APPL2

Summary

APPL2 (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 2, HGNC:18242) is a protein-coding gene on chromosome 12q23.3, encoding DCC-interacting protein 13-beta (Q8NEU8). Multifunctional adapter protein that binds to various membrane receptors, nuclear factors and signaling proteins to regulate many processes, such as cell proliferation, immune response, endosomal trafficking and cell metabolism.

The protein encoded by this gene is one of two effectors of the small GTPase RAB5A/Rab5, which are involved in a signal transduction pathway. Both effectors contain an N-terminal Bin/Amphiphysin/Rvs (BAR) domain, a central pleckstrin homology (PH) domain, and a C-terminal phosphotyrosine binding (PTB) domain, and they bind the Rab5 through the BAR domain. They are associated with endosomal membranes and can be translocated to the nucleus in response to the EGF stimulus. They interact with the NuRD/MeCP1 complex (nucleosome remodeling and deacetylase /methyl-CpG-binding protein 1 complex) and are required for efficient cell proliferation. A chromosomal aberration t(12;22)(q24.1;q13.3) involving this gene and the PSAP2 gene results in 22q13.3 deletion syndrome, also known as Phelan-McDermid syndrome.

Source: NCBI Gene 55198 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 113 total
• MANE Select transcript: NM_018171

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18242
Approved symbol	APPL2
Name	adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 2
Location	12q23.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10659, DIP13B
Ensembl gene	ENSG00000136044
Ensembl biotype	protein_coding
OMIM	606231
Entrez	55198

Gene structure

Transcript identifiers

Ensembl transcripts: 44 — 35 protein_coding, 5 retained_intron, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000258530, ENST00000539978, ENST00000546731, ENST00000546768, ENST00000547439, ENST00000547790, ENST00000547809, ENST00000548425, ENST00000549056, ENST00000549573, ENST00000549974, ENST00000550648, ENST00000551662, ENST00000552945, ENST00000553097, ENST00000553109, ENST00000862266, ENST00000862267, ENST00000862268, ENST00000862269, ENST00000862270, ENST00000862271, ENST00000862272, ENST00000862273, ENST00000862274, ENST00000862275, ENST00000862276, ENST00000862277, ENST00000862278, ENST00000862279, ENST00000862280, ENST00000862281, ENST00000862282, ENST00000919694, ENST00000967974, ENST00000967975, ENST00000967976, ENST00000967977, ENST00000967978, ENST00000967979, ENST00000967980, ENST00000967981, ENST00000967982, ENST00000967983

RefSeq mRNA: 3 — MANE Select: NM_018171 NM_001251904, NM_001251905, NM_018171

CCDS: CCDS58275, CCDS58276, CCDS9101

Canonical transcript exons

ENST00000258530 — 21 exons

Exon	Start	End
ENSE00001350023	105235959	105236174
ENSE00002367052	105173300	105174448
ENSE00003492445	105189991	105190155
ENSE00003493222	105189772	105189824
ENSE00003501040	105229125	105229223
ENSE00003527948	105217069	105217140
ENSE00003550517	105195585	105195627
ENSE00003555445	105207061	105207207
ENSE00003591410	105176035	105176082
ENSE00003605866	105207971	105208029
ENSE00003606430	105197765	105197953
ENSE00003609369	105217666	105217725
ENSE00003614169	105208158	105208199
ENSE00003619723	105195261	105195349
ENSE00003626180	105195445	105195501
ENSE00003631122	105203703	105203785
ENSE00003640144	105177226	105177262
ENSE00003656932	105211230	105211317
ENSE00003658464	105199373	105199531
ENSE00003676940	105188273	105188447
ENSE00003688265	105176876	105177016

Expression profiles

Bgee: expression breadth ubiquitous, 265 present calls, max score 97.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.8238 / max 310.2371, expressed in 1796 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
133032	13.3142	1748
133033	2.8154	1187
133031	1.1620	731
133034	0.4463	229
133030	0.0859	43

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skin of leg	UBERON:0001511	97.43	gold quality
skin of abdomen	UBERON:0001416	97.39	gold quality
rectum	UBERON:0001052	97.25	gold quality
mucosa of transverse colon	UBERON:0004991	96.97	gold quality
ventricular zone	UBERON:0003053	96.66	gold quality
calcaneal tendon	UBERON:0003701	96.66	gold quality
stromal cell of endometrium	CL:0002255	96.57	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.30	gold quality
transverse colon	UBERON:0001157	96.12	gold quality
endocervix	UBERON:0000458	96.04	gold quality
ectocervix	UBERON:0012249	95.99	gold quality
bronchial epithelial cell	CL:0002328	95.84	gold quality
ganglionic eminence	UBERON:0004023	95.81	gold quality
adrenal tissue	UBERON:0018303	95.78	gold quality
right ovary	UBERON:0002118	95.67	gold quality
body of uterus	UBERON:0009853	95.67	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.67	gold quality
tibial nerve	UBERON:0001323	95.54	gold quality
right uterine tube	UBERON:0001302	95.43	gold quality
left ovary	UBERON:0002119	95.37	gold quality
cerebellar hemisphere	UBERON:0002245	95.35	gold quality
right testis	UBERON:0004534	95.34	gold quality
gall bladder	UBERON:0002110	95.32	gold quality
mucosa of stomach	UBERON:0001199	95.31	gold quality
body of pancreas	UBERON:0001150	95.27	gold quality
zone of skin	UBERON:0000014	95.25	gold quality
cerebellar cortex	UBERON:0002129	95.19	gold quality
right adrenal gland	UBERON:0001233	95.13	gold quality
right adrenal gland cortex	UBERON:0035827	95.02	gold quality
right lung	UBERON:0002167	94.97	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.36

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

73 targeting APPL2, 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-4776-3P	100.00	68.73	1340
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-24-3P	99.59	69.97	1934

Literature-anchored findings (GeneRIF, showing 16)

• identification of a pathway directly linking the small GTPase Rab5, a key regulator of endocytosis, to signal transduction and mitogenesis via APPL1 and APPL2, two Rab5 effectors (PMID:15016378)
• The findings suggest a role for APPL1 and APPL2 protein as dynamic scaffolds that modulate RAB5-associated signaling endosomal membranes by their ability to undergo domain-mediated oligomerization, membrane targeting and phosphoinositide binding. (PMID:18034774)
• APPL proteins exert their stimulatory effects on beta-catenin/TCF-dependent transcription by decreasing the activity of a Reptin-containing repressive complex (PMID:19433865)
• significant fluorescence resonance energy transfer between APPL minimal BAR domain FRET pairs (PMID:20814572)
• Data suggest that although annexin A2 is not an exclusive marker of APPL1/2 endosomes, it has an important function in membrane recruitment of APPL proteins, acting in parallel to Rab5. (PMID:21645192)
• Genetic variation(s) in APPL1/2 may be associated with CAD risk in T2DM in Chinese population. (PMID:22340213)
• found significant evidence of association with overweight/obesity for rs2272495 and rs1107756. rs2272495 C allele and rs1107756 T allele both conferred a higher risk of being overweight and obese. (PMID:22462604)
• Data indicate that a high level of APPL2 protein might enhance glioblastoma growth by maintaining low expression level of genes responsible for cell death induction. (PMID:22989406)
• analysis of APPL1 and APPL2 proteins and their interaction with Rab (PMID:23055524)
• It concludes that APPL2(PH) binding to BAR domain and Reptin is mutually exclusive which regulates the nucleocytoplasmic shuttling of Reptin. (PMID:23891720)
• C-APPL1/A-APPL2 allele combination is associated with non-alcoholic fatty liver disease occurrence, with a more severe hepatic steatosis grade and with a reduced adiponectin cytoprotective effect on liver. (PMID:23977033)
• ATM is the central modulator of APPL-mediated effects on radiosensitivity and DNA repair. (PMID:24763056)
• Data show that signal transducing adaptor proteins APPL1 and APPL2 are required for TGFbeta-induced nuclear translocation of TGFbeta type I receptor (TbetaRI)-ICD and for cancer cell invasiveness of prostate and breast cancer cell lines. (PMID:26583432)
• Results show the suppressive effect of OCC-1 RNA on transcription level of the APPL2 gene provides a putative colorectal neoplasm progression index. (PMID:27986894)
• A negative correlation of expression is evident between APPL2 and OCC-1 genes in breast cancer specimen. Unlike OCC-1A/B which encodes a small protein, OCC-1D noncoding RNA overexpression lead to APPL2 downregulation in MCF7 cells. (PMID:30218350)
• The adaptor protein APPL2 controls glucose-stimulated insulin secretion via F-actin remodeling in pancreatic beta-cells. (PMID:33122440)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	APPL2	ENSDARG00000078139
mus_musculus	Appl2	ENSMUSG00000020263
rattus_norvegicus	Appl2	ENSRNOG00000008174

Paralogs (28): ARAP2 (ENSG00000047365), ACAP1 (ENSG00000072818), SMAP2 (ENSG00000084070), ASAP3 (ENSG00000088280), ARFGAP1 (ENSG00000101199), ADAP1 (ENSG00000105963), AGFG2 (ENSG00000106351), GIT1 (ENSG00000108262), SMAP1 (ENSG00000112305), ACAP2 (ENSG00000114331), ARAP3 (ENSG00000120318), ACAP3 (ENSG00000131584), AGAP3 (ENSG00000133612), AGAP2 (ENSG00000135439), GIT2 (ENSG00000139436), ARFGAP2 (ENSG00000149182), ASAP2 (ENSG00000151693), ASAP1 (ENSG00000153317), APPL1 (ENSG00000157500), AGAP1 (ENSG00000157985), AGAP5 (ENSG00000172650), AGFG1 (ENSG00000173744), ADAP2 (ENSG00000184060), ARAP1 (ENSG00000186635), AGAP4 (ENSG00000188234), AGAP6 (ENSG00000204149), AGAP9 (ENSG00000204172), ARFGAP3 (ENSG00000242247)

Protein

Protein identifiers

DCC-interacting protein 13-beta — Q8NEU8 (reviewed: Q8NEU8)

Alternative names: Adapter protein containing PH domain, PTB domain and leucine zipper motif 2

All UniProt accessions (7): Q8NEU8, F8VR68, F8VS86, F8VWV2, F8VXB0, F8W124, H0YH86

UniProt curated annotations — full annotation on UniProt →

Function. Multifunctional adapter protein that binds to various membrane receptors, nuclear factors and signaling proteins to regulate many processes, such as cell proliferation, immune response, endosomal trafficking and cell metabolism. Regulates signaling pathway leading to cell proliferation through interaction with RAB5A and subunits of the NuRD/MeCP1 complex. Plays a role in immune response by modulating phagocytosis, inflammatory and innate immune responses. In macrophages, enhances Fc-gamma receptor-mediated phagocytosis through interaction with RAB31 leading to activation of PI3K/Akt signaling. In response to LPS, modulates inflammatory responses by playing a key role on the regulation of TLR4 signaling and in the nuclear translocation of RELA/NF-kappa-B p65 and the secretion of pro- and anti-inflammatory cytokines. Also functions as a negative regulator of innate immune response via inhibition of AKT1 signaling pathway by forming a complex with APPL1 and PIK3R1. Plays a role in endosomal trafficking of TGFBR1 from the endosomes to the nucleus. Plays a role in cell metabolism by regulating adiponecting and insulin signaling pathways and adaptative thermogenesis. In muscle, negatively regulates adiponectin-simulated glucose uptake and fatty acid oxidation by inhibiting adiponectin signaling pathway through APPL1 sequestration thereby antagonizing APPL1 action. In muscles, negatively regulates insulin-induced plasma membrane recruitment of GLUT4 and glucose uptake through interaction with TBC1D1. Plays a role in cold and diet-induced adaptive thermogenesis by activating ventromedial hypothalamus (VMH) neurons throught AMPK inhibition which enhances sympathetic outflow to subcutaneous white adipose tissue (sWAT), sWAT beiging and cold tolerance. Also plays a role in other signaling pathways namely Wnt/beta-catenin, HGF and glucocorticoid receptor signaling. Positive regulator of beta-catenin/TCF-dependent transcription through direct interaction with RUVBL2/reptin resulting in the relief of RUVBL2-mediated repression of beta-catenin/TCF target genes by modulating the interactions within the beta-catenin-reptin-HDAC complex. May affect adult neurogenesis in hippocampus and olfactory system via regulating the sensitivity of glucocorticoid receptor. Required for fibroblast migration through HGF cell signaling.

Subunit / interactions. Homodimer. Homotetramer. Binds RAB5A/Rab5 through an N-terminal domain. This interaction is essential for its recruitment to endosomal membranes as well as its role in cell proliferation. Binds subunits of the NuRD/MeCP1 complex. Interacts with FSHR; interaction is independent of follicle stimulating hormone stimulation. Interacts with APPL1; the interaction is decreased by adiponectin in a time-dependent manner. Forms a complex comprising APPL1, RUVBL2, CTNNB1, HDAC1 and HDAC2; interaction reduces interaction between CTNNB1, HDAC1, HDAC2 and RUVBL2 leading to the decrease of deacetylase activity of this complex; affects the recruitment of repressive complexes to the Wnt target genes. Interacts (via BAR domain) with TBC1D1; interaction is dependent of TBC1D1 phosphorylation at ‘Ser-235’; interaction diminishes the phosphorylation of TBC1D1 at ‘Thr-596’, resulting in inhibition of SLC2A4 translocation and glucose uptake. Interacts with ANXA2; targets APPL2 to endosomes and acting in parallel to RAB5A. Interacts with RAB31 (in GTP-bound form); interaction contributes to or enhances recruitment of APPL2 to the phagosomes; interaction enhances Fc-gamma receptor-mediated phagocytosis through PI3K/Akt signaling in macrophages. Interacts with PIK3R1; forms a complex with PIK3R1 and APPL1. Interacts (via BAR domain) with ADIPOR1; hinders the accessibility of APPL1 to ADIPOR1; negatively regulates adiponectin signaling; ADIPOQ dissociates this interaction and facilitates the recruitment of APPL1 to ADIPOR1. Interacts (via BAR domain) with ADIPOR2; ADIPOQ dissociates this interaction.

Subcellular location. Early endosome membrane. Nucleus. Cell membrane. Endosome membrane. Cytoplasm. Cytoplasmic vesicle. Phagosome. Cell projection. Ruffle. Ruffle membrane. Phagosome membrane.

Tissue specificity. High levels in brain, heart, kidney and skeletal muscle.

Disease relevance. A chromosomal aberration involving APPL2/DIP13B is found in patients with chromosome 22q13.3 deletion syndrome. Translocation t(12;22)(q24.1;q13.3) with SHANK3/PSAP2.

Domain organisation. The BAR domain is necessary and sufficient for mediating homotypic and heterotypic interactions; associates with cytoplasmic membrane structures; mediates interaction with TBC1D1 and ADIPOR1. The PH and PID domains mediate phosphoinositide binding. The PID domain mediates phosphatidylserine binding and allows localization to cytosolic membrane structures and nucleus. The PH domain allows localization to the plasma membrane, cytosolic vesicles and distinct nuclear and perinuclear structures and is sufficient for RUVBL2 interaction.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8NEU8-1	1	yes
Q8NEU8-2	2
Q8NEU8-3	3

RefSeq proteins (3): NP_001238833, NP_001238834, NP_060641* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001849	PH_domain	Domain
IPR004148	BAR_dom	Domain
IPR006020	PTB/PI_dom	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR027267	AH/BAR_dom_sf	Homologous_superfamily
IPR047181	DP13A/B	Family
IPR047236	PH_DP13A/B	Domain
IPR047237	PTB_APPL	Domain
IPR047239	BAR_APPL2	Domain

Pfam: PF00169, PF00640, PF16746

UniProt features (34 total): helix 9, strand 9, sequence conflict 4, domain 3, region of interest 2, splice variant 2, chain 1, sequence variant 1, turn 1, compositionally biased region 1, site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
5C5B	X-RAY DIFFRACTION	2.9
4H8S	X-RAY DIFFRACTION	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NEU8-F1	82.09	0.61

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): 234–235 (breakpoint for chromosomal translocation)

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 450 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, GGGACCA_MIR133A_MIR133B, GOBP_LIPID_MODIFICATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_CARBOHYDRATE_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_PINOCYTOSIS, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_RESPONSE_TO_COLD, LU_IL4_SIGNALING, GOBP_PROTEIN_HOMOTETRAMERIZATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE

GO Biological Process (25): diet induced thermogenesis (GO:0002024), protein import into nucleus (GO:0006606), signal transduction (GO:0007165), transforming growth factor beta receptor signaling pathway (GO:0007179), cold acclimation (GO:0009631), regulation of fibroblast migration (GO:0010762), signaling (GO:0023052), adiponectin-activated signaling pathway (GO:0033211), regulation of toll-like receptor 4 signaling pathway (GO:0034143), cellular response to hepatocyte growth factor stimulus (GO:0035729), glucose homeostasis (GO:0042593), regulation of innate immune response (GO:0045088), negative regulation of fatty acid oxidation (GO:0046322), negative regulation of D-glucose import across plasma membrane (GO:0046325), negative regulation of neurogenesis (GO:0050768), protein homotetramerization (GO:0051289), positive regulation of phagocytosis, engulfment (GO:0060100), positive regulation of cold-induced thermogenesis (GO:0120162), negative regulation of cytokine production involved in inflammatory response (GO:1900016), negative regulation of cellular response to insulin stimulus (GO:1900077), positive regulation of macropinocytosis (GO:1905303), positive regulation of Fc-gamma receptor signaling pathway involved in phagocytosis (GO:1905451), regulation of G1/S transition of mitotic cell cycle (GO:2000045), negative regulation of neural precursor cell proliferation (GO:2000178), homeostatic process (GO:0042592)

GO Molecular Function (6): phosphatidylserine binding (GO:0001786), phosphatidylinositol binding (GO:0035091), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein-containing complex binding (GO:0044877), protein binding (GO:0005515)

GO Cellular Component (20): ruffle (GO:0001726), nucleus (GO:0005634), endosome (GO:0005768), plasma membrane (GO:0005886), endosome membrane (GO:0010008), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), early endosome membrane (GO:0031901), vesicle (GO:0031982), early phagosome (GO:0032009), ruffle membrane (GO:0032587), early phagosome membrane (GO:0036186), macropinosome (GO:0044354), extracellular exosome (GO:0070062), cytoplasm (GO:0005737), cytoplasmic vesicle membrane (GO:0030659), phagocytic vesicle membrane (GO:0030670), cell projection (GO:0042995), phagocytic vesicle (GO:0045335), bounding membrane of organelle (GO:0098588)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
anion binding	2
binding	2
cytoplasmic vesicle	2
phagocytic vesicle	2
response to dietary excess	1
adaptive thermogenesis	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cellular response to transforming growth factor beta stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
response to cold	1
fibroblast migration	1
regulation of cell migration	1
regulation of biological process	1
hormone-mediated signaling pathway	1
cytokine-mediated signaling pathway	1
toll-like receptor 4 signaling pathway	1
regulation of pattern recognition receptor signaling pathway	1
response to hepatocyte growth factor	1
cellular response to growth factor stimulus	1
carbohydrate homeostasis	1
regulation of response to biotic stimulus	1
regulation of defense response	1
regulation of response to external stimulus	1
innate immune response	1
regulation of immune response	1
fatty acid oxidation	1
negative regulation of fatty acid metabolic process	1
regulation of fatty acid oxidation	1
negative regulation of D-glucose transmembrane transport	1
regulation of D-glucose import across plasma membrane	1
D-glucose import across plasma membrane	1

Protein interactions and networks

STRING

864 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
APPL2	RABL2B	Q9UNT1	895
APPL2	RABL2A	Q9UBK7	895
APPL2	SHANK3	Q9BYB0	861
APPL2	ADIPOR2	Q86V24	621
APPL2	ALG12	Q9BV10	584
APPL2	C2orf42	Q9NWW7	510
APPL2	PGM2L1	Q6PCE3	510
APPL2	SMAP2	Q8WU79	489
APPL2	RAB5A	P20339	485
APPL2	SLC25A42	Q86VD7	432
APPL2	PIM3	Q86V86	429
APPL2	SHANK2	Q9UPX8	423
APPL2	TMEM161A	Q9NX61	419
APPL2	ADIPOR1	Q96A54	400
APPL2	MYBBP1A	Q9BQG0	387

IntAct

143 interactions, top by confidence:

A	B	Type	Score
APPL2	APPL1	psi-mi:“MI:0915”(physical association)	0.960
APPL1	APPL2	psi-mi:“MI:0915”(physical association)	0.960
APPL2	APPL1	psi-mi:“MI:0403”(colocalization)	0.960
APPL1	APPL2	psi-mi:“MI:0403”(colocalization)	0.960
APPL2	RAB22A	psi-mi:“MI:0915”(physical association)	0.830
RAB22A	APPL2	psi-mi:“MI:0915”(physical association)	0.830
RAB5C	APPL2	psi-mi:“MI:0915”(physical association)	0.780
APPL2	RAB5C	psi-mi:“MI:0915”(physical association)	0.780

BioGRID (106): APPL2 (Two-hybrid), APPL2 (Two-hybrid), APPL2 (Two-hybrid), RAB22A (Two-hybrid), SUV39H2 (Two-hybrid), APPL2 (Two-hybrid), RAB22A (Two-hybrid), APPL2 (Affinity Capture-MS), MLST8 (Two-hybrid), LGALS9C (Two-hybrid), LIX1 (Two-hybrid), KMT2C (Two-hybrid), MAPRE3 (Two-hybrid), C17orf82 (Two-hybrid), DOK3 (Two-hybrid)

ESM2 similar proteins: A0JN62, A2RT67, A2RUS2, A2VDU2, A4IFB6, A4IIM3, A7MBL8, B1H2P5, B4F779, O94967, P48553, Q08CL8, Q0VEJ0, Q14161, Q15650, Q3TLI0, Q4R350, Q5RAQ5, Q5RCP7, Q5RDV5, Q5TKA1, Q5XIA4, Q5ZIW2, Q5ZJK1, Q68CZ1, Q6AYF1, Q6QD73, Q7TSG1, Q7ZYH1, Q8BH15, Q8BIK4, Q8BKH7, Q8C735, Q8CG73, Q8CGF6, Q8IWR0, Q8IZQ1, Q8N6S4, Q8N960, Q8NEU8

Diamond homologs: B4F779, Q8K3G9, Q8K3H0, Q8NEU8, Q9UKG1

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 67 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
RNA Polymerase III Transcription Initiation From Type 2 Promoter	5	44.1×	1e-05
RNA Polymerase III Transcription Initiation From Type 1 Promoter	5	42.5×	1e-05
RNA Polymerase III Transcription Initiation From Type 3 Promoter	5	42.5×	1e-05
RNA Polymerase III Transcription Initiation	5	35.0×	3e-05
RNA Polymerase III Transcription	5	34.0×	3e-05
RNA Polymerase III Abortive And Retractive Initiation	5	29.0×	5e-05
Clathrin-mediated endocytosis	6	10.7×	1e-03
PIP3 activates AKT signaling	6	8.3×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
endocytosis	7	11.9×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	90
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3227 predictions. Top by Δscore:

Variant	Effect	Δscore
12:105176912:A:AC	donor_gain	1.0000
12:105176913:C:CC	donor_gain	1.0000
12:105176917:G:C	donor_gain	1.0000
12:105190152:CTGG:C	acceptor_gain	1.0000
12:105190153:TGG:T	acceptor_gain	1.0000
12:105190156:C:CC	acceptor_gain	1.0000
12:105195498:TCCA:T	acceptor_gain	1.0000
12:105195499:CCA:C	acceptor_gain	1.0000
12:105195499:CCAC:C	acceptor_gain	1.0000
12:105195500:CA:C	acceptor_gain	1.0000
12:105195500:CAC:C	acceptor_gain	1.0000
12:105195502:C:CC	acceptor_gain	1.0000
12:105199371:A:AC	donor_gain	1.0000
12:105199372:C:CC	donor_gain	1.0000
12:105199372:CTTT:C	donor_gain	1.0000
12:105199375:T:A	donor_gain	1.0000
12:105207055:CCCTA:C	donor_loss	1.0000
12:105207056:CCTAC:C	donor_loss	1.0000
12:105207057:CTA:C	donor_loss	1.0000
12:105207058:TAC:T	donor_loss	1.0000
12:105207059:ACCT:A	donor_loss	1.0000
12:105207207:CCTGG:C	acceptor_loss	1.0000
12:105207208:C:CC	acceptor_gain	1.0000
12:105207209:T:C	acceptor_loss	1.0000
12:105207211:G:GC	acceptor_gain	1.0000
12:105207212:T:C	acceptor_gain	1.0000
12:105207212:T:TC	acceptor_gain	1.0000
12:105211226:TTA:T	donor_loss	1.0000
12:105211227:TA:T	donor_loss	1.0000
12:105211228:ACC:A	donor_loss	1.0000

AlphaMissense

4404 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:105188336:C:G	R524P	1.000
12:105188408:C:T	G500E	1.000
12:105195499:C:A	W366C	1.000
12:105195499:C:G	W366C	1.000
12:105195501:A:G	W366R	1.000
12:105195501:A:T	W366R	1.000
12:105195616:A:G	L355P	1.000
12:105197804:C:G	R338P	1.000
12:105197891:A:G	L309P	1.000
12:105197926:C:A	W297C	1.000
12:105197926:C:G	W297C	1.000
12:105197928:A:G	W297R	1.000
12:105197928:A:T	W297R	1.000
12:105199385:A:G	L284P	1.000
12:105176958:C:T	G577D	0.999
12:105176959:C:G	G577R	0.999
12:105188297:A:G	L537P	0.999
12:105188334:C:G	A525P	0.999
12:105188339:G:T	A523D	0.999
12:105188340:C:G	A523P	0.999
12:105188409:C:G	G500R	0.999
12:105188409:C:T	G500R	0.999
12:105188417:C:G	R497P	0.999
12:105190041:G:C	F452L	0.999
12:105190041:G:T	F452L	0.999
12:105190042:A:G	F452S	0.999
12:105190043:A:G	F452L	0.999
12:105190048:A:T	I450N	0.999
12:105195500:C:G	W366S	0.999
12:105195613:T:G	Q356P	0.999

dbSNP variants (sampled 300 via entrez): RS1000063575 (12:105232252 C>G,T), RS1000247758 (12:105213610 T>C), RS1000327100 (12:105203337 T>C,G), RS1000370326 (12:105201929 C>CT), RS1000405220 (12:105174628 G>T), RS1000421560 (12:105208307 C>T), RS1000472585 (12:105218070 T>G), RS1000476933 (12:105214357 C>A), RS1000545648 (12:105218418 A>G), RS1000547390 (12:105189715 A>C), RS1000601188 (12:105190195 T>C), RS1000667449 (12:105230795 C>G,T), RS1000756955 (12:105175436 T>C), RS1000764640 (12:105214132 G>A), RS1000773090 (12:105236303 C>G,T)

Disease associations

OMIM: gene MIM:606231 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST004863_63	Mosquito bite size	7.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008378	mosquito bite reaction size measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression	3
sodium arsenite	decreases expression, increases expression	3
Arsenic	decreases methylation, increases abundance, decreases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
geldanamycin	increases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	increases abundance, decreases expression	1
cobaltous chloride	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
7-(benzylamino)-1,3,4,8-tetrahydropyrrolo(4,3,2-de)quinolin-8(1H)-one	decreases expression	1
Temozolomide	decreases expression	1
Vorinostat	decreases expression	1
Air Pollutants, Occupational	affects expression	1
Cadmium	increases abundance, increases expression	1
Cisplatin	increases expression	1
Dimethyl Sulfoxide	increases expression	1
Doxorubicin	decreases expression	1

Clinical trials (associated diseases)

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