APLP2

Summary

APLP2 (amyloid beta precursor like protein 2, HGNC:598) is a protein-coding gene on chromosome 11q24.3, encoding Amyloid beta precursor like protein 2 (Q06481). May play a role in the regulation of hemostasis.

This gene encodes amyloid precursor- like protein 2 (APLP2), which is a member of the APP (amyloid precursor protein) family including APP, APLP1 and APLP2. This protein is ubiquitously expressed. It contains heparin-, copper- and zinc- binding domains at the N-terminus, BPTI/Kunitz inhibitor and E2 domains in the middle region, and transmembrane and intracellular domains at the C-terminus. This protein interacts with major histocompatibility complex (MHC) class I molecules. The synergy of this protein and the APP is required to mediate neuromuscular transmission, spatial learning and synaptic plasticity. This protein has been implicated in the pathogenesis of Alzheimer’s disease. Multiple alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 334 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 159 total
• MANE Select transcript: NM_001142276

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:598
Approved symbol	APLP2
Name	amyloid beta precursor like protein 2
Location	11q24.3
Locus type	gene with protein product
Status	Approved
Aliases	APPH
Ensembl gene	ENSG00000084234
Ensembl biotype	protein_coding
OMIM	104776
Entrez	334

Gene structure

Transcript identifiers

Ensembl transcripts: 61 — 43 protein_coding, 9 protein_coding_CDS_not_defined, 7 retained_intron, 2 nonsense_mediated_decay

ENST00000263574, ENST00000278756, ENST00000338167, ENST00000345598, ENST00000461918, ENST00000525215, ENST00000525604, ENST00000526330, ENST00000527702, ENST00000528499, ENST00000529235, ENST00000529483, ENST00000529701, ENST00000530132, ENST00000530493, ENST00000532456, ENST00000533195, ENST00000533532, ENST00000533616, ENST00000533618, ENST00000533713, ENST00000533860, ENST00000534001, ENST00000534582, ENST00000534761, ENST00000650012, ENST00000881671, ENST00000881672, ENST00000881673, ENST00000881674, ENST00000881675, ENST00000881676, ENST00000881677, ENST00000881678, ENST00000881679, ENST00000881680, ENST00000881681, ENST00000881682, ENST00000881683, ENST00000881684, ENST00000881685, ENST00000881686, ENST00000881687, ENST00000881688, ENST00000881689, ENST00000881690, ENST00000917763, ENST00000917764, ENST00000917765, ENST00000917766, ENST00000917767, ENST00000917768, ENST00000917769, ENST00000917770, ENST00000917771, ENST00000917772, ENST00000917773, ENST00000969908, ENST00000969909, ENST00000969910, ENST00000969911

RefSeq mRNA: 30 — MANE Select: NM_001142276 NM_001142276, NM_001142277, NM_001142278, NM_001243299, NM_001328682, NM_001328684, NM_001328685, NM_001328686, NM_001382526, NM_001382527, NM_001382528, NM_001382529, NM_001382530, NM_001382531, NM_001382532, NM_001382533, NM_001382534, NM_001382535, NM_001382536, NM_001382537, NM_001382538, NM_001382539, NM_001382540, NM_001382541, NM_001382542, NM_001382543, NM_001382544, NM_001382545, NM_001382546, NM_001642

CCDS: CCDS44773, CCDS44774, CCDS44775, CCDS58196, CCDS8486

Canonical transcript exons

ENST00000338167 — 17 exons

Exon	Start	End
ENSE00000541209	130123612	130123779
ENSE00002185583	130143347	130144805
ENSE00003499847	130129048	130129206
ENSE00003524562	130120706	130120818
ENSE00003527308	130141919	130142074
ENSE00003533331	130122305	130122513
ENSE00003541263	130127766	130127840
ENSE00003543423	130130038	130130166
ENSE00003581010	130109429	130109602
ENSE00003583200	130110538	130110661
ENSE00003602308	130133629	130133728
ENSE00003604190	130140398	130140483
ENSE00003627874	130135563	130135715
ENSE00003658624	130069894	130070082
ENSE00003664207	130126700	130126830
ENSE00003667345	130141498	130141572
ENSE00003692516	130121614	130121810

Expression profiles

Bgee: expression breadth ubiquitous, 306 present calls, max score 99.72.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 302.9552 / max 7723.6845, expressed in 1825 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
117595	283.8265	1825
117594	5.5519	1608
117596	5.4377	1514
117605	2.6495	1098
117606	2.3267	1033
206498	1.4410	943
117607	1.3214	547
117608	0.2899	88
117609	0.0862	24
117615	0.0243	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
renal medulla	UBERON:0000362	99.72	gold quality
choroid plexus epithelium	UBERON:0003911	99.51	gold quality
trigeminal ganglion	UBERON:0001675	99.50	gold quality
medial globus pallidus	UBERON:0002477	99.49	gold quality
monocyte	CL:0000576	99.46	gold quality
lower lobe of lung	UBERON:0008949	99.42	gold quality
descending thoracic aorta	UBERON:0002345	99.40	gold quality
synovial joint	UBERON:0002217	99.38	gold quality
mononuclear cell	CL:0000842	99.36	gold quality
dorsal root ganglion	UBERON:0000044	99.36	gold quality
left lobe of thyroid gland	UBERON:0001120	99.35	gold quality
thyroid gland	UBERON:0002046	99.35	gold quality
leukocyte	CL:0000738	99.34	gold quality
right lung	UBERON:0002167	99.34	gold quality
calcaneal tendon	UBERON:0003701	99.34	gold quality
globus pallidus	UBERON:0001875	99.31	gold quality
thoracic aorta	UBERON:0001515	99.30	gold quality
ascending aorta	UBERON:0001496	99.28	gold quality
right lobe of thyroid gland	UBERON:0001119	99.26	gold quality
cerebellum	UBERON:0002037	99.26	gold quality
cerebellar cortex	UBERON:0002129	99.25	gold quality
cerebellar hemisphere	UBERON:0002245	99.25	gold quality
tendon	UBERON:0000043	99.24	gold quality
cerebellar vermis	UBERON:0004720	99.22	gold quality
upper lobe of lung	UBERON:0008948	99.21	gold quality
upper lobe of left lung	UBERON:0008952	99.20	gold quality
postcentral gyrus	UBERON:0002581	99.19	gold quality
smooth muscle tissue	UBERON:0001135	99.18	gold quality
parietal lobe	UBERON:0001872	99.18	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.18	gold quality

Single-cell (SCXA)

Detected in 26 experiment(s), a significant marker in 21.

Experiment	Marker?	Max mean expression
E-GEOD-150728	yes	3028.45
E-MTAB-6701	yes	121.33
E-HCAD-1	yes	81.46
E-CURD-122	yes	76.51
E-HCAD-6	yes	31.09
E-MTAB-9221	yes	30.34
E-MTAB-9467	yes	29.60
E-CURD-112	yes	23.22
E-MTAB-6678	yes	23.13
E-GEOD-81547	yes	22.49
E-MTAB-9067	yes	17.21
E-GEOD-137537	yes	16.37
E-HCAD-10	yes	16.16
E-GEOD-135922	yes	13.07
E-MTAB-9388	yes	13.03

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

84 targeting APLP2, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-139-5P	99.80	69.50	1399
HSA-MIR-199A-3P	99.75	70.48	929
HSA-MIR-199B-3P	99.75	70.48	929
HSA-MIR-3129-5P	99.75	70.46	914
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-132-3P	99.73	70.56	1424
HSA-MIR-212-3P	99.73	70.65	1424
HSA-MIR-1296-3P	99.72	64.04	636
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-7106-5P	99.53	67.47	3574

Literature-anchored findings (GeneRIF, showing 35)

• APLP1 and APLP2 are processed by the gamma-secretase in a Presenilin 1-dependent manner and the extreme carboxyl-terminal fragments produced by this processing (APP-like Intracellular Domain are able to enhance Fe65-dependent gene activation (PMID:12228233)
• crystals of extracellular fragment X3 of a human sperm membrane protein YWK-II/APPH have been grow by the vapour-diffusion method [YWK-II PROTEIN] (PMID:12595709)
• Sustained levels of APP and the elevated levels of APLP2, in spite of the reduced mRNA expression, are due to altered proteolytic processing of these proteins. (PMID:14597230)
• APLP1 and APLP2 and APP are processed similarly to act via the same nuclear target and are regulated by BACE 1 in neurons (PMID:14699153)
• APLP-1 and APLP-2 are processed by alpha- and gamma-secretase-like cleavages, and their intracellular domains can be released by cleavage at epsilon-sites. APLP-2 processing appears to be the most elaborate and to involve alternative cleavage sites. (PMID:14970212)
• The APLP2 gene has no CAGA box, but it does have a GAGA sequence in a location similar to that of the CAGA box in the APP gene. (PMID:15208260)
• Interaction of human and murine Abeta peptides, Abeta40 and Abeta42. Interspecies Abeta aggregates and fibres are readily formed and are more stable than homogenous human fibres. (Amyloid beta 40 and 42) (PMID:15584916)
• APLP2 is shed by disintegrins and metalloproteinases. Overexpression of secretase or TACE in HEK293 cells increases the release of neurotrophic soluble APLP2 severalfold. (PMID:16279945)
• findings show an increase in the immunoreactivities for the nuclear C-terminal fragments of APLP2 and for GSK-3beta in the brains of Alzheimer disease patients (PMID:16645641)
• APLP2 and APP have roles in sperm function (PMID:17405931)
• YWK-II (APLP2 protein) is a G(o)-coupled receptor for Mullerian inhibiting substance in mediating ERK1/2 activation leading to anti-apoptotic activity or cell survival. (PMID:17452623)
• APLP2/MHC association is influenced by multiple domains of the MHC class I heavy chain and by beta(2)m’s effects on the conformation of the heavy chain. (PMID:18452037)
• APLP2 modulates the stability and endocytosis of K(d) molecules (PMID:18641335)
• Coexpression of APP with APLP1 or APLP2 leads to diminished generation of Abeta42 (PMID:19126676)
• APLP2 has a multistep trafficking function that influences the expression of major histocompatibility complex class I molecules at the plasma membrane (PMID:19808674)
• The interaction between APLP2 and ataxin-7 and proteolytic processing of APLP2 may contribute to the pathogenesis of spinocerebellar ataxia type 7. (PMID:20732423)
• APLP-2 (and APLP1) are capable of activating gene transcription via binding to Mint3. (PMID:21178287)
• proteolytic cleavage sites of the amyloid precursor-like protein 2 by the proteases ADAM10, BACE1 and gamma-secretase (PMID:21695060)
• Regulation of major histocompatibility complex class I molecule expression on cancer cells by amyloid precursor-like protein 2. (PMID:21826533)
• APP and its mammalian homologs, amyloid precursor-like proteins APLP1 and APLP2, participate under physiological conditions via trans-cellular dimerization in synaptogenesis. (PMID:21952790)
• Aberrant enhancement of YWK-II/APLP2 by nuclear export of Bat3 may play a role in cancer development by inhibiting cell apoptosis. (PMID:22641691)
• our discoveries establish a role for APLP2 in the growth of pancreatic cancer cells and show that inhibitors preventing APLP2 cleavage reduce the viability of pancreatic cancer cells. (PMID:22797723)
• amyloid precursor protein-like protein-2, but not amyloid precursor protein, is involved in mediating postendocytic delivery of PCSK9 to lysosomes and is therefore important for PCSK9 function (PMID:23430252)
• Data show that amyloid precursor-like protein 2 (APLP2) expression is elevated in pancreatic cancer metastases. (PMID:25576918)
• APLP1 and APLP2, behave similarly to APP in that they both associate with assembled NMDA receptors in the endoplasmic reticulum (PMID:25683482)
• We conclude that PCSK9 enhances the degradation of the LDLR independently of either APLP2 or sortilin both ex vivo and in mice. (PMID:26085104)
• This paper demonstrates an important role for APLP2 in refractive development in mice and humans, suggesting a high level of evolutionary conservation of the signaling pathways underlying refractive eye development. (PMID:26313004)
• These findings suggest that the identified APLP2, RRM2, and PRC1 signature could be useful for distinguishing between benign (follicular adenoma) and malignant (follicular carcionma and follicular variant of papillary carcinoma) tumors of the thyroid follicular epithelium. (PMID:27796194)
• the expression of APLP2 might correlate with tumor development and be a prognostic factor for patients with glioblastoma (PMID:29663738)
• our findings indicate that beta2m regulates pancreatic cancer cell migration, and furthermore suggest that APLP2 is an intermediary in this process. (PMID:30810435)
• APLP2 gene polymorphisms are associated with high TC and LDL-C levels in Chinese population in Xinjiang, China. (PMID:32716039)
• APLP2 is predominantly cleaved by beta-secretase and gamma-secretase in the human brain. (PMID:36691315)
• Comprehensive intratumoral heterogeneity landscaping of liver hepatocellular carcinoma and discerning of APLP2 in cancer progression. (PMID:37515494)
• Mycobacterium tuberculosis suppresses APLP2 expression to enhance its survival in macrophage. (PMID:37844466)
• Implication of Amyloid Precursor-like Protein 2 Expression in Cutaneous Squamous Cell Carcinoma Pathogenesis. (PMID:38148084)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	aplp2	ENSDARG00000054864
mus_musculus	Aplp2	ENSMUSG00000031996
rattus_norvegicus	Aplp2	ENSRNOG00000047179
drosophila_melanogaster	Appl	FBGN0000108
caenorhabditis_elegans		WBGENE00000149

Paralogs (2): APLP1 (ENSG00000105290), APP (ENSG00000142192)

Protein

Protein identifiers

Amyloid beta precursor like protein 2 — Q06481 (reviewed: Q06481)

Alternative names: APPH, Amyloid beta (A4) precursor-like protein 2, Amyloid protein homolog, Amyloid-like protein 2, CDEI box-binding protein, Sperm membrane protein YWK-II

All UniProt accessions (6): Q06481, A0A140VJE9, E9PPD0, E9PQS3, E9PSC7, Q9UED0

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in the regulation of hemostasis. The soluble form may have inhibitory properties towards coagulation factors. May interact with cellular G-protein signaling pathways. May bind to the DNA 5’-GTCACATG-3’(CDEI box). Inhibits trypsin, chymotrypsin, plasmin, factor XIA and plasma and glandular kallikrein. Modulates the Cu/Zn nitric oxide-catalyzed autodegradation of GPC1 heparan sulfate side chains in fibroblasts.

Subunit / interactions. Interacts with CPEB1. Interacts (via NPXY motif) with DAB2 (via PID domain); the interaction is impaired by tyrosine phosphorylation of the NPXY motif. Interacts (via cytoplasmic domain) with APBB2/FE65L. Interacts (via intracellular domain) with APBB3/FE65L2.

Subcellular location. Cell membrane. Nucleus.

Tissue specificity. Expressed in placenta, brain, heart, lung, liver, kidney and endothelial tissues.

Post-translational modifications. The BPTI/Kunitz inhibitor domain is O-glycosylated.

Similarity. Belongs to the APP family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q06481-1	1	yes
Q06481-2	2
Q06481-3	3
Q06481-4	4
Q06481-5	5
Q06481-6	6

RefSeq proteins (30): NP_001135748, NP_001135749, NP_001135750, NP_001230228, NP_001315611, NP_001315613, NP_001315614, NP_001315615, NP_001369455, NP_001369456, NP_001369457, NP_001369458, NP_001369459, NP_001369460, NP_001369461, NP_001369462, NP_001369463, NP_001369464, NP_001369465, NP_001369466, NP_001369467, NP_001369468, NP_001369469, NP_001369470, NP_001369471, NP_001369472, NP_001369473, NP_001369474, NP_001369475, NP_001633 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002223	Kunitz_BPTI	Domain
IPR008154	Amyloid_glyco_extra	Domain
IPR008155	Amyloid_glyco	Family
IPR011178	Amyloid_glyco_Cu-bd	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR015849	Amyloid_glyco_heparin-bd	Domain
IPR019543	APP_amyloid_C	Domain
IPR019744	APP_CUBD_CS	Conserved_site
IPR019745	Amyloid_glyco_intracell_CS	Conserved_site
IPR020901	Prtase_inh_Kunz-CS	Conserved_site
IPR024329	Amyloid_glyco_E2_domain	Domain
IPR036176	E2_sf	Homologous_superfamily
IPR036454	Amyloid_glyco_heparin-bd_sf	Homologous_superfamily
IPR036669	Amyloid_Cu-bd_sf	Homologous_superfamily
IPR036880	Kunitz_BPTI_sf	Homologous_superfamily

Pfam: PF00014, PF02177, PF10515, PF12924, PF12925

UniProt features (57 total): helix 10, disulfide bond 9, splice variant 5, region of interest 4, sequence conflict 4, compositionally biased region 3, binding site 3, strand 3, domain 3, site 2, topological domain 2, turn 2, signal peptide 1, chain 1, short sequence motif 1, modified residue 1, glycosylation site 1, transmembrane region 1, sequence variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
5JBT	X-RAY DIFFRACTION	1.4
5TPT	X-RAY DIFFRACTION	2.42
8RQ6	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q06481-F1	68.87	0.37

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 (2): 186 (required for cu(2+) reduction); 320–321 (reactive bond)

Ligand- & substrate-binding residues (3): 163; 167; 184

Post-translational modifications (1): 590

Disulfide bonds (9): 56–80, 91–133, 116–123, 149–203, 160–190, 174–202, 310–360, 319–343, 335–356

Glycosylation sites (1): 626

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-8957275	Post-translational protein phosphorylation
R-HSA-109582	Hemostasis
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification
R-HSA-76002	Platelet activation, signaling and aggregation
R-HSA-76005	Response to elevated platelet cytosolic Ca2+

MSigDB gene sets: 794 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, GGGACCA_MIR133A_MIR133B, GOBP_LIPID_MODIFICATION, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, LIANG_HEMATOPOIESIS_STEM_CELL_NUMBER_SMALL_VS_HUGE_UP, 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

GO Biological Process (3): G protein-coupled receptor signaling pathway (GO:0007186), axonogenesis (GO:0007409), central nervous system development (GO:0007417)

GO Molecular Function (8): DNA binding (GO:0003677), serine-type endopeptidase inhibitor activity (GO:0004867), heparin binding (GO:0008201), identical protein binding (GO:0042802), transition metal ion binding (GO:0046914), protein binding (GO:0005515), peptidase inhibitor activity (GO:0030414), metal ion binding (GO:0046872)

GO Cellular Component (7): nucleus (GO:0005634), endoplasmic reticulum lumen (GO:0005788), plasma membrane (GO:0005886), membrane (GO:0016020), platelet alpha granule membrane (GO:0031092), extracellular exosome (GO:0070062), platelet alpha granule (GO:0031091)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Metabolism of proteins	2
Response to elevated platelet cytosolic Ca2+	1
Post-translational protein modification	1
Hemostasis	1
Platelet activation, signaling and aggregation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor activity	1
signal transduction	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axon development	1
nervous system development	1
system development	1
nucleic acid binding	1
serine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
glycosaminoglycan binding	1
sulfur compound binding	1
protein binding	1
metal ion binding	1
binding	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
cation binding	1
intracellular membrane-bounded organelle	1
endoplasmic reticulum	1
intracellular organelle lumen	1
membrane	1
cell periphery	1
cellular anatomical structure	1
secretory granule membrane	1
platelet alpha granule	1
extracellular vesicle	1
secretory granule	1

Protein interactions and networks

STRING

2010 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
APLP2	APBB1	O00213	926
APLP2	BACE1	P56817	753
APLP2	APBB2	Q92870	748
APLP2	TNFRSF21	O75509	730
APLP2	APBA1	Q02410	694
APLP2	MAPK8IP1	Q9UQF2	692
APLP2	PSEN1	P49768	690
APLP2	PSEN2	P49810	683
APLP2	NCSTN	Q92542	642
APLP2	PSENEN	Q9NZ42	628
APLP2	APH1A	Q96BI3	622
APLP2	ADAM10	O14672	620
APLP2	MME	P08473	609
APLP2	XYLT1	Q86Y38	608
APLP2	SPON1	Q9HCB6	604

IntAct

133 interactions, top by confidence:

A	B	Type	Score
APBB2	APP	psi-mi:“MI:0914”(association)	0.830
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
APBA2	APP	psi-mi:“MI:0914”(association)	0.690
APLP2	APBB2	psi-mi:“MI:0915”(physical association)	0.670
APBA3	APLP2	psi-mi:“MI:0915”(physical association)	0.660
APLP2	PIGR	psi-mi:“MI:0407”(direct interaction)	0.560
PLXNA4	APLP2	psi-mi:“MI:0407”(direct interaction)	0.560
APLP2	APBB1	psi-mi:“MI:0915”(physical association)	0.550
APLP2	APBB3	psi-mi:“MI:0915”(physical association)	0.550
APLP2	APLP2	psi-mi:“MI:0915”(physical association)	0.540
APP	APLP2	psi-mi:“MI:0915”(physical association)	0.540
APLP2	APLP1	psi-mi:“MI:0915”(physical association)	0.540
APLP2	APLP2	psi-mi:“MI:0407”(direct interaction)	0.540
APLP1	APLP2	psi-mi:“MI:0407”(direct interaction)	0.540
APLP2	APP	psi-mi:“MI:0407”(direct interaction)	0.540
PTPN1	GOLIM4	psi-mi:“MI:0914”(association)	0.530
MRAP2	GOLIM4	psi-mi:“MI:0914”(association)	0.530
FCGRT	GOLIM4	psi-mi:“MI:0914”(association)	0.530
APOD	CCN1	psi-mi:“MI:0914”(association)	0.530
APBA3	DUSP11	psi-mi:“MI:0914”(association)	0.530
APBB3	RHOBTB1	psi-mi:“MI:0914”(association)	0.530
TMEM43	ENDOD1	psi-mi:“MI:0914”(association)	0.530
APBA3	CLSTN1	psi-mi:“MI:0914”(association)	0.530

BioGRID (152): APLP2 (Affinity Capture-MS), APLP2 (Affinity Capture-MS), APLP2 (Affinity Capture-MS), APLP2 (Affinity Capture-MS), APLP2 (Affinity Capture-MS), APLP2 (Affinity Capture-MS), APLP2 (Affinity Capture-MS), APLP2 (Affinity Capture-MS), APLP2 (Affinity Capture-MS), APLP2 (Affinity Capture-MS), APLP2 (Affinity Capture-MS), APLP2 (Affinity Capture-MS), APLP2 (Affinity Capture-MS), NKTR (Affinity Capture-MS), APLP2 (Affinity Capture-RNA)

ESM2 similar proteins: A1XQX3, A1XQY0, A1XQY3, A6QLD2, D0PRN4, E9PUN2, O35181, O35464, O93279, O94933, O94991, P05067, P08592, P12023, P15379, P15943, P49415, P53601, P56975, P58401, P79307, Q06335, Q06481, Q27394, Q3UH99, Q3V1G4, Q58EG3, Q5IS80, Q5R3F8, Q60495, Q63376, Q68BL8, Q68FM6, Q6DR98, Q6QD51, Q6ZSJ9, Q76KF0, Q76M96, Q7TMB7, Q810B7

Diamond homologs: A0A3G2FQK2, A0A6B7FA07, A0A6B7FBD3, A0A6B7FEJ3, A0A6P8HC43, A5X2X1, A8Y7N4, A8Y7N7, A8Y7N8, A8Y7N9, A8Y7P0, A8Y7P2, A8Y7P6, B1B5I8, B2G331, B5KL37, B6ZIW0, C0HJF3, C0HJF4, C0HJU6, C0HJU7, C0HK72, C0HK73, C0HK74, C0HLA7, C0HLB2, C0HMC7, C1IBY4, C8YJ94, C8YJ95, C8YJ96, C8YJ97, D8KY58, H2A0N9, H6VC05, O54819, P00990, P00991, P00994, P05067

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
MAPK8	up-regulates	APLP2	phosphorylation
CDK1	unknown	APLP2	phosphorylation
PRKCA	unknown	APLP2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 144 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
FCERI mediated MAPK activation	5	19.9×	4e-04
NCAM signaling for neurite out-growth	6	18.8×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	130
Likely benign	4
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

2996 predictions. Top by Δscore:

Variant	Effect	Δscore
11:130109423:T:A	acceptor_gain	1.0000
11:130109424:G:A	acceptor_gain	1.0000
11:130109427:A:AG	acceptor_gain	1.0000
11:130109427:AG:A	acceptor_gain	1.0000
11:130109428:G:GC	acceptor_gain	1.0000
11:130109428:GG:G	acceptor_gain	1.0000
11:130109428:GGC:G	acceptor_gain	1.0000
11:130109428:GGCT:G	acceptor_gain	1.0000
11:130109428:GGCTC:G	acceptor_gain	1.0000
11:130109599:GGAG:G	donor_gain	1.0000
11:130109600:GAGG:G	donor_gain	1.0000
11:130109602:GGTAA:G	donor_loss	1.0000
11:130109604:T:A	donor_loss	1.0000
11:130110532:TAACA:T	acceptor_gain	1.0000
11:130110533:A:AG	acceptor_gain	1.0000
11:130110533:AACAG:A	acceptor_gain	1.0000
11:130110534:A:G	acceptor_gain	1.0000
11:130110534:ACAG:A	acceptor_loss	1.0000
11:130110534:ACAGA:A	acceptor_gain	1.0000
11:130110535:C:G	acceptor_gain	1.0000
11:130110536:A:AG	acceptor_gain	1.0000
11:130110536:AGAT:A	acceptor_gain	1.0000
11:130110536:AGATG:A	acceptor_gain	1.0000
11:130110537:G:GT	acceptor_gain	1.0000
11:130110537:GA:G	acceptor_gain	1.0000
11:130110537:GAT:G	acceptor_gain	1.0000
11:130110537:GATG:G	acceptor_gain	1.0000
11:130110537:GATGT:G	acceptor_gain	1.0000
11:130110658:CTCGG:C	donor_loss	1.0000
11:130110659:TCGG:T	donor_loss	1.0000

AlphaMissense

5013 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:130123757:T:G	C356W	1.000
11:130126777:T:C	F390L	1.000
11:130126778:T:C	F390S	1.000
11:130126779:C:A	F390L	1.000
11:130126779:C:G	F390L	1.000
11:130129106:T:C	L452P	1.000
11:130110655:T:C	C133R	0.999
11:130123617:T:A	C310S	0.999
11:130123617:T:C	C310R	0.999
11:130123618:G:C	C310S	0.999
11:130123644:T:A	C319S	0.999
11:130123644:T:C	C319R	0.999
11:130123645:G:A	C319Y	0.999
11:130123645:G:C	C319S	0.999
11:130123646:C:G	C319W	0.999
11:130123692:T:A	C335S	0.999
11:130123692:T:C	C335R	0.999
11:130123693:G:C	C335S	0.999
11:130123694:C:G	C335W	0.999
11:130123716:T:A	C343S	0.999
11:130123716:T:C	C343R	0.999
11:130123717:G:A	C343Y	0.999
11:130123717:G:C	C343S	0.999
11:130123733:C:A	N348K	0.999
11:130123733:C:G	N348K	0.999
11:130123755:T:A	C356S	0.999
11:130123755:T:C	C356R	0.999
11:130123756:G:A	C356Y	0.999
11:130123756:G:C	C356S	0.999
11:130123767:T:A	C360S	0.999

dbSNP variants (sampled 300 via entrez): RS1000030702 (11:130125894 A>G), RS1000111125 (11:130115079 T>C), RS1000120947 (11:130110049 A>G), RS1000167875 (11:130129428 G>C), RS1000264089 (11:130138864 G>T), RS1000264993 (11:130088630 C>T), RS1000394617 (11:130122980 T>C), RS1000407971 (11:130106431 G>A), RS1000483082 (11:130106648 A>G), RS1000524764 (11:130133554 T>A,C), RS1000532040 (11:130081227 G>A,T), RS1000545026 (11:130143220 G>A,T), RS1000560877 (11:130070902 C>T), RS1000568163 (11:130087424 G>A,T), RS1000592982 (11:130086993 A>C)

Disease associations

OMIM: gene MIM:104776 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006585_2543	Blood protein levels	2.000000e-33
GCST006585_746	Blood protein levels	4.000000e-20

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression	7
Tretinoin	increases metabolic processing, increases secretion, affects cotreatment, increases expression	6
Copper	affects binding, increases response to substance, affects localization	3
Tobacco Smoke Pollution	affects expression, decreases expression, increases expression	3
(+)-JQ1 compound	increases expression	2
Decitabine	affects methylation, increases expression	2
Arsenic Trioxide	affects cotreatment, increases expression	2
Vehicle Emissions	increases abundance, increases expression	2
Lead	affects expression, affects splicing, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression, decreases expression	2
Genistein	decreases expression, increases reaction	2
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
deoxynivalenol	decreases expression	1
trichostatin A	affects expression	1
sodium arsenite	increases expression	1
nivalenol	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
Am 580	increases expression	1
N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide	decreases reaction, increases secretion, decreases secretion	1
CGP 52608	affects binding, increases reaction	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
N-benzyloxycarbonyl-valyl-leucyl-leucinal	decreases secretion	1
dorsomorphin	affects cotreatment, increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Rosiglitazone	increases expression	1
Resveratrol	affects cotreatment, increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SC93	HAP1 APLP2 (-) 1	Cancer cell line	Male
CVCL_SC94	HAP1 APLP2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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