PACSIN2

Summary

PACSIN2 (protein kinase C and casein kinase substrate in neurons 2, HGNC:8571) is a protein-coding gene on chromosome 22q13.2, encoding Protein kinase C and casein kinase substrate in neurons protein 2 (Q9UNF0). Regulates the morphogenesis and endocytosis of caveolae.

This gene is a member of the protein kinase C and casein kinase substrate in neurons family. The encoded protein is involved in linking the actin cytoskeleton with vesicle formation by regulating tubulin polymerization. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 11252 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 69 total — 1 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_001184970

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8571
Approved symbol	PACSIN2
Name	protein kinase C and casein kinase substrate in neurons 2
Location	22q13.2
Locus type	gene with protein product
Status	Approved
Aliases	SDPII
Ensembl gene	ENSG00000100266
Ensembl biotype	protein_coding
OMIM	604960
Entrez	11252

Gene structure

Transcript identifiers

Ensembl transcripts: 58 — 56 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000263246, ENST00000337959, ENST00000402229, ENST00000403744, ENST00000407585, ENST00000418133, ENST00000422336, ENST00000445706, ENST00000453079, ENST00000453643, ENST00000507586, ENST00000634914, ENST00000859848, ENST00000859849, ENST00000859850, ENST00000859851, ENST00000859852, ENST00000859853, ENST00000859854, ENST00000859855, ENST00000859856, ENST00000859857, ENST00000859858, ENST00000859859, ENST00000859860, ENST00000859861, ENST00000859862, ENST00000859863, ENST00000859864, ENST00000859865, ENST00000859866, ENST00000859867, ENST00000859868, ENST00000859869, ENST00000859870, ENST00000859871, ENST00000859872, ENST00000859873, ENST00000859874, ENST00000859875, ENST00000859876, ENST00000940159, ENST00000940160, ENST00000940161, ENST00000940162, ENST00000971201, ENST00000971202, ENST00000971203, ENST00000971204, ENST00000971205, ENST00000971206, ENST00000971207, ENST00000971208, ENST00000971209, ENST00000971210, ENST00000971211, ENST00000971212, ENST00000971213

RefSeq mRNA: 10 — MANE Select: NM_001184970 NM_001184970, NM_001184971, NM_001349968, NM_001349969, NM_001349970, NM_001349971, NM_001349972, NM_001349973, NM_001349974, NM_007229

CCDS: CCDS43023, CCDS54536

Canonical transcript exons

ENST00000263246 — 11 exons

Exon	Start	End
ENSE00001301340	42869773	42871469
ENSE00001321544	43015021	43015149
ENSE00003465303	42884386	42884561
ENSE00003476692	42876137	42876333
ENSE00003516909	42879048	42879169
ENSE00003610074	42882184	42882304
ENSE00003631637	42888643	42888798
ENSE00003654416	42876888	42877010
ENSE00003688246	42893457	42893613
ENSE00003691492	42890947	42891182
ENSE00003785686	42912021	42912157

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 98.52.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 37.3390 / max 757.4708, expressed in 1818 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
194499	32.1953	1814
194500	2.1103	1312
194487	1.4783	448
194497	0.6070	132
194486	0.3576	164
194496	0.1933	115
194495	0.1892	112
194488	0.1024	45
194498	0.0485	11
194485	0.0368	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	98.52	gold quality
tibia	UBERON:0000979	98.40	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.23	gold quality
colonic mucosa	UBERON:0000317	98.21	gold quality
visceral pleura	UBERON:0002401	98.09	gold quality
body of pancreas	UBERON:0001150	98.08	gold quality
cartilage tissue	UBERON:0002418	98.05	gold quality
endothelial cell	CL:0000115	97.59	gold quality
renal medulla	UBERON:0000362	97.54	gold quality
urethra	UBERON:0000057	97.49	gold quality
cardia of stomach	UBERON:0001162	97.49	gold quality
skin of hip	UBERON:0001554	97.46	gold quality
nephron tubule	UBERON:0001231	97.42	gold quality
middle temporal gyrus	UBERON:0002771	97.30	gold quality
popliteal artery	UBERON:0002250	97.27	gold quality
tibial artery	UBERON:0007610	97.26	gold quality
saphenous vein	UBERON:0007318	97.19	gold quality
choroid plexus epithelium	UBERON:0003911	97.12	gold quality
pleura	UBERON:0000977	96.94	gold quality
vein	UBERON:0001638	96.90	gold quality
aorta	UBERON:0000947	96.87	gold quality
parietal pleura	UBERON:0002400	96.81	gold quality
ileal mucosa	UBERON:0000331	96.75	gold quality
inferior olivary complex	UBERON:0002127	96.75	gold quality
secondary oocyte	CL:0000655	96.70	gold quality
substantia nigra pars compacta	UBERON:0001965	96.62	gold quality
coronary artery	UBERON:0001621	96.61	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.61	gold quality
blood vessel layer	UBERON:0004797	96.59	gold quality
descending thoracic aorta	UBERON:0002345	96.57	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	17.86
E-ANND-3	yes	15.13
E-GEOD-134144	yes	9.04

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

82 targeting PACSIN2, 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-1277-5P	100.00	73.95	5056
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-8084	99.73	69.57	1760

Literature-anchored findings (GeneRIF, showing 27)

• Thus, syndapin-dynamin complexes are crucial and sufficient to promote vesicle formation from the trans-Golgi network. (PMID:16551695)
• These findings suggest a novel function for PACSIN proteins 1, 2, and 3 in dynamic microtubule nucleation. (PMID:18456257)
• The regulated deformation of membranes and promotion of tubule constrictions by Pacsin suggests a more versatile function of these proteins in vesiculation and endocytosis. (PMID:19549836)
• Since the curvature of the neck of the microspike and that of the tubulation share similar geometry, the pacsin2 EFC/F-BAR domain is considered to facilitate both microspike formation and tubulation. (PMID:20188097)
• PACSIN2 regulates cell spreading and cell migration, which are dependent on cyclin D1 expression. (PMID:21200149)
• Results indicate that PACSIN2 mediates membrane sculpting by caveolin-1 in caveola morphology and recruits dynamin-2 for caveola fission. (PMID:21610094)
• Data identify the BAR-domain protein PACSIN2 as a Rac1 interactor that regulates Rac1-mediated cell spreading and migration. (PMID:21693584)
• important role in the formation of plasma membrane caveolae (PMID:21807942)
• These data indicate that polymorphism in PACSIN2 significantly modulates TPMT activity and influences the risk of GI toxicity associated with mercaptopurine therapy. (PMID:22846425)
• a novel role for the F-BAR-domain protein PACSIN2 in regulating EGF receptor surface levels and EGF-induced downstream signaling. (PMID:23129763)
• Cooperation of MICAL-L1, pacsin 2 (syndapin2), and phosphatidic acid in tubular recycling endosome biogenesis. (PMID:23596323)
• proposed a packing model for the assembly of PACSIN 2 on membrane, where the proteins are connected by tip-to-tip and wedge loop-mediated lateral interactions on the surface of membrane to generate various diameter tubules (PMID:23888307)
• PC1 modulates actin cytoskeleton rearrangements and directional cell migration through the Pacsin 2/N-Wasp complex. (PMID:24385601)
• FlnA binding to PACSIN2 F-BAR domain regulates membrane tubulation in megakaryocytes and platelets. (PMID:25838348)
• PACSIN2 phosphorylation decreases its membrane-binding activity, thereby decreasing its stabilizing effect on caveolae and triggering dynamin-mediated removal of caveolae. (PMID:26092940)
• Pacsin2 recruitment is important for maintenance of cell-cell adhesion by stabilizing the VE-cadherin complex within focal adherens junctions and inhibition of its internalization. (PMID:27417273)
• To our knowledge, this is the first study showing PACSIN2 genotype association with hematological toxicity in ALL patients undergoing maintenance therapy. (PMID:27452984)
• our results provide new insights into the mechanism of cellular intoxication by TcdA and the role of PACSIN2 in endocytosis. (PMID:27942025)
• observations indicate that PACSIN2 promotes the cell-to-cell spreading of HIV-1 by connecting Gag to the actin cytoskeleton. (PMID:29891700)
• Authors found that caveolins (CAV1 and CAV2) and the membrane sculpting F-BAR protein PACSIN2 promote L. monocytogenes protrusion engulfment during spread, and that PACSIN2 specifically localizes to protrusions. (PMID:31242077)
• PACSIN2 rs2413739 influence on thiopurine pharmacokinetics: validation studies in pediatric patients. (PMID:31792371)
• PACSIN2 Interacts with Nonstructural Protein 5A and Regulates Hepatitis C Virus Assembly. (PMID:31801866)
• A junctional PACSIN2/EHD4/MICAL-L1 complex coordinates VE-cadherin trafficking for endothelial migration and angiogenesis. (PMID:33972531)
• Dynamin 2 and BAR domain protein pacsin 2 cooperatively regulate formation and maturation of podosomes. (PMID:34325130)
• Reciprocal interactions among Cobll1, PACSIN2, and SH3BP1 regulate drug resistance in chronic myeloid leukemia. (PMID:35352878)
• PACSIN2 as a modulator of autophagy and mercaptopurine cytotoxicity: mechanisms in lymphoid and intestinal cells. (PMID:36596605)
• Pacsin 2-dependent N-cadherin internalization regulates the migration behaviour of malignant cancer cells. (PMID:37132654)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pacsin2	ENSDARG00000078014
mus_musculus	Pacsin2	ENSMUSG00000016664
rattus_norvegicus	Pacsin2	ENSRNOG00000009756
drosophila_melanogaster	Synd	FBGN0053094
caenorhabditis_elegans		WBGENE00018467

Paralogs (2): PACSIN1 (ENSG00000124507), PACSIN3 (ENSG00000165912)

Protein

Protein identifiers

Protein kinase C and casein kinase substrate in neurons protein 2 — Q9UNF0 (reviewed: Q9UNF0)

Alternative names: Syndapin-2, Syndapin-II

All UniProt accessions (7): Q9UNF0, A0A0U1RR22, B0QYG7, B0QYG8, B0QYG9, H0Y923, Q6FIA3

UniProt curated annotations — full annotation on UniProt →

Function. Regulates the morphogenesis and endocytosis of caveolae. Lipid-binding protein that is able to promote the tubulation of the phosphatidic acid-containing membranes it preferentially binds. Plays a role in intracellular vesicle-mediated transport. Involved in the endocytosis of cell-surface receptors like the EGF receptor, contributing to its internalization in the absence of EGF stimulus. Essential for endothelial organization in sprouting angiogenesis, modulates CDH5-based junctions. Facilitates endothelial front-rear polarity during migration by recruiting EHD4 and MICALL1 to asymmetric adherens junctions between leader and follower cells. (Microbial infection) Specifically enhances the efficiency of HIV-1 virion spread by cell-to-cell transfer. Also promotes the protrusion engulfment during cell-to-cell spread of bacterial pathogens like Listeria monocytogenes. Involved in lipid droplet formation, which is important for HCV virion assembly.

Subunit / interactions. Homodimer. May form heterooligomers with other PACSINs. Interacts (via NPF motifs) with EHD1 (via EH domain). Interacts (via NPF motifs) with EHD2 (via EH domain); this interaction probably stabilizes the caveolae. Interacts with EHD3. Interacts (via the SH3 domain) with MICALL1. Interacts with RAC1. Interacts (via SH3 domain) with DNM1, SYN1, SYNJ1 and WASL. Interacts (via F-BAR domain) with CAV1. Interacts with TRPV4. Forms a complex with EHD4 and MICALL1; the complex controls CDH5 trafficking and coordinates angiogenesis. (Microbial infection) Interacts with ubiquitinated HIV-1 gag (via p6-gag domain); this interaction allows PACSIN2 recruitment to viral assembly sites and its subsequent incorporation into virions. (Microbial infection) Interacts (via F-BAR domain) with Rous sarcoma virus p2B; this interaction allows PACSIN2 recruitment to viral assembly sites. (Microbial infection) Interacts (via N-terminus) with Hepatatis C virus (HCV) non-structural protein 5A (via N-terminus); this interaction attenuates protein kinase C alpha (PRKCA)-mediated phosphorylation of PACSIN2 at Ser-313 by disrupting the interaction between PACSIN2 and PRKCA.

Subcellular location. Cytoplasm. Cytoskeleton. Cytoplasmic vesicle membrane. Cell projection. Ruffle membrane. Early endosome. Recycling endosome membrane. Cell membrane. Membrane. Caveola. Cell junction. Adherens junction.

Tissue specificity. Widely expressed.

Post-translational modifications. Phosphorylated by casein kinase 2 (CK2). Phosphorylation by PKC probably decreases the membrane binding and tubulation capacities of PACSIN2, thereby modulating the lifetime of caveolae.

Domain organisation. The F-BAR domain forms a coiled coil and mediates membrane-binding and membrane tubulation. Autoinhibition of these functions is mediated by an interaction between the SH3 and F-BAR domains. The F-Bar domain also mediates the binding to the cell actin cytoskeleton through the interaction with CAV-1. (Microbial infection) The SH3 domain is required for the cell-to-cell spreading of HIV-1 virions.

Similarity. Belongs to the PACSIN family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UNF0-1	1	yes
Q9UNF0-2	2

RefSeq proteins (10): NP_001171899, NP_001171900, NP_001336897, NP_001336898, NP_001336899, NP_001336900, NP_001336901, NP_001336902, NP_001336903, NP_009160 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001060	FCH_dom	Domain
IPR001452	SH3_domain	Domain
IPR027267	AH/BAR_dom_sf	Homologous_superfamily
IPR031160	F_BAR_dom	Domain
IPR035743	PACSIN1/PACSIN2_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR037453	PACSIN2_F-BAR	Domain

Pfam: PF00611, PF14604

UniProt features (43 total): helix 11, modified residue 5, sequence conflict 5, compositionally biased region 4, sequence variant 3, short sequence motif 3, domain 2, mutagenesis site 2, turn 2, region of interest 2, chain 1, splice variant 1, strand 1, coiled-coil region 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
3ABH	X-RAY DIFFRACTION	2
3Q0K	X-RAY DIFFRACTION	2.6
3ACO	X-RAY DIFFRACTION	2.7
3HAJ	X-RAY DIFFRACTION	2.78

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UNF0-F1	82.46	0.68

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 (5): 53, 273, 313, 399, 446

Mutagenesis-validated functional residues (2):

Position	Phenotype
313	increased protein interaction with hcv ns5a.
313	decreased protein interaction with hcv ns5a.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8856828	Clathrin-mediated endocytosis

MSigDB gene sets: 232 (showing top): GOBP_MEMBRANE_BIOGENESIS, GOBP_CELL_MIGRATION_INVOLVED_IN_SPROUTING_ANGIOGENESIS, GOBP_PLASMA_MEMBRANE_ORGANIZATION, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_NEGATIVE_REGULATION_OF_ENDOCYTOSIS, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_DN, DARWICHE_PAPILLOMA_RISK_HIGH_DN, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN, GOBP_VESICLE_MEDIATED_TRANSPORT, GOCC_RUFFLE, REACTOME_MEMBRANE_TRAFFICKING, GOBP_MEMBRANE_RAFT_ORGANIZATION, EFC_Q6, RODRIGUES_NTN1_TARGETS_DN

GO Biological Process (12): cell migration involved in sprouting angiogenesis (GO:0002042), cytoskeleton organization (GO:0007010), actin cytoskeleton organization (GO:0030036), regulation of endocytosis (GO:0030100), protein localization to endosome (GO:0036010), negative regulation of endocytosis (GO:0045806), cell projection morphogenesis (GO:0048858), modulation of chemical synaptic transmission (GO:0050804), caveola assembly (GO:0070836), caveolin-mediated endocytosis (GO:0072584), plasma membrane tubulation (GO:0097320), endocytosis (GO:0006897)

GO Molecular Function (8): phospholipid binding (GO:0005543), cytoskeletal protein binding (GO:0008092), protein-macromolecule adaptor activity (GO:0030674), identical protein binding (GO:0042802), cadherin binding (GO:0045296), phosphatidic acid binding (GO:0070300), protein binding (GO:0005515), lipid binding (GO:0008289)

GO Cellular Component (22): cytoplasm (GO:0005737), endosome (GO:0005768), early endosome (GO:0005769), cytosol (GO:0005829), plasma membrane (GO:0005886), caveola (GO:0005901), adherens junction (GO:0005912), focal adhesion (GO:0005925), cilium (GO:0005929), nuclear speck (GO:0016607), ruffle membrane (GO:0032587), centriolar satellite (GO:0034451), recycling endosome membrane (GO:0055038), extracellular exosome (GO:0070062), glutamatergic synapse (GO:0098978), cytoskeleton (GO:0005856), cell-cell junction (GO:0005911), membrane (GO:0016020), cytoplasmic vesicle membrane (GO:0030659), cytoplasmic vesicle (GO:0031410), cell projection (GO:0042995), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Membrane Trafficking	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
endocytosis	3
protein binding	3
binding	2
cytoplasmic vesicle	2
cytoplasm	2
sprouting angiogenesis	1
blood vessel endothelial cell migration	1
organelle organization	1
cytoskeleton organization	1
actin filament-based process	1
regulation of cellular component organization	1
regulation of vesicle-mediated transport	1
protein localization to organelle	1
regulation of endocytosis	1
negative regulation of transport	1
negative regulation of cellular component organization	1
cell morphogenesis	1
anatomical structure morphogenesis	1
cell projection organization	1
chemical synaptic transmission	1
regulation of trans-synaptic signaling	1
plasma membrane raft assembly	1
plasma membrane organization	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
lipid binding	1
molecular adaptor activity	1
cell adhesion molecule binding	1
phospholipid binding	1
anion binding	1
intracellular anatomical structure	1
endomembrane system	1
endosome	1
membrane	1
cell periphery	1
plasma membrane raft	1
cell-cell junction	1

Protein interactions and networks

STRING

1148 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PACSIN2	EHD1	Q9H4M9	895
PACSIN2	WASL	O00401	893
PACSIN2	EHD2	Q9NZN4	856
PACSIN2	EHD3	Q9NZN3	838
PACSIN2	TRIP10	Q15642	788
PACSIN2	CAVIN1	Q6NZI2	776
PACSIN2	CAV1	Q03135	772
PACSIN2	MICALL1	Q8N3F8	760
PACSIN2	FNBP1	Q96RU3	757
PACSIN2	SYNJ1	O43426	746
PACSIN2	DNM2	P50570	738
PACSIN2	ROR1	Q01973	632
PACSIN2	AMPH	P49418	614
PACSIN2	EPS15	P42566	610
PACSIN2	DNM1	Q05193	606

IntAct

152 interactions, top by confidence:

A	B	Type	Score
PACSIN1	PACSIN2	psi-mi:“MI:0915”(physical association)	0.930
PACSIN2	PACSIN1	psi-mi:“MI:0915”(physical association)	0.930
PACSIN2	PACSIN2	psi-mi:“MI:0915”(physical association)	0.850
PACSIN2	PACSIN2	psi-mi:“MI:0407”(direct interaction)	0.850
PACSIN1	COBL	psi-mi:“MI:0914”(association)	0.750
COBL	PACSIN2	psi-mi:“MI:0915”(physical association)	0.740
PACSIN3	PACSIN2	psi-mi:“MI:0915”(physical association)	0.740
PACSIN2	COBL	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
DIDO1	OGT	psi-mi:“MI:0914”(association)	0.670
NCKIPSD	GEMIN2	psi-mi:“MI:0914”(association)	0.640
FASLG	PACSIN2	psi-mi:“MI:0915”(physical association)	0.590
PACSIN2	FASLG	psi-mi:“MI:0915”(physical association)	0.590
PACSIN2	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
MEOX2	PACSIN2	psi-mi:“MI:0915”(physical association)	0.560
PACSIN2	APP1	psi-mi:“MI:0915”(physical association)	0.560
APP1	PACSIN2	psi-mi:“MI:0915”(physical association)	0.560
RIC8A	PACSIN2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (271): PACSIN2 (Two-hybrid), PACSIN2 (Two-hybrid), PACSIN1 (Two-hybrid), PACSIN2 (Affinity Capture-RNA), PACSIN2 (Affinity Capture-RNA), PACSIN2 (Affinity Capture-MS), COBL (Affinity Capture-MS), COBLL1 (Affinity Capture-MS), THG1L (Affinity Capture-MS), WIPF2 (Affinity Capture-MS), MPRIP (Affinity Capture-MS), PACSIN1 (Two-hybrid), PACSIN2 (Two-hybrid), HSPD1 (Co-fractionation), PACSIN2 (Co-fractionation)

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: A3LXQ8, A6H7G2, A6ZR73, A7MBI0, B3LRN4, B5VHP4, B8R1V5, C4Y1G1, C7GKW5, E7KBW4, E7KMS3, E7LTJ6, E7Q311, E7QE10, G5EC32, O13154, O35179, O35180, O42287, O60861, O74749, O75886, O76041, O77506, O88811, P08487, P10569, P10686, P14317, P18302, P19174, P20929, P34121, P34416, P40073, P49710, P70297, Q01406, Q07266, Q09822

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PRKACA	“down-regulates activity”	PACSIN2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 128 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
EPHB-mediated forward signaling	6	17.3×	2e-04
RHO GTPases Activate WASPs and WAVEs	5	17.2×	1e-03
EPH-ephrin mediated repulsion of cells	7	16.7×	1e-04
EPH-Ephrin signaling	7	12.6×	2e-04
Recycling pathway of L1	5	12.2×	3e-03
FCGR3A-mediated phagocytosis	5	10.2×	5e-03
Regulation of actin dynamics for phagocytic cup formation	5	10.0×	5e-03
RHOQ GTPase cycle	5	9.8×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
ephrin receptor signaling pathway	5	14.9×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	56
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1077183	Single allele	Pathogenic

SpliceAI

3626 predictions. Top by Δscore:

Variant	Effect	Δscore
22:42835471:CCA:C	acceptor_gain	1.0000
22:42835472:CA:C	acceptor_gain	1.0000
22:42835489:GAAGA:G	acceptor_gain	1.0000
22:42835490:AAGA:A	acceptor_gain	1.0000
22:42835491:AGA:A	acceptor_gain	1.0000
22:42835492:GA:G	acceptor_gain	1.0000
22:42835492:GACTA:G	acceptor_loss	1.0000
22:42835493:AC:A	acceptor_loss	1.0000
22:42835494:C:CA	acceptor_loss	1.0000
22:42835494:C:CC	acceptor_gain	1.0000
22:42835495:T:A	acceptor_loss	1.0000
22:42840942:A:AC	donor_gain	1.0000
22:42840943:C:CT	donor_gain	1.0000
22:42840943:CTG:C	donor_gain	1.0000
22:42840943:CTGCA:C	donor_gain	1.0000
22:42847508:ACTT:A	donor_loss	1.0000
22:42847509:CTTA:C	donor_loss	1.0000
22:42847512:A:AC	donor_gain	1.0000
22:42847513:C:CC	donor_gain	1.0000
22:42847513:C:CT	donor_loss	1.0000
22:42847628:CACAC:C	acceptor_gain	1.0000
22:42847630:CAC:C	acceptor_gain	1.0000
22:42876133:CTA:C	donor_loss	1.0000
22:42876135:A:AG	donor_loss	1.0000
22:42876135:ACCAG:A	donor_gain	1.0000
22:42876136:CCAG:C	donor_gain	1.0000
22:42876136:CCAGC:C	donor_gain	1.0000
22:42876152:G:C	donor_gain	1.0000
22:42876202:T:TA	donor_gain	1.0000
22:42876255:C:CT	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000006525 (22:43014042 C>A), RS1000007919 (22:42890614 G>A,C), RS1000022335 (22:42992368 G>A), RS1000035356 (22:42992052 C>G,T), RS1000092331 (22:42949217 C>T), RS1000117937 (22:43008756 C>T), RS1000139838 (22:42986036 T>C), RS1000142504 (22:42959954 A>G), RS1000163248 (22:42994336 C>A), RS1000167505 (22:42885869 G>C), RS1000170725 (22:43009085 G>A,T), RS1000180219 (22:42929265 A>G), RS1000181198 (22:42916036 G>C), RS1000196115 (22:42973318 C>T), RS1000253937 (22:42917571 T>C)

Disease associations

OMIM: gene MIM:604960 | disease phenotypes: MIM:618430

GenCC curated gene-disease

Mondo (2): developmental delay with variable intellectual impairment and behavioral abnormalities (MONDO:0032745), myoepithelial tumor (MONDO:0002380)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST001370_51	Prostate cancer (SNP x SNP interaction)	2.000000e-06
GCST004599_222	Mean platelet volume	7.000000e-64
GCST004603_152	Platelet count	4.000000e-29
GCST004616_178	Platelet distribution width	4.000000e-148
GCST90002395_624	Mean platelet volume	4.000000e-132
GCST90002401_280	Platelet distribution width	6.000000e-99
GCST90002401_281	Platelet distribution width	1.000000e-24
GCST90002402_651	Platelet count	4.000000e-52

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count
EFO:0007984	platelet component distribution width

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009208	Myoepithelioma	C04.557.435.585

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066445 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

3 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2413739	Toxicity	3	mercaptopurine;methotrexate	Acute lymphoblastic leukemia
rs2413739	Toxicity	3	mercaptopurine	Acute lymphoblastic leukemia
rs2413739	Efficacy	3	azathioprine	Irritable Bowel Syndrome

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2413739	PACSIN2	3	4.50	3	mercaptopurine;azathioprine;mercaptopurine;methotrexate

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.24	Kd	579	nM	CHEMBL3752910
6.24	ED50	579	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149903: Binding affinity to human PACSIN2 incubated for 45 mins by Kinobead based pull down assay	kd	0.5790	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	3
sodium arsenite	decreases expression, increases expression	3
Acetaminophen	increases expression, affects response to substance	2
Air Pollutants	affects cotreatment, increases abundance, increases expression, increases oxidation, affects expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Cisplatin	increases expression, affects expression	2
Ozone	affects cotreatment, increases expression, increases oxidation, increases abundance, affects expression	2
Smoke	decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
bisphenol F	affects cotreatment, decreases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases expression, increases oxidation, increases abundance	1
pirinixic acid	affects binding, decreases expression, increases activity	1
beta-lapachone	increases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
methacrylaldehyde	affects cotreatment, increases expression, increases oxidation, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol S	increases expression	1
Decitabine	affects expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	affects binding, decreases reaction	1
Acrolein	affects cotreatment, increases expression, increases oxidation, increases abundance	1
Arbutin	decreases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Caffeine	increases phosphorylation	1
Dexamethasone	affects cotreatment, decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652945	Binding	Binding affinity to human PACSIN2 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

2 cell lines: 1 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1ZR	Abcam HeLa PACSIN2 KO	Cancer cell line	Female
CVCL_D9M5	Ubigene HEK293 PACSIN2 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03600649	PHASE1	UNKNOWN	Clinical Trial of SP-2577 (Seclidemstat) in Patients With Relapsed or Refractory Ewing or Ewing-related Sarcomas
NCT05266196	PHASE1/PHASE2	UNKNOWN	A Rollover Protocol to Allow for Continued Access to the LSD1 Inhibitor Seclidemstat (SP-2577)
NCT06239272	PHASE1/PHASE2	RECRUITING	NRSTS2021, A Risk Adapted Study Evaluating Maintenance Pazopanib, Limited Margin, Dose-Escalated Radiation Therapy and Selinexor in Non-Rhabdomyosarcoma Soft Tissue Sarcoma (NRSTS)
NCT06625190	PHASE1/PHASE2	RECRUITING	Alpha/Beta T and B Cell Depletion With Zoledronic Acid for Solid Tumors
NCT06244420	Not specified	COMPLETED	Malignant Myoepithelioma of Bone and Soft Tissues: Diagnostic Imaging and Histology in Relation to Prognosis