PSTPIP1

Summary

PSTPIP1 (proline-serine-threonine phosphatase interacting protein 1, HGNC:9580) is a protein-coding gene on chromosome 15q24.3, encoding Proline-serine-threonine phosphatase-interacting protein 1 (O43586). Involved in regulation of the actin cytoskeleton.

This gene encodes a cytoskeletal protein that is highly expressed in hemopoietic tissues. This protein functions via its interaction with several different proteins involved in cytoskeletal organization and inflammatory processes. It binds to the cytoplasmic tail of CD2, an effector of T cell activation and adhesion, downregulating CD2-triggered adhesion. It binds PEST-type protein tyrosine phosphatases (PTP) and directs them to c-Abl kinase to mediate c-Abl dephosphorylation, thereby, regulating c-Abl activity. It also interacts with pyrin, which is found in association with the cytoskeleton in myeloid/monocytic cells and modulates immunoregulatory functions. Mutations in this gene are associated with PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) syndrome. It is hypothesized that the disease-causing mutations compromise physiologic signaling necessary for the maintenance of a proper inflammatory response.

Source: NCBI Gene 9051 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pyogenic arthritis-pyoderma gangrenosum-acne syndrome (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 840 total — 4 pathogenic
• Phenotypes (HPO): 37
• MANE Select transcript: NM_003978

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9580
Approved symbol	PSTPIP1
Name	proline-serine-threonine phosphatase interacting protein 1
Location	15q24.3
Locus type	gene with protein product
Status	Approved
Aliases	PSTPIP, CD2BP1L, CD2BP1, CD2BP1S, H-PIP, PAPAS
Ensembl gene	ENSG00000140368
Ensembl biotype	protein_coding
OMIM	606347
Entrez	9051

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 9 protein_coding, 6 retained_intron, 4 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000379595, ENST00000557995, ENST00000558012, ENST00000558407, ENST00000558870, ENST00000559161, ENST00000559295, ENST00000559750, ENST00000559785, ENST00000559795, ENST00000559856, ENST00000559859, ENST00000560064, ENST00000560223, ENST00000560377, ENST00000560621, ENST00000560796, ENST00000561315, ENST00000697622, ENST00000697623, ENST00000884367

RefSeq mRNA: 5 — MANE Select: NM_003978 NM_001321135, NM_001321136, NM_001321137, NM_001411086, NM_003978

CCDS: CCDS45312, CCDS81910, CCDS92045

Canonical transcript exons

ENST00000558012 — 15 exons

Exon	Start	End
ENSE00002547754	76995126	76995609
ENSE00003468313	77031180	77031278
ENSE00003468751	77027852	77027914
ENSE00003484630	77030502	77030581
ENSE00003503526	77025498	77025604
ENSE00003517244	77035802	77035935
ENSE00003574802	77035508	77035563
ENSE00003598273	77032298	77032394
ENSE00003601905	77029529	77029574
ENSE00003615714	77018457	77018531
ENSE00003618186	77032862	77032952
ENSE00003632373	77025284	77025318
ENSE00003636486	77028554	77028652
ENSE00003666113	77018148	77018248
ENSE00003889612	77037045	77037475

Expression profiles

Bgee: expression breadth ubiquitous, 179 present calls, max score 98.74.

FANTOM5 (CAGE): breadth broad, TPM avg 11.7381 / max 1175.1100, expressed in 531 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
147849	5.7420	428
147854	3.5296	356
147853	1.0456	291
147850	0.6148	195
147851	0.3319	133
147852	0.2365	112
147855	0.1208	61
147856	0.1170	55

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	98.74	gold quality
monocyte	CL:0000576	96.29	gold quality
leukocyte	CL:0000738	95.88	gold quality
mononuclear cell	CL:0000842	95.85	gold quality
blood	UBERON:0000178	95.78	gold quality
spleen	UBERON:0002106	94.24	gold quality
bone marrow cell	CL:0002092	90.36	gold quality
lymph node	UBERON:0000029	88.40	gold quality
bone marrow	UBERON:0002371	87.83	gold quality
vermiform appendix	UBERON:0001154	87.61	gold quality
tendon of biceps brachii	UBERON:0008188	87.19	gold quality
calcaneal tendon	UBERON:0003701	86.95	gold quality
upper lobe of left lung	UBERON:0008952	86.43	gold quality
descending thoracic aorta	UBERON:0002345	86.08	gold quality
ascending aorta	UBERON:0001496	85.89	gold quality
thoracic aorta	UBERON:0001515	85.72	gold quality
tendon	UBERON:0000043	84.92	gold quality
right lung	UBERON:0002167	84.04	gold quality
upper lobe of lung	UBERON:0008948	83.55	gold quality
apex of heart	UBERON:0002098	83.23	gold quality
gall bladder	UBERON:0002110	83.19	gold quality
omental fat pad	UBERON:0010414	83.14	gold quality
peritoneum	UBERON:0002358	83.03	gold quality
small intestine Peyer’s patch	UBERON:0003454	83.03	gold quality
adipose tissue of abdominal region	UBERON:0007808	82.22	gold quality
mucosa of transverse colon	UBERON:0004991	82.06	gold quality
trabecular bone tissue	UBERON:0002483	80.97	gold quality
right adrenal gland cortex	UBERON:0035827	80.44	gold quality
left coronary artery	UBERON:0001626	79.99	gold quality
right adrenal gland	UBERON:0001233	79.64	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.59
E-MTAB-7606	no	938.20

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

11 targeting PSTPIP1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-3191-3P	99.45	63.94	356
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-6734-3P	99.15	66.27	1627
HSA-MIR-4722-5P	98.46	66.34	1611
HSA-MIR-4768-3P	98.16	66.02	2330
HSA-MIR-6791-3P	97.45	64.31	1123
HSA-MIR-6829-3P	97.45	64.31	1137
HSA-MIR-152-5P	96.42	66.59	960
HSA-MIR-3917	88.03	62.50	44

Literature-anchored findings (GeneRIF, showing 40)

• CD2BP1-mediated biochemical pathway(s) may function in common inflammatory disorders with apparent etiological overlap, such as rheumatoid arthritis and inflammatory bowel disease (PMID:11971877)
• PSTPIP1 acts downstream of CD2/CD2AP to link CD2 engagement to the WASp-evoked actin polymerization required for synapse formation and T cell activation. (PMID:12530983)
• PSTPIP1/CD2BP1 protein binds to pyrin (PMID:14595024)
• the intracellular Fas ligand (FasL) domain binding to the adaptor protein PSTPIP results in a cytoplasmic localization of FasL (PMID:16204241)
• CD2BP1 directly and negatively impacts T cell activation via isolated CD2 antigen triggering or T-cell receptor stimulation dependent on coordinate CD2 engagement. (PMID:16670297)
• PSTPIP1 mutants require pyrin to induce formation of ASC pyroptosome, a molecular platform that recruits and activates caspase-1. (PMID:17964261)
• PSTPIP1 is a novel component of the leukocyte uropod that regulates endocytosis and cell migration (PMID:18480402)
• These findings support the use of monogenic loci as candidates for investigating the genetic component of complex disease and provide preliminary evidence of association between SNPs in autoinflammatory genes and psoriatic JIA. (PMID:18576390)
• demonstrate that pyrin can recruit PSTPIP1 into aggregations (specks) of ASC, another pyrin binding protein. ASC specks are associated with inflammasome activity (PMID:19584923)
• PAPA syndrome occurs without identifiable mutation in CD2BB1 (PMID:19700023)
• The CCTG repeat in the PSTPIP1 promoter may play a role in the pathogenesis of aseptic abscess syndrome and Crohn’s disease. (PMID:19731031)
• non-mutated gene and pyoderma gangrenosum in IBD unresponsive to anakinra treatment (PMID:21438098)
• novel mutaations found in PSTPIP1 gene in patients with pyoderma gangrenosum (PMID:21790734)
• PSTPIP1 has a role in the pathogenesis of pyoderma gangrenosum through filopodia formation resulting in extracellular matrix degradation (PMID:24421327)
• Case Report: missense mutation in PSTPIP1, the gene responsible for PAPA syndrome. (PMID:24960411)
• we have shown that PSTPIP1 regulates T-cell activation upon CD3 and CD28 stimulation, independently of CD2 costimulation. PSTPIP1 acts downstream of proximal TCR signaling, inhibiting several transcription factors. (PMID:25040622)
• Molecular interactions between HPIP and FAK, and HPIP and calpain2 regulate cell adhesion and migration through modulation of focal adhesion dynamics. (PMID:25486428)
• genetic polymorphism is associated with hyperzincemia and hypercalprotectinemia (PMID:26025129)
• PSTPIP1 was found to interact with pyrin at the leading edge during cell migration. (PMID:26179737)
• these structural variations in CD2BP1 gene due to the mutations could be one of the strongest reasons to demonstrate the involvement of these gene variations in the patients with rheumatoid arthritis. (PMID:27184502)
• our study demonstrated that knockdown of HPIP significantly inhibits the proliferation and migration/invasion of HNSCC cells by suppressing the PI3K/Akt signaling pathway. (PMID:27458096)
• HPIP expression is associated with high-grade ovarian tumors. (PMID:28039608)
• we demonstrated that HPIP silencing suppressed TGF-beta1-induced EMT in lung cancer cells by inhibiting Smad2 activation. (PMID:28075456)
• Case Report: classical pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome with E250K mutation of PSTPIP1. (PMID:28628471)
• Here we show a role for PSTPIP1 that revealed itself in patients with CVID by contribution to T-cell deficiency through altered F-actin polymerization (PMID:29432774)
• We identified HPIP protein expression as a novel independent poor prognostic indicator in cervical cancer (PMID:30033330)
• Overexpression of HPIP is associated with endometrial cancer. (PMID:31241209)
• Phenotypic Associations of PSTPIP1 Sequence Variants in PSTPIP1-Associated Autoinflammatory Diseases. (PMID:33218716)
• HSCT is effective in patients with PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome. (PMID:33338535)
• Rare cases of PAMI syndrome in both father and son with the same missense mutation in PSTPIP1 gene and literature review. (PMID:33458872)
• Genetic variations in gamma-secretase and PSTPIP1 in hidradenitis suppurativa in Singaporean Chinese. (PMID:33460495)
• PAMI syndrome: A rare cause that can be easily misdiagnosed. (PMID:34047005)
• HPIP protooncogene differentially regulates metabolic adaptation and cell fate in breast cancer cells under glucose stress via AMPK and RNF2 dependent pathways. (PMID:34302919)
• Excess Serum Interleukin-18 Distinguishes Patients With Pathogenic Mutations in PSTPIP1. (PMID:34492165)
• Clinical and genetic characteristics of PSTPIP1-associated myeloid-related proteinemia inflammatory syndrome. (PMID:34620178)
• A reciprocal feedback loop between HIF-1alpha and HPIP controls phenotypic plasticity in breast cancer cells. (PMID:34767928)
• Strong inflammatory signatures in the neutrophils of PAMI syndrome. (PMID:36203570)
• Detection of a rare variant in PSTPIP1 through three generations in a family with an initial diagnosis of FMF/MKD-overlapping phenotype. (PMID:36692132)
• Rare missense variants in the SH3 domain of PSTPIP1 are associated with hidradenitis suppurativa. (PMID:37013170)
• PSTPIP1-Associated Myeloid-Related Proteinemia Inflammatory (PAMI) Syndrome: A Systematic Review. (PMID:37628706)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	pstpip1b	ENSDARG00000053568
danio_rerio	pstpip1a	ENSDARG00000060860
mus_musculus	Pstpip1	ENSMUSG00000032322
rattus_norvegicus	Pstpip1	ENSRNOG00000016413

Paralogs (5): GAS7 (ENSG00000007237), SGIP1 (ENSG00000118473), FCHO1 (ENSG00000130475), PSTPIP2 (ENSG00000152229), FCHO2 (ENSG00000157107)

Protein

Protein identifiers

Proline-serine-threonine phosphatase-interacting protein 1 — O43586 (reviewed: O43586)

Alternative names: CD2-binding protein 1, H-PIP

All UniProt accessions (12): O43586, A0A0S2Z5P3, B4E1Z9, H0YKF1, H0YKY3, H0YLI2, H0YLM9, H0YLW8, H0YLX8, H0YNR2, H0YNS1, J3KPG6

UniProt curated annotations — full annotation on UniProt →

Function. Involved in regulation of the actin cytoskeleton. May regulate WAS actin-bundling activity. Bridges the interaction between ABL1 and PTPN18 leading to ABL1 dephosphorylation. May play a role as a scaffold protein between PTPN12 and WAS and allow PTPN12 to dephosphorylate WAS. Has the potential to physically couple CD2 and CD2AP to WAS. Acts downstream of CD2 and CD2AP to recruit WAS to the T-cell:APC contact site so as to promote the actin polymerization required for synapse induction during T-cell activation. Down-regulates CD2-stimulated adhesion through the coupling of PTPN12 to CD2. Also has a role in innate immunity and the inflammatory response. Recruited to inflammasomes by MEFV. Induces formation of pyroptosomes, large supramolecular structures composed of oligomerized PYCARD dimers which form prior to inflammatory apoptosis. Binding to MEFV allows MEFV to bind to PYCARD and facilitates pyroptosome formation. Regulates endocytosis and cell migration in neutrophils.

Subunit / interactions. Homodimer. Homotrimer. Interacts (via coiled-coil domain) with CD2AP, PTPN12 and PTPN18. Interacts (via SH3 domain) with ABL1 and WAS. Interacts (via SH3 and coiled-coil domains) with MEFV (via B-box zinc finger); the interaction allows binding of MEFV to PYCARD and facilitates formation of PYCARD pyroptosomes. Interacts with CD2, DNM2 and FASLG.

Subcellular location. Cytoplasm. Cell membrane. Cell projection. Uropodium. Cytoskeleton. Perinuclear region. Lamellipodium. Cleavage furrow.

Tissue specificity. Highly expressed in the peripheral blood leukocytes, granulocytes and monocytes, namely in T-cells and natural killer cells, and in spleen. Weakly expressed in the thymus, small intestine, lung and placenta.

Post-translational modifications. Dephosphorylated on Tyr-345 by PTPN18, this event negatively regulates the association of PSTPIP1 with SH2 domain-containing proteins as tyrosine kinase. Phosphorylation of Tyr-345 is probably required for subsequent phosphorylation at other tyrosine residues. Phosphorylation is induced by activation of the EGFR and PDGFR in a ABL1 dependent manner. The phosphorylation regulates the interaction with WAS and with MEFV.

Disease relevance. Pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) [MIM:604416] A rare autosomal dominant autoinflammatory disease that typically presents with recurrent sterile, erosive arthritis in childhood, occurring spontaneously or after minor trauma, occasionally resulting in significant joint destruction. By puberty, joint symptoms tend to subside and cutaneous symptoms increase. Cutaneous manifestations include pathergy, frequently with abscesses at the sites of injections, severe cystic acne, and recurrent nonhealing sterile ulcers, often diagnosed as pyoderma gangrenosum. The disease is caused by variants affecting the gene represented in this entry. Autoinflammatory syndrome with cytopenia, hyperzincemia, and hypercalprotectinemia (AICZC) [MIM:601979] An autosomal dominant, autoinflammatory disorder characterized by severe systemic and cutaneous inflammation, hepatosplenomegaly, arthritis, pancytopenia, failure to thrive, and marked elevation of zinc and calprotectin blood levels. AICZC shows intrafamilial variable expressivity and incomplete penetrance. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The F-BAR domain is important for filament formation. The SH3 domain is not required for filament formation or localization to the uropod.

Isoforms (2)

UniProt ID	Names	Canonical?
O43586-1	1, CD2BP1L	yes
O43586-2	2, CD2BP1S

RefSeq proteins (5): NP_001308064, NP_001308065, NP_001308066, NP_001398015, NP_003969* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001060	FCH_dom	Domain
IPR001452	SH3_domain	Domain
IPR027267	AH/BAR_dom_sf	Homologous_superfamily
IPR030777	PSTPIP1_SH3	Domain
IPR031160	F_BAR_dom	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily

Pfam: PF00018, PF00611

UniProt features (35 total): sequence variant 11, helix 6, strand 6, mutagenesis site 3, domain 2, modified residue 2, chain 1, sequence conflict 1, turn 1, coiled-coil region 1, splice variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
7AAL	X-RAY DIFFRACTION	1.97
7AAN	X-RAY DIFFRACTION	2.14
7AAM	X-RAY DIFFRACTION	2.15
2DIL	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43586-F1	86.83	0.76

Functional residue map

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

Post-translational modifications (2): 318, 345

Mutagenesis-validated functional residues (3):

Position	Phenotype
232	abolishes binding to mefv. cytoplasmic filaments are finer with fewer branches.
266	no effect on filament formation.
345	decreases binding to mefv.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-844456	The NLRP3 inflammasome
R-HSA-9660826	Purinergic signaling in leishmaniasis infection

MSigDB gene sets: 275 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, MYOGENIN_Q6, GOBP_INFLAMMATORY_RESPONSE, REACTOME_THE_NLRP3_INFLAMMASOME, REACTOME_INFLAMMASOMES, REACTOME_NUCLEOTIDE_BINDING_DOMAIN_LEUCINE_RICH_REPEAT_CONTAINING_RECEPTOR_NLR_SIGNALING_PATHWAYS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_VESICLE_MEDIATED_TRANSPORT, MODULE_75, AP1_Q4_01, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GNF2_ICAM3, GNF2_S100A4, MODULE_99

GO Biological Process (6): endocytosis (GO:0006897), inflammatory response (GO:0006954), cell adhesion (GO:0007155), signal transduction (GO:0007165), innate immune response (GO:0045087), immune system process (GO:0002376)

GO Molecular Function (2): identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (10): uropod (GO:0001931), cytoplasm (GO:0005737), cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), membrane (GO:0016020), lamellipodium (GO:0030027), cleavage furrow (GO:0032154), perinuclear region of cytoplasm (GO:0048471), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Inflammasomes	1
Cell recruitment (pro-inflammatory response)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cellular process	2
plasma membrane bounded cell projection	2
cytoplasm	2
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
defense response	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
immune response	1
defense response to symbiont	1
biological_process	1
protein binding	1
binding	1
cell trailing edge	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
membrane	1
cell periphery	1
cell leading edge	1
cell division site	1
plasma membrane region	1

Protein interactions and networks

STRING

2138 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PSTPIP1	MEFV	O15553	997
PSTPIP1	PTPN12	Q05209	995
PSTPIP1	WAS	P42768	984
PSTPIP1	PTS	Q03393	901
PSTPIP1	CD2	P06729	886
PSTPIP1	ABL1	P00519	765
PSTPIP1	LPIN2	Q92539	712
PSTPIP1	PTPN18	Q99952	682
PSTPIP1	MVK	Q03426	667
PSTPIP1	CASP1	P29466	667
PSTPIP1	IL1RN	P18510	659
PSTPIP1	WASL	O00401	640
PSTPIP1	TRIP10	Q15642	630
PSTPIP1	BBOX1	O75936	618
PSTPIP1	FNBP1	Q96RU3	602

IntAct

255 interactions, top by confidence:

A	B	Type	Score
PSTPIP1	PTPN12	psi-mi:“MI:0915”(physical association)	0.830
PTPN12	PSTPIP1	psi-mi:“MI:0915”(physical association)	0.830
PSTPIP1	PRPF31	psi-mi:“MI:0915”(physical association)	0.810
PRPF31	PSTPIP1	psi-mi:“MI:0915”(physical association)	0.810
MEFV	MEFV	psi-mi:“MI:0915”(physical association)	0.770
PSTPIP1	CD2	psi-mi:“MI:0915”(physical association)	0.740
PSTPIP1	PSTPIP1	psi-mi:“MI:0915”(physical association)	0.730
PSTPIP1	TULP3	psi-mi:“MI:0915”(physical association)	0.720
PSTPIP1	RTP5	psi-mi:“MI:0915”(physical association)	0.720
FAM90A1	PSTPIP1	psi-mi:“MI:0915”(physical association)	0.720
LSM4	PSTPIP1	psi-mi:“MI:0915”(physical association)	0.720
PCDHB14	PSTPIP1	psi-mi:“MI:0915”(physical association)	0.720
TULP3	PSTPIP1	psi-mi:“MI:0915”(physical association)	0.720
RTP5	PSTPIP1	psi-mi:“MI:0915”(physical association)	0.720
PSTPIP1	FAM90A1	psi-mi:“MI:0915”(physical association)	0.720
PSTPIP1	LSM4	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (115): PSTPIP1 (Two-hybrid), PSTPIP1 (Two-hybrid), PSTPIP1 (Two-hybrid), PSTPIP1 (Two-hybrid), BUB3 (Two-hybrid), LSM4 (Two-hybrid), PRPF31 (Two-hybrid), FAM90A1 (Two-hybrid), UBE2W (Two-hybrid), PCDHB14 (Two-hybrid), SH2D4A (Two-hybrid), FBXL18 (Two-hybrid), TRAF3IP3 (Two-hybrid), RTP5 (Two-hybrid), PSTPIP1 (Affinity Capture-MS)

ESM2 similar proteins: A7MBI0, D3ZYR1, O13154, O43586, O55148, O60749, O60861, P09760, P16591, P70451, P97531, P97814, Q0JRZ9, Q15642, Q2HWF0, Q3KR97, Q3UQN2, Q4V920, Q5R411, Q5R807, Q5RCJ1, Q5T0N5, Q5U3Q6, Q60780, Q61644, Q6DCZ7, Q6GNV5, Q6GUF4, Q8CJ53, Q8I190, Q8I1A6, Q8I1C0, Q8I1I3, Q8K012, Q8T390, Q91VH2, Q99JB8, Q99M15, Q99N27, Q9BY11

Diamond homologs: A1X283, A1ZAY1, A2AAY5, A4RE77, A6NI72, A6SED8, A7EK16, A8MVU1, A8N2Y6, A8PWF6, B0CRJ3, F1M707, O00443, O43586, O77774, O89032, P0CP00, P0CP01, P10569, P14598, P29366, P62484, P97814, Q09014, Q1LYG0, Q2HDI2, Q2KJB5, Q54FG5, Q5I0D6, Q5RAY1, Q5TCX8, Q5TCZ1, Q61194, Q6WKZ7, Q7Z8J6, Q8IVI9, Q8VDG6, Q9NYB9, Q9QX73, Q9Y7Z8

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
PSTPIP1	down-regulates	ABL1
PSTPIP1	down-regulates	DNM2	binding
ABL1	unknown	PSTPIP1	phosphorylation
PTPN12	“down-regulates activity”	PSTPIP1	dephosphorylation
ABL1	“up-regulates activity”	PSTPIP1	phosphorylation
PSTPIP1	“up-regulates activity”	PTPN18	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 85 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Peptide chain elongation	16	33.3×	8e-19
Viral mRNA Translation	16	33.3×	8e-19
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	16	32.9×	8e-19
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	17	32.8×	1e-19
Selenocysteine synthesis	16	31.5×	1e-18
Eukaryotic Translation Termination	16	31.5×	1e-18
ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA	16	30.9×	1e-18
Formation of a pool of free 40S subunits	16	29.4×	3e-18

GO biological processes:

GO term	Partners	Fold	FDR
cytoplasmic translation	16	39.5×	4e-19
translation	16	21.9×	4e-15
mRNA splicing, via spliceosome	7	8.6×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	0
Uncertain significance	385
Likely benign	290
Benign	59

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
3340543	NM_003978.5(PSTPIP1):c.769G>A (p.Glu257Lys)	Pathogenic
4434	NM_003978.5(PSTPIP1):c.748G>C (p.Glu250Gln)	Pathogenic
4435	NM_003978.5(PSTPIP1):c.688G>A (p.Ala230Thr)	Pathogenic
97810	NM_003978.5(PSTPIP1):c.748G>A (p.Glu250Lys)	Pathogenic

SpliceAI

3192 predictions. Top by Δscore:

Variant	Effect	Δscore
15:77018145:CAGTG:C	acceptor_loss	1.0000
15:77018146:A:AG	acceptor_gain	1.0000
15:77018147:G:GA	acceptor_gain	1.0000
15:77018147:GT:G	acceptor_gain	1.0000
15:77018147:GTGC:G	acceptor_gain	1.0000
15:77018147:GTGCA:G	acceptor_gain	1.0000
15:77018246:GAG:G	donor_gain	1.0000
15:77018247:AGG:A	donor_loss	1.0000
15:77018249:G:T	donor_loss	1.0000
15:77018250:T:G	donor_loss	1.0000
15:77018453:GCA:G	acceptor_loss	1.0000
15:77018454:CA:C	acceptor_loss	1.0000
15:77018455:A:AG	acceptor_gain	1.0000
15:77018455:AG:A	acceptor_gain	1.0000
15:77018456:G:A	acceptor_loss	1.0000
15:77018456:G:GG	acceptor_gain	1.0000
15:77018456:GG:G	acceptor_gain	1.0000
15:77018456:GGGCC:G	acceptor_gain	1.0000
15:77018529:CAAGT:C	donor_loss	1.0000
15:77018530:AAGT:A	donor_loss	1.0000
15:77018531:AGT:A	donor_loss	1.0000
15:77018532:G:GG	donor_gain	1.0000
15:77018532:GTAAG:G	donor_loss	1.0000
15:77018533:T:G	donor_loss	1.0000
15:77025317:GC:G	donor_gain	1.0000
15:77025598:G:GT	donor_gain	1.0000
15:77025601:GAAG:G	donor_gain	1.0000
15:77025604:GGTGA:G	donor_loss	1.0000
15:77025605:G:A	donor_loss	1.0000
15:77025606:T:A	donor_loss	1.0000

AlphaMissense

2731 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:77031205:G:C	R223P	0.999
15:77037148:T:A	V408D	0.999
15:77018479:G:T	G54W	0.998
15:77018480:G:A	G54E	0.998
15:77018489:T:C	L57P	0.998
15:77025513:G:A	G88D	0.998
15:77030552:T:A	W205R	0.998
15:77030552:T:C	W205R	0.998
15:77031220:G:C	R228P	0.998
15:77018458:G:C	A47P	0.997
15:77018464:G:C	A49P	0.997
15:77018479:G:A	G54R	0.996
15:77018479:G:C	G54R	0.996
15:77018480:G:T	G54V	0.996
15:77037111:T:A	W396R	0.996
15:77037111:T:C	W396R	0.996
15:77018236:T:C	L42P	0.995
15:77018457:G:C	R46S	0.995
15:77018457:G:T	R46S	0.995
15:77025512:G:C	G88R	0.995
15:77025521:C:G	H91D	0.995
15:77025543:T:C	L98P	0.995
15:77025576:G:C	R109P	0.995
15:77028587:G:C	A151P	0.995
15:77030554:G:C	W205C	0.995
15:77030554:G:T	W205C	0.995
15:77032314:G:C	R253P	0.995
15:77037163:T:C	L413P	0.995
15:76995604:T:C	F11L	0.994
15:76995606:T:A	F11L	0.994

dbSNP variants (sampled 300 via entrez): RS1000003654 (15:77011367 C>T), RS1000045073 (15:77009086 T>C), RS1000096703 (15:77011128 G>A), RS1000100601 (15:77014453 G>A), RS1000171620 (15:77027036 T>C), RS1000255528 (15:77029332 C>G,T), RS1000350378 (15:77030413 G>A,C), RS1000365695 (15:77035145 G>A), RS1000458437 (15:76999568 C>T), RS1000553000 (15:77015676 G>T), RS1000557854 (15:77004746 G>A), RS1000642747 (15:77025602 A>C), RS1000704139 (15:77020531 T>C), RS1000889088 (15:76998330 G>A), RS1000900713 (15:77020856 C>G)

Disease associations

OMIM: gene MIM:606347 | disease phenotypes: MIM:604416, MIM:109650, MIM:601979

GenCC curated gene-disease

Disease	Classification	Inheritance
pyogenic arthritis-pyoderma gangrenosum-acne syndrome	Definitive	Autosomal dominant
hyperzincemia with functional zinc depletion	Strong	Autosomal dominant
autoinflammatory syndrome	Moderate	Autosomal dominant
recurrent infections-inflammatory syndrome due to zinc metabolism disorder syndrome	Supportive	Unknown

Mondo (5): pyogenic arthritis-pyoderma gangrenosum-acne syndrome (MONDO:0011462), autoinflammatory syndrome (MONDO:0019751), Behcet disease (MONDO:0007191), hyperzincemia with functional zinc depletion (MONDO:0011174), (MONDO:0016676)

Orphanet (4): PAPA syndrome (Orphanet:69126), Autoinflammatory syndrome (Orphanet:93665), Behçet disease (Orphanet:117), Hyperzincemia and hypercalprotectinemia (Orphanet:251523)

HPO phenotypes

37 total (30 of 37 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000093	Proteinuria
HP:0000939	Osteoporosis
HP:0000988	Skin rash
HP:0001061	Acne
HP:0001369	Arthritis
HP:0001376	Limitation of joint mobility
HP:0001433	Hepatosplenomegaly
HP:0001876	Pancytopenia
HP:0001894	Thrombocytosis
HP:0001935	Microcytic anemia
HP:0001945	Fever
HP:0002014	Diarrhea
HP:0002240	Hepatomegaly
HP:0002583	Colitis
HP:0002633	Vasculitis
HP:0002716	Lymphadenopathy
HP:0002721	Immunodeficiency
HP:0002829	Arthralgia
HP:0002987	Elbow flexion contracture
HP:0006380	Knee flexion contracture
HP:0010702	Increased circulating immunoglobulin concentration
HP:0011227	Elevated circulating C-reactive protein concentration
HP:0011424	Increased serum zinc
HP:0012378	Fatigue
HP:0012393	Allergy
HP:0012649	Increased inflammatory response
HP:0025452	Pyoderma gangrenosum
HP:0025616	Sterile abscess
HP:0033188	Cystic acne

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST008830_5	Neurofibrillary tangles	9.000000e-06
GCST90002398_287	Neutrophil count	3.000000e-10
GCST90002407_596	White blood cell count	4.000000e-09
GCST90020028_1749	Hip circumference adjusted for BMI	8.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006797	neurofibrillary tangles measurement
EFO:0004833	neutrophil count
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D001528	Behcet Syndrome	C07.465.075; C11.941.879.780.880.200; C14.907.940.100; C16.320.382.250; C17.800.827.368.250; C17.800.862.150
C566595	Hyperzincemia with Functional Zinc Depletion (supp.)
C536253	Pyogenic arthritis, pyoderma gangrenosum, and acne (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression	2
Air Pollutants	affects expression, increases abundance, increases expression	2
Valproic Acid	affects expression, increases methylation	2
Asian ginseng	decreases expression, decreases reaction	1
triphenyl phosphate	affects expression	1
pirinixic acid	increases activity, affects binding, decreases expression	1
bisphenol A	decreases methylation	1
ethyl-p-hydroxybenzoate	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Decitabine	increases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases methylation	1
Diethylhexyl Phthalate	decreases expression, decreases reaction	1
Diuron	decreases expression	1
Lead	affects expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression, affects cotreatment	1
Nickel	increases expression	1
Ozone	affects expression, increases abundance	1
Plant Extracts	affects cotreatment, increases expression	1
Quercetin	decreases expression	1
Smoke	decreases expression	1
Testosterone	decreases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Tobacco Smoke Pollution	affects expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05879419	PHASE4	ACTIVE_NOT_RECRUITING	Recombinant Herpes Zoster Vaccine in Patients With Autoimmune Rheumatic Diseases
NCT00995709	PHASE3	COMPLETED	Phase III Study in Refractory Behcet’s Disease
NCT01532570	PHASE3	COMPLETED	Clinical Study of TA-650 in Patients With Behcet’s Disease (BD) With Special Lesions
NCT02307513	PHASE3	COMPLETED	A Phase 3 Randomized, Double-blind Study to Evaluate the Efficacy and Safety of Apremilast (CC-10004) in Subjects With Active Behçet’s Disease
NCT02505568	PHASE3	COMPLETED	A Study to Evaluate Efficacy and Safety of Infliximab in Participant With Moderate-to-Severe Refractory Intestinal Behcet’s Disease
NCT03209219	PHASE3	COMPLETED	Interferon α2a Versus Cyclosporine for Refractory Behçet’s Disease Uveitis
NCT04528082	PHASE3	RECRUITING	Apremilast Pediatric Study in Children With Active Oral Ulcers Associated With Behçet’s Disease
NCT05767047	PHASE3	RECRUITING	A Study of Apremilast in Children With Oral Ulcers Associated With Behçet’s Disease or Juvenile Psoriatic Arthritis
NCT06145893	PHASE3	RECRUITING	A Study of Efficacy and Safety of Hemay005 Tablets in Patients With Behçet’s Disease
NCT06780462	PHASE3	RECRUITING	Randomized Controlled Multicenter Study Comparing Steroid Therapy Plus Anticoagulants to Steroid Therapy Alone in Deep Venous Thrombosis of Behçet’s Syndrome
NCT06925698	PHASE3	NOT_YET_RECRUITING	Immunosuppressive Therapy Alone Versus Plus Oral Anticoagulation in the Treatment of VT Associated With Behcet’s Disease
NCT00442182	PHASE2	UNKNOWN	The Efficacy and Safety of ITF2357 in AIS
NCT00001865	PHASE2	COMPLETED	HAT in Eye Complications of Behcet’s Disease
NCT00483184	PHASE2	COMPLETED	Low Dose Interferon Alpha Treatment for Oral Ulcers of Behcet’s Disease
NCT00664599	PHASE2	COMPLETED	Rituximab for the Treatment of Severe Ocular Manifestations of Behcet’s Disease
NCT00700297	PHASE2	COMPLETED	Colchicine Randomized Double-Blind Controlled Crossover Study in Behcet’s Disease
NCT00866359	PHASE2	COMPLETED	A Study to Evaluate the Efficacy and Safety of Apremilast (CC-10004) in the Treatment of Behçet Disease
NCT01693653	PHASE2	TERMINATED	Tocilizumab for the Treatment of Behcet’s Syndrome
NCT02648581	PHASE2	COMPLETED	Efficacy and Safety of Ustekinumab, a Human Monoclonal Anti-IL-12/IL-23 Antibody, in Patients With Behçet Disease
NCT02756650	PHASE2	COMPLETED	1 Year of Treatment With Canakinumab in Behçet’s Disease Patients With Neurologic or Vascular Involvement
NCT03554161	PHASE2	TERMINATED	Tocilizumab for the Treatment of Refractory Behcet’s Uveitis
NCT04186559	PHASE2	UNKNOWN	Topical Pentoxifylline Gel on Behcet’s Disease Genital Ulcers
NCT04218565	PHASE2	TERMINATED	Golimumab for the Treatment of Refractory Behcet’s Uveitis
NCT04609397	PHASE2	TERMINATED	A Study to Evaluate the Efficacy and Safety of Hemay005 in the Treatment of Behçet Disease
NCT06386744	PHASE2	COMPLETED	Dusquetide for the Treatment of Behcet’s Disease
NCT06794008	PHASE2	RECRUITING	BCMA-CD19 CAR-T Therapy for Refractory Autoimmune Diseases
NCT07080346	PHASE2	COMPLETED	Upadacitinib for Refractory Behcet’s Syndrome
NCT00550498	PHASE1	TERMINATED	Stem Cell Transplantation in Ocular Lesions of Behcet’s Disease
NCT06371417	PHASE1	RECRUITING	Phase 1b Trial of RAY121 in Immunological Diseases (RAINBOW Trial)
NCT06723106	PHASE1	ENROLLING_BY_INVITATION	Phase 1b Long-term Extension Trial of RAY121 in Immunological Diseases (RAINBOW-LTE Trial)
NCT00887939	Not specified	COMPLETED	Pathogenesis of Physical Induced Urticarial Syndromes
NCT03510442	Not specified	RECRUITING	Natural History, Genetics, and Pathophysiology of Systemic Juvenile Idiopathic Arthritis, Adult-Onset Still’s Disease, and Related Conditions
NCT06248957	Not specified	RECRUITING	SYSTEMS-LEVEL ANALYSES OF IMMUNE DYSREGULATION
NCT02620618	PHASE1/PHASE2	COMPLETED	Intravitreal Infliximab in Refractory Uveitis in Behcet’s Disease: A Safety and Efficacy Clinical Study
NCT00699985	Not specified	COMPLETED	Psychological Symptoms in Patients With Behcet’s Disease by SCL90-R
NCT00931957	Not specified	UNKNOWN	Etanercept: Single Blind Control Study in Ocular Manifestations of Behcet’s Disease
NCT01584778	Not specified	COMPLETED	Behçet’s Disease and Eosinophil Cationic Protein
NCT01720628	Not specified	COMPLETED	The Relationship Between Serum Levels of Angiogenin, bFGF, VEGF and Ocular Involvement in Patients With Behçet’s Disease
NCT01780363	Not specified	COMPLETED	MEVALONATE KINASE GENE MUTATIONS AND THEIR CLINICAL CORRELATIONS IN BEHÇET’S DISEASE
NCT02020200	Not specified	UNKNOWN	The Effect of Methylphenidate on Cognitive Abilities of Adults With Bipolar Disorder