PICALM

Summary

PICALM (phosphatidylinositol binding clathrin assembly protein, HGNC:15514) is a protein-coding gene on chromosome 11q14.2, encoding Phosphatidylinositol-binding clathrin assembly protein (Q13492). Cytoplasmic adapter protein that plays a critical role in clathrin-mediated endocytosis which is important in processes such as internalization of cell receptors, synaptic transmission or removal of apoptotic cells.

This gene encodes a clathrin assembly protein, which recruits clathrin and adaptor protein complex 2 (AP2) to cell membranes at sites of coated-pit formation and clathrin-vesicle assembly. The protein may be required to determine the amount of membrane to be recycled, possibly by regulating the size of the clathrin cage. The protein is involved in AP2-dependent clathrin-mediated endocytosis at the neuromuscular junction. A chromosomal translocation t(10;11)(p13;q14) leading to the fusion of this gene and the MLLT10 gene is found in acute lymphoblastic leukemia, acute myeloid leukemia and malignant lymphomas. The polymorphisms of this gene are associated with the risk of Alzheimer disease. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 8301 — RefSeq curated summary.

At a glance

• GWAS associations: 26
• Clinical variants (ClinVar): 132 total
• Phenotypes (HPO): 3
• Druggable target: yes
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• MANE Select transcript: NM_007166

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15514
Approved symbol	PICALM
Name	phosphatidylinositol binding clathrin assembly protein
Location	11q14.2
Locus type	gene with protein product
Status	Approved
Aliases	CALM, CLTH
Ensembl gene	ENSG00000073921
Ensembl biotype	protein_coding
OMIM	603025
Entrez	8301

Gene structure

Transcript identifiers

Ensembl transcripts: 54 — 45 protein_coding, 5 retained_intron, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000356360, ENST00000393346, ENST00000525162, ENST00000526033, ENST00000526548, ENST00000526907, ENST00000526961, ENST00000528256, ENST00000528398, ENST00000528411, ENST00000529016, ENST00000529760, ENST00000530542, ENST00000530692, ENST00000531558, ENST00000531771, ENST00000531930, ENST00000532041, ENST00000532317, ENST00000532603, ENST00000533350, ENST00000534375, ENST00000534412, ENST00000630913, ENST00000890386, ENST00000890387, ENST00000890388, ENST00000890389, ENST00000890390, ENST00000890391, ENST00000890392, ENST00000890393, ENST00000890394, ENST00000890395, ENST00000890396, ENST00000890397, ENST00000890398, ENST00000890399, ENST00000890400, ENST00000890401, ENST00000890402, ENST00000890403, ENST00000890404, ENST00000890405, ENST00000890406, ENST00000890407, ENST00000890408, ENST00000890409, ENST00000890410, ENST00000890411, ENST00000890412, ENST00000890413, ENST00000958922, ENST00000958923

RefSeq mRNA: 5 — MANE Select: NM_007166 NM_001008660, NM_001206946, NM_001206947, NM_001411034, NM_007166

CCDS: CCDS31653, CCDS55783, CCDS55784, CCDS8272, CCDS91570

Canonical transcript exons

ENST00000393346 — 20 exons

Exon	Start	End
ENSE00000797897	85981129	85981228
ENSE00000797902	85996826	85996929
ENSE00000989275	86000643	86000779
ENSE00000989276	85990250	85990399
ENSE00000989277	85983866	85983973
ENSE00001328176	85981872	85982003
ENSE00002144222	85957175	85959060
ENSE00003486140	85974708	85974812
ENSE00003536057	86022367	86022469
ENSE00003557667	85981745	85981775
ENSE00003566645	86001035	86001158
ENSE00003594776	86003366	86003451
ENSE00003607483	86011030	86011136
ENSE00003607692	86007542	86007583
ENSE00003652321	86031469	86031611
ENSE00003683006	86026292	86026367
ENSE00003690111	85976623	85976682
ENSE00003790712	86012281	86012392
ENSE00003791596	86014870	86014963
ENSE00003845746	86068651	86069084

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 96.1089 / max 1417.7654, expressed in 1828 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
121727	77.8537	1828
121726	10.1348	1648
121725	3.6551	1125
121723	1.3923	761
121729	1.2760	698
121724	0.9979	550
121714	0.2964	137
121722	0.2907	98
121728	0.2120	81

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	99.45	gold quality
popliteal artery	UBERON:0002250	98.92	gold quality
tibial artery	UBERON:0007610	98.92	gold quality
cortical plate	UBERON:0005343	98.89	gold quality
corpus callosum	UBERON:0002336	98.85	gold quality
subcutaneous adipose tissue	UBERON:0002190	98.81	gold quality
gall bladder	UBERON:0002110	98.79	gold quality
aorta	UBERON:0000947	98.74	gold quality
tibial nerve	UBERON:0001323	98.72	gold quality
monocyte	CL:0000576	98.70	gold quality
right coronary artery	UBERON:0001625	98.68	gold quality
peritoneum	UBERON:0002358	98.67	gold quality
omental fat pad	UBERON:0010414	98.67	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.63	gold quality
adipose tissue of abdominal region	UBERON:0007808	98.63	gold quality
metanephros cortex	UBERON:0010533	98.63	gold quality
mononuclear cell	CL:0000842	98.60	gold quality
leukocyte	CL:0000738	98.57	gold quality
adipose tissue	UBERON:0001013	98.56	gold quality
ascending aorta	UBERON:0001496	98.53	gold quality
left coronary artery	UBERON:0001626	98.53	gold quality
thoracic aorta	UBERON:0001515	98.52	gold quality
connective tissue	UBERON:0002384	98.49	gold quality
spinal cord	UBERON:0002240	98.40	gold quality
coronary artery	UBERON:0001621	98.36	gold quality
descending thoracic aorta	UBERON:0002345	98.31	gold quality
smooth muscle tissue	UBERON:0001135	98.27	gold quality
right lung	UBERON:0002167	98.23	gold quality
blood	UBERON:0000178	98.22	gold quality
mucosa of stomach	UBERON:0001199	98.21	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-119	yes	19.30
E-HCAD-35	yes	13.25
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

155 targeting PICALM, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3065-5P	99.97	71.56	3281

Literature-anchored findings (GeneRIF, showing 40)

• A novel chromosomal inversion at 11q23 in acute myeloid leukemia fuses the CALM gene to the MLL gene. (PMID:12461747)
• CALM plays a critical role in the regulation and orderly progression of coated bud formation at the plasma membrane. (PMID:16262731)
• Expression of CATS was able to markedly increase the nuclear localization of CALM and of the leukemogenic fusion protein CALM/AF10 (PMID:16491119)
• Data demonstrate that the leukemia-propagating cell in murine CALM/AF10-positive acute myeloid leukemia differs from normal hematopoietic stem cells by B220 surface expression and immunoglobulin heavy chain rearrangement. (PMID:17097559)
• Presence of CALM-AF10 fusion in children with acute megakaryoblastic leukemia without Down syndrome. (PMID:17170719)
• A novel AF10-CALM fusion transcript is reported in gamma/delta-T cell type lymphopblastic leukemia. (PMID:17597474)
• Expression of a CALM-AF10 fusion gene leads to Hoxa cluster overexpression and acute leukemia in transgenic mice. (PMID:17804713)
• CALM/AF10 (MLLT10) fusion protein might interfere with normal Ikaros (IKZF1)function, and thereby block lymphoid differentiation in CALM/AF10 positive leukemias. (PMID:18037964)
• PICALM protein might contribute to the observed phenotype. (PMID:18074379)
• review discusses the normal structure and function of CALM and AF10, the spectrum of clinical findings seen in patients with CALM-AF10 fusions, CALM-AF10 mouse models and highlights the role of HOXA cluster gene activation in CALM-AF10 leukemia (PMID:18094714)
• Overexpression of CALM leads to the reduction of cell surface VAMP2, whereas knockdown of CALM by RNA interference results in the accumulation of surface VAMP2. (PMID:18182011)
• RNA interference-mediated knockdown of AP180 reduces the generation of Abeta1-40 and Abeta1-42, whereas CALM knockdown has no effect on Abeta generation. (PMID:19450545)
• Having removed Single Nucleotide Polymorphism within the APOE, CLU and PICALM loci from the analysis, focused on those that showed the most evidence for association with Alzheimer’s disease (PMID:19734902)
• Data confirmed genetic associations for Alzheimer’s disease with APOE, CLU, PICALM and CR1 SNPs. (PMID:20534741)
• These results show near-perfect replication and provide the first additional evidence that PICALM is associated with the risk of late onset alzheimer disease. (PMID:20554627)
• While no Alzheimer Disease association was observed with single nucleotide polymorphisms, a trend of association was seen with the Picalm and Clusterin single nucleotide polymorphisms. (PMID:20570404)
• In this review, PICALM is a major Alzheimer’s disease susceptibility gene indirectly implicated in the herpes simplex virus life cycle; PICALM binds to a protein used by the virus for nuclear egress. (PMID:20674675)
• This study confirmed in a completely independent data set that CR1, CLU, and PICALM are AD susceptibility loci in European ancestry populations. (PMID:20697030)
• Polymorphism of the clusterin gene may confer symptomatic specificity in schizophrenia, whereas polymorphism of the clathrin assembly lymphoid myeloid gene does not affect susceptibility to schizophrenia. (PMID:20738160)
• This study showed the presence of picalm in endothelial cells of human brain tissue, and it suggests an increase in PICALM expression in Alzheimer disease. (PMID:20838239)
• results suggest that the PICALM gene rs3851179 polymorphism may not play a major role in the development of LOAD in the Han Chinese population. (PMID:20951388)
• picalm polymorphisms were associated with late-onset Alzheimer disease in an independent cohort from the National Institute on Aging Late-Onset Alzheimer’s Disease Family Study (PMID:21059989)
• we confirmed that PICALM is a genetic determinants of Alzheimer disease. (PMID:21220176)
• Data show that CALM influences the cell surface level of the AMPA receptor subunit GluR2. (PMID:21221849)
• This study suggested that the PICALM rs3851179 showed no statistically significant difference between LOAD cases and controls. (PMID:21297266)
• This study provides compelling independent evidence that genetic variants in CLU, CR1, and PICALM are genetically associated with risk for AD. (PMID:21300948)
• variants in BIN1, CLU, CR1 or PICALM are associated with changes in the CSF levels of biomarkers (PMID:21347408)
• Single nucleotide polymorphisms (SNPs) are not significantly different within PICALM sporadic Alzheimer disease patients and unrelated age- and sex-matched healthy controls of Han Chinese. (PMID:21358043)
• In leukemia cells, full-length CALM-AF10 localized to the nucleus with no consistent effect on growth factor endocyctosis, and suppressed histone H3 lysine 79 methylation regardless of the presence of clathrin (PMID:21706055)
• relationship of Parkinson’s disease with SNPs of CLU, CR1 and PICALM (PMID:21912625)
• AP-2 and epsin-1 are both required to promote efficient internalization of activated PAR1 and recognize discrete receptor sorting signals (PMID:21965661)
• findings showed evidence of CR1, CLU, and PICALM and late-onset Alzheimer’s disease (LOAD) susceptibility in an independent southern Chinese population (PMID:22015308)
• results strongly indicate that the differential regulation of these three genes is not due to the break point effect but as a consequence of the CALM/AF10 fusion gene expression, though the mechanism of regulation is not well understood (PMID:22064352)
• In conclusion, we confirmed association of CLU, CR1, and PICALM genes with the disease status in our cohort through identification of a number of disease-specific variants (PMID:22402018)
• PICALM, an adaptor protein involved in clathrin-mediated endocytosis, regulates APP internalization and subsequent Abeta generation. PICALM contributes to amyloid plaque load in brain likely via its effect on Abeta metabolism. (PMID:22539346)
• The SNP genotype pattern at the PICALM gene is associated with episodic memory. (PMID:22539578)
• AP180 and CALM are endocytic adaptors dedicated to the sorting of small soluble N-ethylmaleimide-sensitive-factor attachment protein receptors. (Review) (PMID:22639918)
• Our results do not provide evidence that the PICALM rs3851179 polymorphism increase susceptibility to Parkinson disease, in the Greek population. (PMID:22715855)
• model system to study the effects of intracellular Abeta in fusion with green fluorescent protein. We sent this fusion protein into the secretory pathway and showed that intracellular traffic pathways are necessary for the generation of toxic species. (PMID:22888099)
• rs592297, a known coding synonymous SNP that is part of an exonic splice enhancer region in exon 5 of the PICALM gene, is in strong linkage disequilibrium with rs3851179. (PMID:22943764)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	picalma	ENSDARG00000012866
danio_rerio	picalmb	ENSDARG00000014137
mus_musculus	Picalm	ENSMUSG00000039361
rattus_norvegicus	Picalm	ENSRNOG00000018322
drosophila_melanogaster	lap	FBGN0086372
caenorhabditis_elegans	unc-11	WBGENE00006751

Paralogs (1): SNAP91 (ENSG00000065609)

Protein

Protein identifiers

Phosphatidylinositol-binding clathrin assembly protein — Q13492 (reviewed: Q13492)

Alternative names: Clathrin assembly lymphoid myeloid leukemia protein

All UniProt accessions (12): Q13492, E9PI56, E9PJT1, E9PK13, E9PKP6, E9PLJ8, H0YCY1, H0YD48, H0YE97, H0YEF7, H0YEH1, H0YEY8

UniProt curated annotations — full annotation on UniProt →

Function. Cytoplasmic adapter protein that plays a critical role in clathrin-mediated endocytosis which is important in processes such as internalization of cell receptors, synaptic transmission or removal of apoptotic cells. Recruits AP-2 and attaches clathrin triskelions to the cytoplasmic side of plasma membrane leading to clathrin-coated vesicles (CCVs) assembly. Furthermore, regulates clathrin-coated vesicle size and maturation by directly sensing and driving membrane curvature. In addition to binding to clathrin, mediates the endocytosis of small R-SNARES (Soluble NSF Attachment Protein REceptors) between plasma membranes and endosomes including VAMP2, VAMP3, VAMP4, VAMP7 or VAMP8. In turn, PICALM-dependent SNARE endocytosis is required for the formation and maturation of autophagic precursors. Modulates thereby autophagy and the turnover of autophagy substrates such as MAPT/TAU or amyloid precursor protein cleaved C-terminal fragment (APP-CTF).

Subunit / interactions. Binds to clathrin; involves primarily the C-terminal sequences, but the full-length protein is required for full binding capacity. Binds phosphatidylinositol 4,5- bisphosphate. Interacts with PIMREG; this interaction may change the subcellular location into the nucleus. Interacts with AP2A1 (via its alpha-appendage domain). Interacts (via N-terminus) with VAMP2; VAMP3; VAMP7 and VAMP8 (Via N-terminus). Interacts with LC3/MAP1LC3A.

Subcellular location. Cell membrane. Membrane. Clathrin-coated pit. Golgi apparatus. Cytoplasmic vesicle. Clathrin-coated vesicle. Nucleus.

Tissue specificity. Expressed in all tissues examined.

Disease relevance. A chromosomal aberration involving PICALM is found in diffuse histiocytic lymphomas. Translocation t(10;11)(p13;q14) with MLLT10.

Similarity. Belongs to the PICALM/SNAP91 family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q13492-1	1, Type I	yes
Q13492-2	2, Type II
Q13492-3	3
Q13492-4	4
Q13492-5	5

RefSeq proteins (5): NP_001008660, NP_001193875, NP_001193876, NP_001397963, NP_009097* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008942	ENTH_VHS	Homologous_superfamily
IPR011417	ANTH_dom	Domain
IPR013809	ENTH	Domain
IPR014712	ANTH_dom_sf	Homologous_superfamily
IPR045192	AP180-like	Family

Pfam: PF07651

UniProt features (25 total): modified residue 5, splice variant 5, sequence variant 5, sequence conflict 3, region of interest 2, initiator methionine 1, chain 1, cross-link 1, domain 1, site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13492-F1	67.38	0.39

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 (1): 648–649 (breakpoint for translocation to form calm/mllt10 fusion protein)

Post-translational modifications (6): 315, 238, 2, 16, 20, 303

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-432722	Golgi Associated Vesicle Biogenesis
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-9696264	RND3 GTPase cycle

MSigDB gene sets: 484 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, GOBP_DENDRITE_DEVELOPMENT, RNGTGGGC_UNKNOWN, AAGCAAT_MIR137, GOBP_COGNITION, MYOGENIN_Q6, GOBP_BEHAVIOR, PAX4_01, MORF_RAB5A, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, GOBP_VESICLE_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_AMIDE_METABOLIC_PROCESS, GCANCTGNY_MYOD_Q6, GOBP_INTRACELLULAR_IRON_ION_HOMEOSTASIS, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION

GO Biological Process (32): intracellular iron ion homeostasis (GO:0006879), endocytosis (GO:0006897), receptor-mediated endocytosis (GO:0006898), vesicle budding from membrane (GO:0006900), axonogenesis (GO:0007409), learning or memory (GO:0007611), negative regulation of gene expression (GO:0010629), synaptic vesicle maturation (GO:0016188), vesicle-mediated transport (GO:0016192), endosomal transport (GO:0016197), hemopoiesis (GO:0030097), regulation of endocytosis (GO:0030100), receptor internalization (GO:0031623), regulation of protein localization (GO:0032880), vesicle cargo loading (GO:0035459), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of Ras protein signal transduction (GO:0046579), negative regulation of receptor-mediated endocytosis (GO:0048261), clathrin coat assembly (GO:0048268), dendrite morphogenesis (GO:0048813), multicellular organismal-level iron ion homeostasis (GO:0060586), protein-containing complex assembly (GO:0065003), clathrin-dependent endocytosis (GO:0072583), regulation of vesicle size (GO:0097494), membrane bending (GO:0097753), amyloid-beta clearance by transcytosis (GO:0150093), positive regulation of amyloid-beta formation (GO:1902004), regulation of amyloid precursor protein catabolic process (GO:1902991), positive regulation of amyloid precursor protein catabolic process (GO:1902993), negative regulation of protein localization to plasma membrane (GO:1903077), negative regulation of protein localization to cell surface (GO:2000009), regulation of receptor-mediated endocytosis (GO:0048259)

GO Molecular Function (12): SNARE binding (GO:0000149), amyloid-beta binding (GO:0001540), 1-phosphatidylinositol binding (GO:0005545), phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), clathrin binding (GO:0030276), small GTPase binding (GO:0031267), clathrin heavy chain binding (GO:0032050), cadherin binding (GO:0045296), tau protein binding (GO:0048156), low-density lipoprotein particle receptor binding (GO:0050750), protein binding (GO:0005515), phospholipid binding (GO:0005543)

GO Cellular Component (22): nucleus (GO:0005634), early endosome (GO:0005769), Golgi apparatus (GO:0005794), cytosol (GO:0005829), plasma membrane (GO:0005886), clathrin-coated pit (GO:0005905), synaptic vesicle (GO:0008021), cell surface (GO:0009986), membrane (GO:0016020), clathrin coat of coated pit (GO:0030132), clathrin-coated vesicle (GO:0030136), vesicle (GO:0031982), presynaptic membrane (GO:0042734), neuronal cell body (GO:0043025), postsynaptic membrane (GO:0045211), clathrin-coated endocytic vesicle (GO:0045334), perinuclear region of cytoplasm (GO:0048471), endosome to plasma membrane transport vesicle (GO:0070381), neurofibrillary tangle (GO:0097418), extrinsic component of presynaptic endocytic zone membrane (GO:0098894), endomembrane system (GO:0012505), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
trans-Golgi Network Vesicle Budding	1
Clathrin-mediated endocytosis	1
Membrane Trafficking	1
RHO GTPase cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
vesicle-mediated transport	4
cellular anatomical structure	4
cytoplasm	3
endocytosis	2
vesicle organization	2
cell morphogenesis involved in neuron differentiation	2
neuron projection morphogenesis	2
transport	2
receptor-mediated endocytosis	2
protein binding	2
intracellular membrane-bounded organelle	2
endomembrane system	2
membrane	2
exocytic vesicle	2
presynapse	2
synaptic membrane	2
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
vesicle budding from membrane	1
membrane invagination	1
import into cell	1
membrane organization	1
axon development	1
behavior	1
cognition	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
developmental maturation	1
cellular process	1
intracellular transport	1
cell development	1
regulation of cellular component organization	1
regulation of vesicle-mediated transport	1
intracellular protein localization	1
regulation of localization	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
Ras protein signal transduction	1

Protein interactions and networks

STRING

2150 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PICALM	CLU	P10909	924
PICALM	MLLT10	P55197	920
PICALM	BIN1	O00499	885
PICALM	ABCA7	Q8IZY2	873
PICALM	EPN2	O95208	873
PICALM	EPN3	Q9H201	870
PICALM	CD2AP	Q9Y5K6	864
PICALM	EPHA1	P21709	846
PICALM	CLINT1	Q14677	829
PICALM	SORL1	Q92673	823
PICALM	APP	P05067	816
PICALM	MS4A6A	Q9H2W1	789
PICALM	MS4A4E	Q96PG1	774
PICALM	APOE	P02649	773
PICALM	PSEN1	P49768	733
PICALM	PSEN2	P49810	733

IntAct

134 interactions, top by confidence:

A	B	Type	Score
MED17	MED19	psi-mi:“MI:0914”(association)	0.840
YBX1	HNRNPR	psi-mi:“MI:0915”(physical association)	0.770
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
FHL2	PICALM	psi-mi:“MI:0407”(direct interaction)	0.640
PICALM	FHL2	psi-mi:“MI:0915”(physical association)	0.640
PICALM	FHL2	psi-mi:“MI:0403”(colocalization)	0.640
STAMBPL1	PIK3C2A	psi-mi:“MI:0914”(association)	0.640
PIMREG	MTA2	psi-mi:“MI:0914”(association)	0.600
EPS15	PICALM	psi-mi:“MI:0407”(direct interaction)	0.590
CLTB	PIK3C2A	psi-mi:“MI:0914”(association)	0.530
RPN1	APBB1	psi-mi:“MI:0914”(association)	0.530
SNRNP27	UBA6	psi-mi:“MI:0914”(association)	0.530
PICALM	PIK3C2A	psi-mi:“MI:0914”(association)	0.530
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
PIP	TBKBP1	psi-mi:“MI:0914”(association)	0.530
CFTR	CNOT1	psi-mi:“MI:0914”(association)	0.480
PICALM	Necap1	psi-mi:“MI:0407”(direct interaction)	0.440
ICAM3	PICALM	psi-mi:“MI:0915”(physical association)	0.400
PICALM	PELI2	psi-mi:“MI:0915”(physical association)	0.370
PICALM	WNK1	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
ANG	DDX39A	psi-mi:“MI:0914”(association)	0.350
OCRL	MYO1C	psi-mi:“MI:0914”(association)	0.350

BioGRID (344): PICALM (Affinity Capture-MS), PICALM (Affinity Capture-MS), PICALM (Affinity Capture-MS), PICALM (Affinity Capture-MS), PICALM (Affinity Capture-MS), PICALM (Affinity Capture-MS), PICALM (Affinity Capture-MS), PICALM (Affinity Capture-MS), PICALM (Affinity Capture-MS), PICALM (Affinity Capture-RNA), PICALM (Affinity Capture-MS), C14orf166 (Co-fractionation), CARS (Co-fractionation), CPPED1 (Co-fractionation), EEF1A1 (Co-fractionation)

ESM2 similar proteins: A3LX75, A3LXQ8, A5DDB7, G5EDY0, O01498, O13821, O42869, O55012, O60167, O74360, O74749, O75886, O88811, O93436, P32525, P38753, P39081, P40343, P41832, P53238, P70297, Q05080, Q06336, Q07622, Q07872, Q10410, Q13492, Q1E878, Q23356, Q54N00, Q54XE8, Q59WD5, Q5A895, Q5AAF4, Q5AL52, Q5XHY7, Q6BNP6, Q6BSD6, Q6CL17, Q6CVA8

Diamond homologs: O55012, O60167, O60641, Q05140, Q13492, Q61548, Q7M6Y3, Q9VI75, Q9XZI6, P38856, P53309, Q8LBH2, Q9LVD8

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
PIMREG	down-regulates	PICALM	relocalization
PICALM	up-regulates	CLTC	binding
PICALM	up-regulates	CLTCL1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 153 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
PD-L1(CD274) glycosylation and translocation to plasma membrane	7	33.6×	2e-07
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	9	28.0×	6e-09
Maturation of spike protein	8	19.7×	7e-07
Maturation of DENV proteins	7	13.7×	7e-05
Clathrin-mediated endocytosis	15	11.8×	1e-09
Cargo recognition for clathrin-mediated endocytosis	11	10.7×	7e-07
Asparagine N-linked glycosylation	11	6.1×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
obsolete protein N-linked glycosylation via asparagine	7	34.4×	9e-07
clathrin coat assembly	5	32.4×	9e-05
protein N-linked glycosylation	8	15.4×	2e-05
endocytosis	12	8.3×	1e-05

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — WDTC.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	56
Likely benign	6
Benign	38

Top pathogenic / likely-pathogenic (0)

SpliceAI

4400 predictions. Top by Δscore:

Variant	Effect	Δscore
11:85960727:T:A	donor_gain	1.0000
11:85962273:A:AC	donor_gain	1.0000
11:85962274:C:CC	donor_gain	1.0000
11:85980769:T:C	donor_gain	1.0000
11:85981224:CATCA:C	acceptor_gain	1.0000
11:85981226:TCA:T	acceptor_gain	1.0000
11:85981227:CA:C	acceptor_gain	1.0000
11:85981227:CAC:C	acceptor_gain	1.0000
11:85981229:C:CC	acceptor_gain	1.0000
11:85981230:T:C	acceptor_gain	1.0000
11:85981231:T:C	acceptor_gain	1.0000
11:85981741:TCA:T	donor_loss	1.0000
11:85981743:A:AC	donor_gain	1.0000
11:85981743:ACTT:A	donor_gain	1.0000
11:85981744:C:CA	donor_gain	1.0000
11:85981744:CT:C	donor_gain	1.0000
11:85981744:CTT:C	donor_gain	1.0000
11:85981744:CTTC:C	donor_gain	1.0000
11:85981746:T:TA	donor_gain	1.0000
11:85981771:AAGAT:A	acceptor_gain	1.0000
11:85981772:AGAT:A	acceptor_gain	1.0000
11:85981773:GAT:G	acceptor_gain	1.0000
11:85981773:GATC:G	acceptor_loss	1.0000
11:85981774:AT:A	acceptor_gain	1.0000
11:85981775:TC:T	acceptor_loss	1.0000
11:85981776:C:CA	acceptor_loss	1.0000
11:85981776:C:CC	acceptor_gain	1.0000
11:85981870:A:AC	donor_gain	1.0000
11:85981870:ACTG:A	donor_gain	1.0000
11:85981870:ACTGC:A	donor_gain	1.0000

AlphaMissense

4296 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:85981880:A:G	L547P	1.000
11:86003417:T:G	H281P	1.000
11:86003418:G:C	H281D	1.000
11:86003426:A:C	L278W	1.000
11:86003426:A:G	L278S	1.000
11:86003438:A:G	L274P	1.000
11:86003438:A:T	L274H	1.000
11:86011073:A:G	L241P	1.000
11:86011075:G:C	F240L	1.000
11:86011075:G:T	F240L	1.000
11:86011077:A:G	F240L	1.000
11:86011094:A:G	L234P	1.000
11:86011105:G:C	C230W	1.000
11:86011126:A:C	F223L	1.000
11:86011126:A:T	F223L	1.000
11:86011128:A:G	F223L	1.000
11:86026348:G:T	A98D	1.000
11:86031528:A:G	W72R	1.000
11:86031528:A:T	W72R	1.000
11:86068743:G:T	A13D	1.000
11:86068755:C:G	R9P	1.000
11:85981889:A:G	L544S	0.999
11:86003412:C:G	A283P	0.999
11:86003416:A:C	H281Q	0.999
11:86003416:A:T	H281Q	0.999
11:86003430:C:G	A277P	0.999
11:86003435:A:G	L275P	0.999
11:86003447:G:A	P271L	0.999
11:86003447:G:C	P271R	0.999
11:86003447:G:T	P271H	0.999

dbSNP variants (sampled 300 via entrez): RS1000001718 (11:85971328 G>A), RS1000004003 (11:86067250 C>A,G), RS1000024741 (11:86018284 A>T), RS1000054863 (11:86011206 T>C,G), RS1000077709 (11:85978978 G>C), RS1000101961 (11:85965484 G>A), RS1000136981 (11:86051511 A>G), RS1000243955 (11:85988753 G>A), RS1000306957 (11:86029230 C>T), RS1000312616 (11:86022860 A>G), RS1000322477 (11:85991223 G>A), RS1000336289 (11:86029719 AAAGAAG>A,AAAG), RS1000365123 (11:86023032 T>C), RS1000372545 (11:85971004 G>C,T), RS1000416755 (11:86049858 C>G,T)

Disease associations

OMIM: gene MIM:603025 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

3 total (3 of 3 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001442	Typified by somatic mosaicism
HP:0004808	Acute myeloid leukemia

GWAS associations

26 associations (top):

Study	Trait	p-value
GCST000479_2	Alzheimer’s disease	1.000000e-09
GCST001026_5	Alzheimer’s disease (late onset)	7.000000e-11
GCST001087_3	Alzheimer’s disease	3.000000e-09
GCST001529_6	Alzheimer’s disease	2.000000e-08
GCST001635_3	Tourette syndrome	9.000000e-06
GCST002245_11	Alzheimer’s disease (late onset)	9.000000e-26
GCST002813_1	Alzheimer’s disease in APOE e4+ carriers	4.000000e-06
GCST002813_7	Alzheimer’s disease in APOE e4+ carriers	1.000000e-07
GCST002813_8	Alzheimer’s disease in APOE e4+ carriers	3.000000e-08
GCST002817_13	Alzheimer’s disease in APOE e4- carriers	2.000000e-06
GCST003461_1	IgG response to Plasmodium falciparum antigens (GLURP, MSP2 FC27, MSP2 3D7)	6.000000e-06
GCST004603_62	Platelet count	4.000000e-09
GCST007319_23	Alzheimer’s disease (late onset)	1.000000e-17
GCST007320_72	Alzheimer’s disease or family history of Alzheimer’s disease	2.000000e-18
GCST007320_95	Alzheimer’s disease or family history of Alzheimer’s disease	7.000000e-18
GCST007321_1	Family history of Alzheimer’s disease	6.000000e-09
GCST007321_28	Family history of Alzheimer’s disease	5.000000e-11
GCST007692_29	Chronic obstructive pulmonary disease	1.000000e-06
GCST007827_15	Alzheimer’s disease or HDL levels (pleiotropy)	1.000000e-14
GCST009019_3	Alzheimer’s disease	2.000000e-11
GCST009021_4	Alzheimer’s disease	4.000000e-18
GCST009496_12	Alzheimer’s disease (onset between ages 58 and 79)	1.000000e-08
GCST010002_244	Refractive error	2.000000e-53
GCST010397_48	Gut microbiota (bacterial taxa, rank normal transformation method)	3.000000e-06
GCST90002395_96	Mean platelet volume	2.000000e-11
GCST90002402_383	Platelet count	5.000000e-17

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007812	Plasmodium falciparum antigen IgG measurement
EFO:0004309	platelet count
EFO:0009268	family history of Alzheimer’s disease
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0007874	gut microbiome measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067239 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs588076	Efficacy	3	Calcium channel blockers	Hypertension

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs588076	PICALM	3	2.25	1	Calcium channel blockers

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression, affects cotreatment, affects expression, increases abundance	4
Valproic Acid	increases expression	3
methylmercuric chloride	increases expression, affects cotreatment	2
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
nickel sulfate	increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
ginger extract	affects cotreatment, affects expression, increases abundance	1
beta-N-methylamino-L-alanine	decreases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression, decreases expression	1
trichostatin A	affects expression	1
tetrahydropalmatine	increases expression	1
beta-lapachone	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
coumarin	increases phosphorylation	1
cupric oxide	increases expression	1
1-nitropyrene	increases expression	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
calfactant	affects cotreatment, increases expression	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol B	increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, increases 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
CHEMBL5652045	Binding	Binding affinity to human PICALM 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

56 cell lines: 55 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0007	U-937	Cancer cell line	Male
CVCL_1775	TUR	Cancer cell line	Male
CVCL_2082	JOSK-I	Cancer cell line	Male
CVCL_2083	JOSK-M	Cancer cell line	Male
CVCL_2810	U-937 cl1-14	Cancer cell line	Male
CVCL_2811	U-937 cl1-22	Cancer cell line	Male
CVCL_2Z95	U937-DC-SIGN	Cancer cell line	Male
CVCL_3680	EL 1	Cancer cell line	Male
CVCL_4V23	U937/ara-C	Cancer cell line	Male
CVCL_6444	SC [Human contaminated U-937]	Cancer cell line	Male

Clinical trials (associated diseases)

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