP, KONDO_COLON_CANCER_HCP_WITH_H3K27ME1, GOTZMANN_EPITHELIAL_TO_MESENCHYMAL_TRANSITION_UP, MCBRYAN_PUBERTAL_BREAST_5_6WK_UP, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION

GO Biological Process (3): protein polyubiquitination (GO:0000209), proteolysis (GO:0006508), intracellular amino acid homeostasis (GO:0080144)

GO Molecular Function (10): endopeptidase activity (GO:0004175), aminopeptidase activity (GO:0004177), serine-type endopeptidase activity (GO:0004252), tripeptidyl-peptidase activity (GO:0008240), identical protein binding (GO:0042802), protein binding (GO:0005515), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), exopeptidase activity (GO:0008238), hydrolase activity (GO:0016787)

GO Cellular Component (5): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), nuclear body (GO:0016604), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
peptidase activity	3
cellular anatomical structure	3
protein ubiquitination	1
protein metabolic process	1
intracellular chemical homeostasis	1
exopeptidase activity	1
endopeptidase activity	1
serine-type peptidase activity	1
serine-type exopeptidase activity	1
protein binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
serine hydrolase activity	1
catalytic activity	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
nucleoplasm	1
intracellular membraneless organelle	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1676 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TPP2	ERAP2	Q6P179	901
TPP2	ERAP1	Q9NZ08	861
TPP2	NRDC	O43847	646
TPP2	THOP1	P52888	632
TPP2	LNPEP	Q9UIQ6	624
TPP2	BLMH	Q13867	621
TPP2	COL3A1	P02461	546
TPP2	NPEPPS	P55786	545
TPP2	TAPBP	O15533	505
TPP2	IDE	P14735	471
TPP2	CDK2	P24941	452
TPP2	LRBA	P50851	444
TPP2	SIRT6	Q8N6T7	441
TPP2	PREP	P48147	432
TPP2	CTSA	P10619	430

IntAct

139 interactions, top by confidence:

A	B	Type	Score
TPP2	POLB	psi-mi:“MI:0915”(physical association)	0.780
POLB	TPP2	psi-mi:“MI:0915”(physical association)	0.780
KBTBD7	METTL15	psi-mi:“MI:0914”(association)	0.730
TPP2	EHHADH	psi-mi:“MI:0915”(physical association)	0.670
PPP1R16A	TPP2	psi-mi:“MI:0915”(physical association)	0.670
TPP2	PPP1R16A	psi-mi:“MI:0915”(physical association)	0.670
EHHADH	TPP2	psi-mi:“MI:0915”(physical association)	0.670
CARNMT1	NUP42	psi-mi:“MI:0914”(association)	0.640
SLC39A5	FAM171A2	psi-mi:“MI:0914”(association)	0.640
SNRNP27	UBA6	psi-mi:“MI:0914”(association)	0.530
CYP1A1	SNX3	psi-mi:“MI:0914”(association)	0.530
ALOX5	DDHD2	psi-mi:“MI:0914”(association)	0.530
KLHL36	HSPA8	psi-mi:“MI:0914”(association)	0.530
DENND2D	HSPA8	psi-mi:“MI:0914”(association)	0.530
RALB	DBT	psi-mi:“MI:0914”(association)	0.530
PDPK1	AGRN	psi-mi:“MI:0914”(association)	0.530

BioGRID (152): TPP2 (Two-hybrid), TPP2 (Two-hybrid), PPP1R16A (Two-hybrid), TPP2 (Affinity Capture-RNA), TPP2 (Affinity Capture-MS), TPP2 (Affinity Capture-MS), TPP2 (Affinity Capture-MS), TPP2 (Affinity Capture-MS), TPP2 (Affinity Capture-MS), ADAM8 (Co-fractionation), HK2 (Co-fractionation), TIPRL (Co-fractionation), TPP2 (Co-fractionation), TPP2 (Co-fractionation), TPP2 (Affinity Capture-MS)

ESM2 similar proteins: A0A3L7I2I8, A0FKG7, A1Z3X3, A4GWN3, A5PK39, E9Q4Z2, O00763, O55236, O60733, O60942, P10687, P10894, P29144, P49754, P82922, P97570, P97789, P97819, Q15147, Q2KJA6, Q32PW3, Q5IH13, Q5KU39, Q5R8R4, Q5ZKK2, Q640G7, Q641K1, Q64514, Q64560, Q69YN2, Q6NY98, Q6NYU2, Q7ZVK4, Q80YV4, Q8BPM2, Q8CI33, Q8IVH8, Q8IZH2, Q8K114, Q8QFR2

Diamond homologs: A5PK39, F4JVN6, P00782, P00783, P04189, P07518, P29142, P29144, P35835, Q09541, Q45670, Q64514, Q64560, Q6ESI7, Q9UT05, Q9V6K1, P00780, P00781, P28842, P11018, P15292, P15293, P16271, Q02470, P27693, Q0WUG6, Q5JIZ5, Q9FHA4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

851 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	17
Likely pathogenic	4
Uncertain significance	344
Likely benign	404
Benign	41

Top pathogenic / likely-pathogenic (21)

Variant ID	HGVS	Classification
1027537	NM_001330588.2(TPP2):c.2343C>G (p.Tyr781Ter)	Pathogenic
1027538	NM_001330588.2(TPP2):c.1499G>A (p.Gly500Asp)	Pathogenic
1027539	NM_001330588.2(TPP2):c.433del (p.Ala145fs)	Pathogenic
1068875	NC_000013.10:g.(?103298624)(103301856_?)del	Pathogenic
1076853	NM_001330588.2(TPP2):c.2420T>G (p.Leu807Ter)	Pathogenic
1455713	NC_000013.10:g.(?103275207)(103279536_?)del	Pathogenic
2100401	NM_001330588.2(TPP2):c.2619T>G (p.Tyr873Ter)	Pathogenic
2413358	NM_001330588.2(TPP2):c.3466_3467del (p.Gly1156fs)	Pathogenic
2817462	NM_001330588.2(TPP2):c.1844dup (p.Tyr616fs)	Pathogenic
2856662	NM_001330588.2(TPP2):c.3071C>G (p.Ser1024Ter)	Pathogenic
2878736	NM_001330588.2(TPP2):c.1320_1321del (p.Gly441fs)	Pathogenic
2880480	NM_001330588.2(TPP2):c.3244C>T (p.Arg1082Ter)	Pathogenic
3726063	NM_001330588.2(TPP2):c.2563C>T (p.Gln855Ter)	Pathogenic
4736460	NM_001330588.2(TPP2):c.1066del (p.Tyr356fs)	Pathogenic
650988	NM_001330588.2(TPP2):c.2433_2434insA (p.Val812fs)	Pathogenic
663284	NM_001330588.2(TPP2):c.2843del (p.Pro948fs)	Pathogenic
995805	NM_001330588.2(TPP2):c.2394-550_2952+659del	Pathogenic
1476641	NM_001330588.2(TPP2):c.2873+1G>A	Likely pathogenic
1804520	NM_001330588.2(TPP2):c.2665C>T (p.Arg889Ter)	Likely pathogenic
4292206	NM_001330588.2(TPP2):c.3012del (p.Tyr1005fs)	Likely pathogenic
583012	NM_001330588.2(TPP2):c.2952+1G>C	Likely pathogenic

SpliceAI

6274 predictions. Top by Δscore:

Variant	Effect	Δscore
13:102597131:G:GT	donor_gain	1.0000
13:102597202:AGGT:A	donor_loss	1.0000
13:102597203:GGTG:G	donor_loss	1.0000
13:102597204:G:C	donor_loss	1.0000
13:102604784:A:AG	acceptor_gain	1.0000
13:102604785:A:AG	acceptor_gain	1.0000
13:102604786:T:G	acceptor_gain	1.0000
13:102604787:TTTCA:T	acceptor_loss	1.0000
13:102604788:TTCA:T	acceptor_loss	1.0000
13:102604789:TCAGG:T	acceptor_loss	1.0000
13:102604790:CAG:C	acceptor_loss	1.0000
13:102604791:A:AG	acceptor_gain	1.0000
13:102604791:AG:A	acceptor_gain	1.0000
13:102604791:AGGTT:A	acceptor_loss	1.0000
13:102604792:G:GT	acceptor_gain	1.0000
13:102604792:GG:G	acceptor_gain	1.0000
13:102604792:GGT:G	acceptor_gain	1.0000
13:102604792:GGTT:G	acceptor_gain	1.0000
13:102604792:GGTTA:G	acceptor_gain	1.0000
13:102604908:G:GT	donor_gain	1.0000
13:102604918:TAAG:T	donor_loss	1.0000
13:102604919:AAG:A	donor_loss	1.0000
13:102604922:G:GG	donor_gain	1.0000
13:102604922:GTGAG:G	donor_loss	1.0000
13:102614097:GTAG:G	acceptor_loss	1.0000
13:102614098:TA:T	acceptor_loss	1.0000
13:102614099:A:AG	acceptor_gain	1.0000
13:102614099:A:AT	acceptor_loss	1.0000
13:102614100:G:GA	acceptor_gain	1.0000
13:102614100:GA:G	acceptor_gain	1.0000

AlphaMissense

8283 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:102597141:G:T	G35W	1.000
13:102597169:A:T	D44V	1.000
13:102627017:C:G	H264D	1.000
13:102627019:T:A	H264Q	1.000
13:102627019:T:G	H264Q	1.000
13:102627020:G:T	G265W	1.000
13:102627021:G:A	G265E	1.000
13:102627026:C:G	H267D	1.000
13:102627027:A:G	H267R	1.000
13:102627028:T:A	H267Q	1.000
13:102627028:T:G	H267Q	1.000
13:102627039:T:A	I271K	1.000
13:102627077:G:T	G284W	1.000
13:102627078:G:A	G284E	1.000
13:102627117:G:A	G297D	1.000
13:102627141:A:T	E305V	1.000
13:102627156:T:C	L310P	1.000
13:102627886:C:A	N326K	1.000
13:102627886:C:G	N326K	1.000
13:102627890:A:C	S328R	1.000
13:102627891:G:T	S328I	1.000
13:102627892:T:A	S328R	1.000
13:102627892:T:G	S328R	1.000
13:102627897:G:A	G330E	1.000
13:102629540:A:C	S359R	1.000
13:102629542:T:A	S359R	1.000
13:102629542:T:G	S359R	1.000
13:102629547:G:A	G361E	1.000
13:102629550:A:T	N362I	1.000
13:102629551:T:A	N362K	1.000

dbSNP variants (sampled 300 via entrez): RS1000006819 (13:102655845 TTTC>T), RS1000037339 (13:102617819 A>G), RS1000132169 (13:102626489 C>T), RS1000204518 (13:102608490 T>A), RS1000234833 (13:102628902 A>G), RS1000240406 (13:102627414 C>A), RS1000253531 (13:102635948 G>A,C), RS1000261228 (13:102677197 C>T), RS1000313267 (13:102602471 G>A,T), RS1000391612 (13:102635515 G>A,C,T), RS1000498034 (13:102660731 T>C), RS1000502570 (13:102614681 A>T), RS1000509357 (13:102644448 C>T), RS1000551248 (13:102655736 A>C), RS1000568713 (13:102652566 C>A)

Disease associations

OMIM: gene MIM:190470 | disease phenotypes: MIM:619220

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 78 with autoimmunity and developmental delay	Definitive	Autosomal recessive
autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
immunodeficiency 78 with autoimmunity and developmental delay	Definitive	AR

Mondo (3): immunodeficiency 78 with autoimmunity and developmental delay (MONDO:0030971), thrombocytopenia (MONDO:0002049), autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome (MONDO:0018636)

Orphanet (0):

HPO phenotypes

30 total (30 of 30 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000265	Mastoiditis
HP:0000403	Recurrent otitis media
HP:0001263	Global developmental delay
HP:0001269	Hemiparesis
HP:0001297	Stroke
HP:0001744	Splenomegaly
HP:0001878	Hemolytic anemia
HP:0001888	Decreased total lymphocyte count
HP:0001890	Autoimmune hemolytic anemia
HP:0001904	Autoimmune neutropenia
HP:0001973	Autoimmune thrombocytopenia
HP:0002110	Bronchiectasis
HP:0002716	Lymphadenopathy
HP:0002725	Systemic lupus erythematosus
HP:0002783	Recurrent lower respiratory tract infections
HP:0002960	Autoimmunity
HP:0003237	Increased circulating IgG concentration
HP:0003496	Increased circulating IgM level
HP:0003593	Infantile onset
HP:0003819	Death in childhood
HP:0006268	Fluctuating splenomegaly
HP:0011342	Mild global developmental delay
HP:0011343	Moderate global developmental delay
HP:0011463	Childhood onset
HP:0011947	Respiratory tract infection
HP:0012115	Hepatitis
HP:0032247	Persistent CMV viremia
HP:0040167	Facial papilloma
HP:0410028	Recurrent oral herpes

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002404_378	Red cell distribution width	3.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009188	Red cell distribution width

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6156 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — S8: Subtilisin

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
example 8 [WO1999033801A1]	Inhibition	9.44	pKi
peptide 4 [PMID: 18294843]	Inhibition	7.7	pKi

ChEMBL bioactivities

4 potent at pChembl≥5 of 6 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.70	Ki	20	nM	CHEMBL263633
6.31	Kd	486.9	nM	CHEMBL5653589
6.31	ED50	486.9	nM	CHEMBL5653589
5.52	IC50	2990	nM	MOLIBRESIB

PubChem BioAssay actives

3 with measured affinity, of 12 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S)-2-[[(2S)-2-[2-[[(2S)-2-[[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]propanoyl]amino]prop-2-enoylamino]-3-methylbutanoyl]amino]propanoic acid	329747: Inhibition of human tripeptidyl peptidase2 from erythrocytes	ki	0.0200	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149646: Binding affinity to human TPP2 incubated for 45 mins by Kinobead based pull down assay	kd	0.4869	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178788: Inhibition of TPP2 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	2.9900	uM

CTD chemical–gene interactions

49 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
bisphenol A	affects cotreatment, decreases methylation, decreases expression	2
aristolochic acid I	decreases expression	1
geldanamycin	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression, affects localization, increases expression	1
arsenite	affects binding, decreases reaction	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
vanadyl sulfate	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole	affects localization, decreases reaction	1
SB 203580	affects localization, decreases reaction	1
U 0126	affects localization, decreases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
torcetrapib	increases expression	1
jinfukang	decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
bisphenol AF	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acetaminophen	decreases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases expression	1
Cadmium	increases abundance, increases palmitoylation, decreases reaction	1
Dinitrochlorobenzene	affects binding	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652688	Binding	Binding affinity to human TPP2 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D1R3	Abcam K-562 TPP2 KO	Cancer cell line	Female
CVCL_D2MQ	Abcam Raji TPP2 KO	Cancer cell line	Male
CVCL_WQ73	Abcam Jurkat TPP2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

240 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00039858	PHASE4	COMPLETED	Evaluation of Argatroban Injection in Pediatric Patients Requiring Anticoagulant Alternatives to Heparin
NCT00239733	PHASE4	TERMINATED	Anti-D for Treating Thrombocytopenia in Adults Infected With Hepatitis C Virus With or Without HIV Co-Infection
NCT00907478	PHASE4	COMPLETED	Study on Bone Marrow Morphology in Adults Receiving Romiplostim for Treatment of Thrombocytopenia Associated With Immune Thrombocytopenia Purpura (ITP)
NCT01727401	PHASE4	TERMINATED	Thromboprophylaxis of Venous Thromboembolism in Acutely-ill Medical Inpatients With Thrombocytopenia
NCT02032134	PHASE4	TERMINATED	Protocol for the Infusion of Buffy Coat-derived Cryopreserved Platelets in Patients With Severe Thrombocytopenia
NCT02267993	PHASE4	COMPLETED	Efficacy and Safety of rhTPO for the Treatment of Thrombocytopenia After Chemotherapy in AML Patients
NCT03633019	PHASE4	UNKNOWN	High-dose Use of rhTPO in CIT Patients
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04906083	PHASE4	UNKNOWN	Avatrombopag in Patients With End-stage Liver Disease and Thrombocytopenia
NCT05217719	PHASE4	UNKNOWN	Effects of Recombinant Human Thrombopoietin on Platelet Levels in ICU Patients
NCT05255003	PHASE4	RECRUITING	STrategies for Anticoagulation in Patients With thRombocytopenia and Cancer-associated Thrombosis
NCT05382013	PHASE4	UNKNOWN	Efficacy and Safety of Avatrombopag for Treating TCP in HBV-ACLF Patients Receiving ALSS Treatment
NCT05944458	PHASE4	COMPLETED	Efficacy of Intravenous N-Acetylcysteine in Preventing Linezolid-Induced Thrombocytopenia in Critically Ill Patients
NCT06562738	PHASE4	RECRUITING	Clinical Study on Efficacy and Safety of Hetrombopag in the Preoperative Patients of Thrombocytopenia
NCT00037791	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00039910	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00073580	PHASE3	COMPLETED	Angiomax in Patients With HIT/HITTS Type II Undergoing Off-Pump Coronary Artery Bypass Grafting (CABG) (CHOOSE)
NCT00102323	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Refractory to Splenectomy
NCT00102336	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Prior to Splenectomy
NCT00116688	PHASE3	COMPLETED	Open Label Extension Study of Romiplostim (AMG 531) in Thrombocytopenic Patients With Immune (Idiopathic) Thrombocytopenic Purpura (ITP)
NCT00128713	PHASE3	COMPLETED	Optimal Platelet Dose Strategy for Management of Thrombocytopenia
NCT00151866	PHASE3	COMPLETED	Efficacy of Transfusions With Platelets Stored in Platelet Additive Solution II Versus Plasma
NCT00261924	PHASE3	COMPLETED	Efficacy and Safety Study of Platelets Treated for Pathogen Inactivation and Stored for Up to Seven Days
NCT00415532	PHASE3	COMPLETED	Romiplostim (AMG 531) Versus Medical Standard of Care for Immune (Idiopathic) Thrombocytopenic Purpura
NCT00420914	PHASE3	TERMINATED	Strategies for Transfusion of Platelets (SToP)
NCT00501345	PHASE3	TERMINATED	Aspirin in Patients With Myocardial Infarction and Thrombocytopenia
NCT00508820	PHASE3	COMPLETED	An Open Label Study of Romiplostim in Adult Thrombocytopenic Subjects With ITP
NCT00678587	PHASE3	TERMINATED	Eltrombopag To Reduce The Need For Platelet Transfusion In Subjects With Chronic Liver Disease And Thrombocytopenia Undergoing Elective Invasive Procedures
NCT01438840	PHASE3	COMPLETED	Efficacy and Safety of Oral E5501 Plus Standard of Care for the Treatment of Thrombocytopenia in Adults With Chronic Immune Thrombocytopenia (Amendment 02)
NCT01444417	PHASE3	COMPLETED	Safety and Efficacy Study of Romiplostim to Treat Immune Thrombocytopenia (ITP) in Pediatric Patients
NCT01805648	PHASE3	UNKNOWN	Efficacy and Safety Study of Maintenance Treatment With rhTPO in Thrombocytopenic Subjects With ITP
NCT02244658	PHASE3	UNKNOWN	Recombinant Human Thrombopoietin (rhTPO) in Management of Chemotherapy-induced Thrombocytopenia in Acute Myelocytic Leukemia
NCT02389621	PHASE3	COMPLETED	Safety and Efficacy Study of Lusutrombopag for Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Elective Invasive Procedures
NCT02444728	PHASE3	TERMINATED	Cyclophosphamide and Hydroxychloroquine for Thrombocytopenia in SLE
NCT02487563	PHASE3	COMPLETED	Prospective Study of Patients With Thrombocytopenia Following HSCT
NCT02578901	PHASE3	COMPLETED	American Trial Using Tranexamic Acid in Thrombocytopenia
NCT03326843	PHASE3	TERMINATED	Avatrombopag for the Treatment of Thrombocytopenia in Adults Scheduled for a Surgical Procedure
NCT03515096	PHASE3	COMPLETED	Eltrombopag vs. rhTPO to Increase Platelet Level After HSCT
NCT05563064	PHASE3	UNKNOWN	Effect of Herbal Formulation on Thrombocytes Count
NCT07442513	PHASE3	RECRUITING	Comparison of Etamsylate Versus Placebo to Prevent Bleeding in HSCT