MAGI1

Summary

MAGI1 (membrane associated guanylate kinase, WW and PDZ domain containing 1, HGNC:946) is a protein-coding gene on chromosome 3p14.1, encoding Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 1 (Q96QZ7). Plays a role in coupling actin fibers to cell junctions in endothelial cells, via its interaction with AMOTL2 and CDH5. It is haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene is a member of the membrane-associated guanylate kinase homologue (MAGUK) family. MAGUK proteins participate in the assembly of multiprotein complexes on the inner surface of the plasma membrane at regions of cell-cell contact. The product of this gene may play a role as scaffolding protein at cell-cell junctions. Alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 9223 — RefSeq curated summary.

At a glance

• Gene–disease (curated): BAP1-related tumor predisposition syndrome (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 3,786 total — 312 pathogenic, 95 likely-pathogenic
• Phenotypes (HPO): 171
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001033057

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:946
Approved symbol	MAGI1
Name	membrane associated guanylate kinase, WW and PDZ domain containing 1
Location	3p14.1
Locus type	gene with protein product
Status	Approved
Aliases	BAP1, MAGI-1, TNRC19, AIP3, WWP3
Ensembl gene	ENSG00000151276
Ensembl biotype	protein_coding
OMIM	602625
Entrez	9223

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 10 protein_coding, 4 retained_intron, 4 protein_coding_CDS_not_defined

ENST00000330909, ENST00000402939, ENST00000460329, ENST00000463103, ENST00000464060, ENST00000468159, ENST00000470990, ENST00000472257, ENST00000476403, ENST00000476703, ENST00000479287, ENST00000480729, ENST00000483466, ENST00000494271, ENST00000496734, ENST00000497477, ENST00000611645, ENST00000621418

RefSeq mRNA: 6 — MANE Select: NM_001033057 NM_001033057, NM_001365903, NM_001365904, NM_001365905, NM_004742, NM_015520

CCDS: CCDS2904, CCDS33780, CCDS33781

Canonical transcript exons

ENST00000402939 — 23 exons

Exon	Start	End
ENSE00001391617	65375745	65375945
ENSE00002207281	65401439	65401470
ENSE00002210723	65361199	65361337
ENSE00002245078	65364853	65364946
ENSE00002256690	65364665	65364725
ENSE00002267378	65429520	65430140
ENSE00002290271	65363465	65363608
ENSE00003425453	65353526	65357132
ENSE00003474910	65478592	65478798
ENSE00003479647	65437155	65437247
ENSE00003492895	65439879	65440012
ENSE00003528568	65442792	65442849
ENSE00003541456	65430699	65430881
ENSE00003550881	65391142	65391358
ENSE00003555685	65493512	65493631
ENSE00003561202	65381877	65382069
ENSE00003598973	65448022	65448057
ENSE00003617298	65383532	65383623
ENSE00003622796	65453258	65453340
ENSE00003629817	65379261	65379554
ENSE00003665573	65470283	65470484
ENSE00003682278	65621972	65622088
ENSE00003922919	66037996	66038918

Expression profiles

Bgee: expression breadth ubiquitous, 133 present calls, max score 95.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.1237 / max 356.1932, expressed in 1524 samples.

FANTOM5 promoters (28 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42916	6.0853	1313
42917	4.6016	1278
42915	2.7239	1059
42914	2.1502	870
42896	0.6183	192
42913	0.5677	285
42895	0.4106	185
42897	0.3044	164
42918	0.2340	127
42889	0.2010	89

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	95.76	gold quality
sural nerve	UBERON:0015488	95.13	gold quality
corpus callosum	UBERON:0002336	94.69	gold quality
ganglionic eminence	UBERON:0004023	90.45	gold quality
calcaneal tendon	UBERON:0003701	89.36	gold quality
superior frontal gyrus	UBERON:0002661	88.74	gold quality
cerebellum	UBERON:0002037	87.33	gold quality
cerebellar cortex	UBERON:0002129	87.29	gold quality
prefrontal cortex	UBERON:0000451	87.23	gold quality
cerebellar hemisphere	UBERON:0002245	87.23	gold quality
liver	UBERON:0002107	86.96	gold quality
right hemisphere of cerebellum	UBERON:0014890	86.78	gold quality
stomach	UBERON:0000945	86.65	gold quality
islet of Langerhans	UBERON:0000006	86.63	gold quality
thoracic mammary gland	UBERON:0005200	86.62	gold quality
colonic epithelium	UBERON:0000397	86.38	gold quality
thyroid gland	UBERON:0002046	85.82	gold quality
body of stomach	UBERON:0001161	85.65	gold quality
frontal cortex	UBERON:0001870	85.55	gold quality
left lobe of thyroid gland	UBERON:0001120	85.37	gold quality
endometrium	UBERON:0001295	85.13	gold quality
kidney	UBERON:0002113	84.98	gold quality
pancreas	UBERON:0001264	84.95	gold quality
subcutaneous adipose tissue	UBERON:0002190	84.82	gold quality
right uterine tube	UBERON:0001302	84.81	gold quality
gall bladder	UBERON:0002110	84.66	gold quality
primary visual cortex	UBERON:0002436	84.62	gold quality
right lobe of thyroid gland	UBERON:0001119	84.32	gold quality
tonsil	UBERON:0002372	84.29	gold quality
adult mammalian kidney	UBERON:0000082	84.23	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-131882	yes	8504.65
E-CURD-119	yes	8457.83
E-GEOD-111727	yes	132.41
E-MTAB-6678	yes	12.46
E-ANND-3	yes	9.92

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

79 targeting MAGI1, 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-LET-7F-1-3P	100.00	74.02	3928
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-6832-5P	99.58	64.82	1132

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 31)

• interaction with synaptopodin and alpha-actinin-4 (PMID:12042308)
• Dll1 is presented on the surface of AJs formed at the apical termini of processes through interaction with MAGI1 to activate Notch on neighboring cells in the developing central nervous system (PMID:15908431)
• In vitro binding assays using the partial cDNA as a GST fusion protein confirm the binding to full-length MAGI-1 expressed in HEK293 cells. (PMID:16019084)
• MAGI-1 is important for vascular endothelial-cadherin-dependent Rap1 activation upon cell-cell contact. (PMID:16339077)
• MAGI-1 cleavage appears to be an important step in the disassembly of cell-cell contacts during apoptosis. (PMID:17191119)
• Structural basis for controlling the dimerization and stability of the WW domains of MAGI1 is reported. (PMID:18562638)
• Data conclude that the up-regulation of sdk-1 in podocytes is an important pathogenic factor in glomerulosclerosis and that the mechanism involves disruption of the actin cytoskeleton possibly via alterations in MAGI-1 function. (PMID:20562105)
• These results demonstrate that oncogenic HPV E6 proteins disrupt cellular tight junctions through the degradation of MAGI-1. (PMID:21123374)
• Mutations designed in the C-terminal flanking region of the human MAGI-1 PDZ domain resulted in a significant decrease in binding affinity for human papillomavirus E6 peptides. (PMID:21238461)
• HPV16 E6 association with PDZ domain-containing proteins, MAGI1, Dlg1 or Scrib, stabilized the levels of E6. (PMID:21489588)
• MAGI1 may inhibit the cancer cell migration and invasion of hepatocellular carcinoma via regulating PTEN. (PMID:21685691)
• MAGI1 expression is decreased in hepatocellular carcinoma, which correlates with poor prognosis, suggesting MAGI1 as a novel prognostic marker (PMID:21942217)
• Results presented herein provide further evidence for a role of MAGI1 in bipolar affective disorder and schizophrenia etiology. (PMID:22381734)
• The PDZ1 and PDZ3 domains of MAGI-1 regulate the eight-exon isoform of the CXADR-like membrane protein. (PMID:22718816)
• The data suggests that inactivation of MAGI-1 by the NS1 protein from avian influenza A virus elicits an interferon-beta induction signal. (PMID:22911767)
• Variants in MAGI1 were associated with a Crohn’s disease phenotype involving a complicated stricturing disease course. (PMID:25557950)
• A deletion at ADAMTS9-MAGI1 locus is associated with psoriatic arthritis risk. (PMID:25990289)
• MAGI1 rs35855737 is a novel locus for neuroticism. [Meta-Analysis] (PMID:25993607)
• Here we present the result of a 4-stage genome-wide association study composed of 5,953 adolescent idiopathic scoliosis patients and 8,137 controls. Overall, we identified three novel susceptible loci including rs7593846 at 2p14 near MEIS1 , rs7633294 at 3p14.1 near MAGI1 and rs9810566 at 3q26.2 near TNIK (PMID:28334814)
• Study presented a combined molecular dynamics/infrared spectroscopy approach to the study of ligand binding (11-residue peptide derived from the C terminus of HPV16 E6) by the PDZ1 domain of MAGI1, focusing in particular on the far-infrared region of the spectrum. (PMID:28636914)
• it negatively controls the cell growth of various types of cells and positively controls cell-cell interaction and the decreased expression of MAGI-1 in human T cells contributes to the development of several types of T-cell leukemia, partly through the stimulation of the Akt and MEK pathways. (PMID:29043551)
• Decreased MAGI1 expression in the colonic mucosa might contribute to the pathogenesis of microscopic colitis. (PMID:29204743)
• The authors report MAGI1 as a novel fluid shear stress-induced transcript/protein in endothelial cells that regulates eNOS (endothelial nitric oxide synthase) phosphorylation and nitric oxide production through PKA/AMPK-dependent phosphorylation. (PMID:31035633)
• MAGI1 was markedly decreased in the Renal cell carcinoma (RCC) and indicated poor survival. Furthermore, we found that MAGI1 suppressed the invasion and migration of human RCC cells. Mechanistic investigations revealed that MAGI1 stabilized the PTEN/MAGI1/beta-catenin complex to inhibit beta-catenin signaling pathway. Moreover, MAGI1 was targeted by miR-520h which was transcriptionally activated by c-Myb. (PMID:31352641)
• Genome-Wide Association Study of Ocular Sarcoidosis Confirms HLA Associations and Implicates Barrier Function and Autoimmunity in African Americans. (PMID:32141793)
• MAGI1 inhibits the AMOTL2/p38 stress pathway and prevents luminal breast tumorigenesis. (PMID:33707576)
• MAGI1, a Scaffold Protein with Tumor Suppressive and Vascular Functions. (PMID:34198584)
• Molecular insights into the interaction of HPV-16 E6 variants against MAGI-1 PDZ1 domain. (PMID:35115618)
• Stimulated expression of ELR+ chemokines, VEGFA and TNF-AIP3 promote mycobacterial dissemination in extrapulmonary tuberculosis patients and Cavia porcellus model of tuberculosis. (PMID:35763913)
• MAGI1 Prevents Senescence and Promotes the DNA Damage Response in ER[+] Breast Cancer. (PMID:37566008)
• MiR-205-5p-Mediated MAGI1 Inhibition Attenuates the Injury Induced by Diabetic Nephropathy. (PMID:38325349)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	magi1b	ENSDARG00000003169
danio_rerio	magi1a	ENSDARG00000070145
mus_musculus	Magi1	ENSMUSG00000045095
rattus_norvegicus	Magi1	ENSRNOG00000022060

Paralogs (6): MAGI3 (ENSG00000081026), GRIP2 (ENSG00000144596), SAV1 (ENSG00000151748), GRIP1 (ENSG00000155974), MAGI2 (ENSG00000187391), MAGIX (ENSG00000269313)

Protein

Protein identifiers

Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 1 — Q96QZ7 (reviewed: Q96QZ7)

Alternative names: Atrophin-1-interacting protein 3, BAI1-associated protein 1, Membrane-associated guanylate kinase inverted 1, Trinucleotide repeat-containing gene 19 protein, WW domain-containing protein 3

All UniProt accessions (7): Q96QZ7, A0A087WT53, A0A087WXD2, H7C4S7, H7C4U7, H7C535, H7C5T8

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in coupling actin fibers to cell junctions in endothelial cells, via its interaction with AMOTL2 and CDH5. May regulate acid-induced ASIC3 currents by modulating its expression at the cell surface.

Subunit / interactions. Part of a complex composed of AMOTL2, MAGI1 and CDH5, within the complex AMOTL2 acts as a scaffold protein for the interaction of MAGI1 with CDH5. The complex is required for coupling actin fibers to cell junctions in endothelial cells. Interacts through its WW 2 domain with SYNPO and through its PDZ 5 domain with ACTN4. Interacts with cytoplasmic domain of ADGRB1. Interacts via its WW domains with DRPLA. Interacts with ESAM, LRP2 and CXADR. May interact with CTNNB1. Interacts through its PDZ 1 domain with NET1. Interacts with ASIC3 and AMOT. Interacts with FCHSD2. Interacts with IGSF5/JAM4 and through its PDZ 2 and 3 domains with NPHS1 forming a tripartite complex. Interacts with DDN. Interacts with DLL1. Interacts with KCNJ10 and possibly with KCNJ10/KCNJ16 heterodimer; this interaction may facilitate KCNJ10/KCNJ16 potassium channel expression at the basolateral membrane in kidney tubular cells. Interacts with PRRG4 (via cytoplasmic domain). Interacts (via PDZ domain) with RAPGEF2.

Subcellular location. Cell junction. Tight junction. Cell membrane.

Tissue specificity. Widely expressed with the exception of skeletal muscle. Isoform 1, isoform 2 and isoform 6 are highly expressed in colon, kidney, lung, liver, and pancreas. Isoform 5 is predominantly expressed in brain and heart. Isoform 3 and isoform 4 are highly expressed in pancreas and brain.

Isoforms (7)

UniProt ID	Names	Canonical?
Q96QZ7-1	1, MAGI-1C-alpha-beta1	yes
Q96QZ7-2	2, MAGI-1C-beta
Q96QZ7-3	3, MAGI-1A-alpha-beta1
Q96QZ7-4	4, MAGI-1A-alpha
Q96QZ7-5	5, MAGI-1B-alpha-beta
Q96QZ7-6	6, MAGI-1C-beta2
Q96QZ7-7	7, MAGI-1C-beta3

RefSeq proteins (6): NP_001028229, NP_001352832, NP_001352833, NP_001352834, NP_004733, NP_056335 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001202	WW_dom	Domain
IPR001478	PDZ	Domain
IPR008144	Guanylate_kin-like_dom	Domain
IPR008145	GK/Ca_channel_bsu	Domain
IPR020590	Guanylate_kinase_CS	Conserved_site
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036020	WW_dom_sf	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily

Pfam: PF00397, PF00595, PF00625, PF16663, PF16666

UniProt features (96 total): strand 32, compositionally biased region 11, helix 10, domain 9, splice variant 9, region of interest 8, modified residue 7, sequence conflict 4, turn 4, chain 1, binding site 1

Structure

Experimental structures (PDB)

16 structures.

PDB	Method	Resolution (Å)
3BPU	X-RAY DIFFRACTION	1.6
2Q9V	X-RAY DIFFRACTION	2
2R4H	X-RAY DIFFRACTION	2.05
5N7D	X-RAY DIFFRACTION	2.3
5N7F	X-RAY DIFFRACTION	2.3
6TWX	X-RAY DIFFRACTION	2.3
6TWY	X-RAY DIFFRACTION	2.3
1WBP	X-RAY DIFFRACTION	2.4
6TWU	X-RAY DIFFRACTION	2.4
7P71	X-RAY DIFFRACTION	2.6
5N7G	X-RAY DIFFRACTION	2.95
2KPK	SOLUTION NMR
2KPL	SOLUTION NMR
2YSD	SOLUTION NMR
2YSE	SOLUTION NMR
2ZAJ	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96QZ7-F1	60.25	0.23

Functional residue map

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

Ligand- & substrate-binding residues (1): 103–110

Post-translational modifications (7): 357, 730, 741, 800, 1071, 1361, 1412

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 792 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_ENDOTHELIAL_CELL_DEVELOPMENT, RNGTGGGC_UNKNOWN, RRAGTTGT_UNKNOWN, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, YAATNRNNNYNATT_UNKNOWN, WANG_CLIM2_TARGETS_UP, GOBP_MYELOID_CELL_HOMEOSTASIS, PAX4_01, GOBP_MYELOID_CELL_DEVELOPMENT, GOBP_INFLAMMATORY_RESPONSE, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GCANCTGNY_MYOD_Q6, CMYB_01

GO Biological Process (6): endothelial cell morphogenesis (GO:0001886), cell adhesion (GO:0007155), signal transduction (GO:0007165), cell surface receptor signaling pathway (GO:0007166), positive regulation of cell-cell adhesion (GO:0022409), protein-containing complex assembly (GO:0065003)

GO Molecular Function (4): ATP binding (GO:0005524), alpha-actinin binding (GO:0051393), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (14): nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), adherens junction (GO:0005912), bicellular tight junction (GO:0005923), cell junction (GO:0030054), cell projection (GO:0042995), cell periphery (GO:0071944), nucleus (GO:0005634), endomembrane system (GO:0012505), membrane (GO:0016020), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
cellular process	2
nuclear lumen	2
endothelial cell development	1
epithelial cell morphogenesis	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
signal transduction	1
regulation of cell-cell adhesion	1
positive regulation of cell adhesion	1
cell-cell adhesion	1
cellular component assembly	1
protein-containing complex organization	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
actinin binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
anchoring junction	1
cell-cell junction	1
apical junction complex	1
tight junction	1
intracellular membrane-bounded organelle	1
vacuole	1
plasma membrane	1
cell junction	1

Protein interactions and networks

STRING

744 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAGI1	IGSF5	Q9NSI5	935
MAGI1	SYNPO	Q8N3V7	923
MAGI1	ACTN4	O43707	922
MAGI1	ATN1	P54259	811
MAGI1	RAPGEF2	Q9Y4G8	751
MAGI1	ADGRB1	O14514	708
MAGI1	AMOT	Q4VCS5	698
MAGI1	ADGRB2	O60241	689
MAGI1	CTNND2	Q9UQB3	662
MAGI1	TJP1	Q07157	647
MAGI1	TRIM3	O75382	639
MAGI1	ASIC3	Q9UHC3	592
MAGI1	CALCOCO2	Q13137	589
MAGI1	PICK1	Q9NRD5	547
MAGI1	ASIC2	Q16515	503

IntAct

1075 interactions, top by confidence:

A	B	Type	Score
MED21	MED19	psi-mi:“MI:0914”(association)	0.880
MAGI1	E6	psi-mi:“MI:0915”(physical association)	0.860
E6	MAGI1	psi-mi:“MI:0407”(direct interaction)	0.860
MAGI1	E6	psi-mi:“MI:0915”(physical association)	0.810
PTPN14	YAP1	psi-mi:“MI:0914”(association)	0.810
E6	MAGI1	psi-mi:“MI:0407”(direct interaction)	0.810
MAGI1	NET1	psi-mi:“MI:0407”(direct interaction)	0.740
NET1	MAGI1	psi-mi:“MI:0407”(direct interaction)	0.740
NET1	MAGI1	psi-mi:“MI:0915”(physical association)	0.740
MAGI1	FCHSD2	psi-mi:“MI:0915”(physical association)	0.720
FCHSD2	MAGI1	psi-mi:“MI:0915”(physical association)	0.720
CIT	TAX1BP3	psi-mi:“MI:0914”(association)	0.690
E	MAGI1	psi-mi:“MI:0915”(physical association)	0.670
MAGI1	E6	psi-mi:“MI:0407”(direct interaction)	0.660
E6	MAGI1	psi-mi:“MI:0915”(physical association)	0.660
Tax	MAGI1	psi-mi:“MI:0407”(direct interaction)	0.660
MAGI1	Tax	psi-mi:“MI:0915”(physical association)	0.660
E6	MAGI1	psi-mi:“MI:0407”(direct interaction)	0.660
MAGI1	E6	psi-mi:“MI:0915”(physical association)	0.660
Tax	MAGI1	psi-mi:“MI:0915”(physical association)	0.660
MAGI1	RPS6KA1	psi-mi:“MI:0407”(direct interaction)	0.650
MAGI1	CYSLTR2	psi-mi:“MI:0407”(direct interaction)	0.620

BioGRID (224): MAGI1 (Affinity Capture-MS), MAGI1 (Affinity Capture-RNA), MAGI1 (Affinity Capture-RNA), MAGI1 (Affinity Capture-MS), MAGI1 (Affinity Capture-MS), MAGI1 (Two-hybrid), MAGI1 (Proximity Label-MS), MAGI1 (Affinity Capture-MS), MAGI1 (Affinity Capture-MS), MAGI1 (Affinity Capture-MS), MAGI1 (Affinity Capture-MS), MAGI1 (Affinity Capture-MS), MAGI1 (Affinity Capture-MS), MAGI1 (Affinity Capture-MS), MAGI1 (Affinity Capture-MS)

ESM2 similar proteins: A1A5G4, D3YZU1, E9Q9R9, F1MAD2, O15018, O35346, O35867, O60759, P34152, P97306, P97879, Q00944, Q4L1J4, Q5F488, Q5I0L6, Q5JV73, Q5RD32, Q5SGD7, Q5TCQ9, Q68DX3, Q69Z98, Q6DD51, Q6P9H4, Q6RHR9, Q6ZWJ1, Q812E4, Q8BH60, Q8BMA3, Q8IWQ3, Q8TDM6, Q8TDW5, Q8TEW0, Q8TEW8, Q91VY6, Q925T6, Q96QZ7, Q99469, Q99NH2, Q9CSB4, Q9EQJ9

Diamond homologs: A0A8C0NGY6, A0A8I3PQN6, A1A5G4, A1CQG2, A1D3C5, A2QQ28, A4IIJ3, B0XQ72, B3LWS4, B3P3M8, B4HEJ6, B4K6I9, B4M5X4, B4NAD3, B4PSQ2, B8N7E5, D6C652, G0S9J5, H2LBU8, O14326, O88382, P39940, P46934, P46935, P46936, P46937, P46938, Q0CCL1, Q19404, Q1L8J7, Q2EJA0, Q2UBP1, Q32NJ6, Q45VV3, Q4L1J4, Q4WTF3, Q54T86, Q5BDP1, Q5F488, Q5RBF2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
RPS6KA1	“up-regulates activity”	MAGI1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 147 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
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	5	35.7×	4e-05
RHO GTPases activate PKNs	6	20.2×	6e-05
RHOQ GTPase cycle	6	11.6×	5e-04
Translocation of SLC2A4 (GLUT4) to the plasma membrane	7	11.5×	2e-04
Apoptosis	6	10.7×	7e-04
RHOB GTPase cycle	6	9.8×	1e-03
Signaling by NTRKs	5	9.6×	4e-03
Transcriptional and post-translational regulation of MITF-M expression and activity	5	9.5×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

3786 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	312
Likely pathogenic	95
Uncertain significance	1519
Likely benign	997
Benign	61

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012196	NM_004656.4(BAP1):c.67+2T>C	Pathogenic
1013479	NM_004656.4(BAP1):c.993del (p.Lys331fs)	Pathogenic
1064792	NM_004656.4(BAP1):c.34C>A (p.Pro12Thr)	Pathogenic
1069122	NM_004656.4(BAP1):c.593dup (p.Asp199fs)	Pathogenic
1070605	NM_004656.4(BAP1):c.1883C>A (p.Ser628Ter)	Pathogenic
1070749	NM_004656.4(BAP1):c.799_800del (p.Gln267fs)	Pathogenic
1070831	NM_004656.4(BAP1):c.1470_1471insA (p.Glu491fs)	Pathogenic
1071620	NM_004656.4(BAP1):c.2017G>T (p.Glu673Ter)	Pathogenic
1071927	NM_004656.4(BAP1):c.669C>A (p.Tyr223Ter)	Pathogenic
1072297	NM_004656.4(BAP1):c.436dup (p.Arg146fs)	Pathogenic
1073043	NM_004656.4(BAP1):c.944dup (p.Ala316fs)	Pathogenic
1073050	NM_004656.4(BAP1):c.203del (p.Asp68fs)	Pathogenic
1073322	NM_004656.4(BAP1):c.581-2A>G	Pathogenic
1073405	NM_004656.4(BAP1):c.132T>G (p.Tyr44Ter)	Pathogenic
1073757	NM_004656.4(BAP1):c.830_831del (p.Gln277fs)	Pathogenic
1073906	NM_004656.4(BAP1):c.721dup (p.Tyr241fs)	Pathogenic
1074041	NM_004656.4(BAP1):c.555del (p.Gly185_Leu186insTer)	Pathogenic
1075173	NM_004656.4(BAP1):c.102_109del (p.Asp34fs)	Pathogenic
1075700	NM_004656.4(BAP1):c.1766_1770del (p.Ile589fs)	Pathogenic
1076668	NM_004656.4(BAP1):c.1383dup (p.Pro462fs)	Pathogenic
1171962	NM_004656.4(BAP1):c.1213G>T (p.Glu405Ter)	Pathogenic
1173080	NM_004656.4(BAP1):c.176G>C (p.Arg59Pro)	Pathogenic
1173081	NM_004656.4(BAP1):c.272G>C (p.Cys91Ser)	Pathogenic
1183824	NM_004656.4(BAP1):c.1514C>A (p.Ser505Ter)	Pathogenic
1216875	NM_004656.4(BAP1):c.132del (p.Val43_Tyr44insTer)	Pathogenic
1362781	NM_004656.4(BAP1):c.1778del (p.Gln593fs)	Pathogenic
1365414	NM_004656.4(BAP1):c.1139_1151del (p.Gly380fs)	Pathogenic
1386236	NM_004656.4(BAP1):c.606_607delinsTT (p.Trp202_Thr203delinsCysSer)	Pathogenic
1396376	NM_004656.4(BAP1):c.1786del (p.Ser596fs)	Pathogenic
1417901	NM_004656.4(BAP1):c.49dup (p.Leu17fs)	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

9591 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000000855 (3:65941450 C>T), RS1000001038 (3:65442425 T>A,C), RS1000005255 (3:65690013 G>T), RS1000008882 (3:65831490 G>A,C), RS1000013278 (3:65611690 CAT>C), RS1000015900 (3:65857798 C>T), RS1000016832 (3:66021909 T>C), RS1000021455 (3:65908652 T>A,G), RS1000027643 (3:65988054 C>T), RS1000031343 (3:65480521 C>G), RS1000033654 (3:65946313 C>T), RS1000037844 (3:65538869 C>T), RS1000041481 (3:65519291 T>A,C), RS1000042189 (3:65620573 T>A,C), RS1000052075 (3:65613640 A>G)

Disease associations

OMIM: gene MIM:602625 | disease phenotypes: MIM:614327, MIM:619762, MIM:606661, MIM:155720, MIM:155255, MIM:612219, MIM:254500

GenCC curated gene-disease

Disease	Classification	Inheritance
BAP1-related tumor predisposition syndrome	Definitive	Autosomal dominant
Kury-Isidor syndrome	Strong	Autosomal dominant
renal cell carcinoma	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
BAP1-related tumor predisposition syndrome	Definitive	AD

Mondo (13): BAP1-related tumor predisposition syndrome (MONDO:0013692), hereditary neoplastic syndrome (MONDO:0015356), neurodevelopmental disorder (MONDO:0700092), Kury-Isidor syndrome (MONDO:0859230), melanoma, uveal, susceptibility to, 2 (MONDO:0011696), astrocytoma (excluding glioblastoma) (MONDO:0019781), uveal melanoma (MONDO:0006486), medulloblastoma (MONDO:0007959), Ewing sarcoma (MONDO:0012817), ganglioglioma (MONDO:0016733), plasma cell myeloma (MONDO:0009693), clear cell renal carcinoma (MONDO:0005005), renal cell carcinoma (MONDO:0005086)

Orphanet (10): BAP1-related tumor predisposition syndrome (Orphanet:289539), Inherited cancer-predisposing syndrome (Orphanet:140162), Uveal melanoma (Orphanet:39044), Medulloblastoma (Orphanet:616), OBSOLETE: Neuroepithelioma (Orphanet:2677), Skeletal Ewing sarcoma (Orphanet:319), Ganglioglioma (Orphanet:251949), Multiple myeloma (Orphanet:29073), AL amyloidosis (Orphanet:85443), Clear cell renal carcinoma (Orphanet:319276)

HPO phenotypes

171 total (30 of 171 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000020	Urinary incontinence
HP:0000044	Hypogonadotropic hypogonadism
HP:0000126	Hydronephrosis
HP:0000141	Amenorrhea
HP:0000207	Triangular mouth
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000248	Brachycephaly
HP:0000280	Coarse facial features
HP:0000343	Long philtrum
HP:0000360	Tinnitus
HP:0000369	Low-set ears
HP:0000403	Recurrent otitis media
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000488	Retinopathy
HP:0000490	Deeply set eye
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis
HP:0000520	Proptosis
HP:0000539	Abnormality of refraction
HP:0000541	Retinal detachment
HP:0000572	Visual loss
HP:0000602	Ophthalmoplegia
HP:0000618	Blindness
HP:0000687	Widely spaced teeth
HP:0000712	Emotional lability

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001241_15	Bipolar disorder	2.000000e-06
GCST002149_14	Schizophrenia	1.000000e-08
GCST004521_123	Autism spectrum disorder or schizophrenia	3.000000e-12
GCST004521_201	Autism spectrum disorder or schizophrenia	4.000000e-08
GCST004902_20	Parkinson’s disease	3.000000e-08

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D001254	Astrocytoma	C04.557.465.625.600.380.080; C04.557.470.670.380.080; C04.557.580.625.600.380.080
D002292	Carcinoma, Renal Cell	C04.557.470.200.025.390; C04.588.945.947.535.160; C12.050.351.937.820.535.160; C12.050.351.968.419.473.160; C12.200.758.820.750.160; C12.200.777.419.473.160; C12.900.820.535.160; C12.950.419.473.160; C12.950.983.535.160
D018303	Ganglioglioma	C04.557.465.625.600.380.350; C04.557.470.670.380.350; C04.557.580.625.600.380.350
D008527	Medulloblastoma	C04.557.465.625.600.380.515; C04.557.465.625.600.590.500; C04.557.470.670.380.515; C04.557.470.670.590.500; C04.557.580.625.600.380.515; C04.557.580.625.600.590.500
D009101	Multiple Myeloma	C04.557.595.500; C14.907.454.460; C15.378.147.780.650; C15.378.463.515.460; C20.683.515.845; C20.683.780.650
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D065886	Neurodevelopmental Disorders	F03.625
D012512	Sarcoma, Ewing	C04.557.450.565.575.650.800; C04.557.450.795.620.800

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295927 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	increases expression	2
Benzo(a)pyrene	decreases expression, decreases methylation, increases methylation	2
Nickel	decreases expression	2
Valproic Acid	decreases methylation, increases expression	2
Aflatoxin B1	increases methylation	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	decreases expression	1
methyleugenol	decreases expression	1
bisphenol A	affects methylation	1
beta-lapachone	decreases expression	1
arsenite	decreases reaction, affects binding	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	affects methylation	1
manganese chloride	decreases expression, increases abundance	1
sulindac sulfide	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
aflatoxin B2	increases methylation	1
nickel sulfate	decreases expression	1
hydroquinone	affects expression, affects reaction, affects cotreatment	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
deguelin	decreases expression	1
abrine	decreases expression	1
pyrachlostrobin	decreases expression	1
bisphenol Z	decreases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
jinfukang	affects cotreatment, decreases expression	1
picoxystrobin	decreases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4137229	Binding	Inhibition of human recombinant guanylate kinase 1 mediated GMP to GTP conversion at 25 to 400 uM preincubated for 10 mins followed by enzyme addition measured up to 60 mins by UV absorbance method	Prodrugs of the Phosphoribosylated Forms of Hydroxypyrazinecarboxamide Pseudobase T-705 and Its De-Fluoro Analogue T-1105 as Potent Influenza Virus Inhibitors. — J Med Chem

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7TY	Ubigene A-549 MAGI1 KO	Cancer cell line	Male
CVCL_D8PM	Ubigene HCT 116 MAGI1 KO	Cancer cell line	Male
CVCL_D9IY	Ubigene HEK293 MAGI1 KO	Transformed cell line	Female
CVCL_E0GV	Ubigene HeLa MAGI1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00414765	PHASE4	COMPLETED	Aldesleukin in Participants With Metastatic Renal Cell Carcinoma or Metastatic Melanoma
NCT00777504	PHASE4	UNKNOWN	Study to the Optimal Duration of Therapy With Oral Angiogenesis Inhibitors
NCT00930345	PHASE4	TERMINATED	Biological, Pathological and Imagery Markers in the First-line Treatment of Metastatic Clear-cell Renal Cell Carcinoma
NCT01206764	PHASE4	COMPLETED	A Trial of Everolimis in Patients With Advanced Renal Cell Carcinoma.
NCT01266837	PHASE4	COMPLETED	Open Label, Single Arm Trial to Characterize Patients With Metastatic RCC Treated With Everolimus After Failure of the First VEGF-targeted Therapy (MARC-2)
NCT02056587	PHASE4	COMPLETED	Everolimus in Patients With Metastatic Renal Cell Carcinoma Following Progression on Prior Bevacizumab Treatment
NCT02338570	PHASE4	TERMINATED	Outcome-related Factors in Patients With Metastatic Renal Cell Carcinoma Treated With Everolimus (ORCHIDEE)
NCT02596035	PHASE4	COMPLETED	An Investigational Immuno-therapy Safety Trial of Nivolumab in Patients With Advanced or Metastatic Renal Cell Carcinoma
NCT02982954	PHASE4	COMPLETED	A Study to Evaluate the Safety of Nivolumab and Ipilimumab in Subjects With Previously Untreated Advanced or Metastatic Renal Cell Cancer
NCT05949424	PHASE4	UNKNOWN	OPTI - DOSE: Optimal Dosing of Oral Anticancer Drugs in Older Adults
NCT07028125	PHASE4	RECRUITING	Digital Monitoring of Self-reported Symptoms by Patients Treated With Cabozantinib Plus Nivolumab for Advanced Clear-cell Renal Carcinoma
NCT07405086	PHASE4	RECRUITING	Morning Versus Afternoon Administration of Immunotherapy for the Treatment of Advanced or Metastatic Solid Tumors, The Knight SHIFT Study
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00033904	PHASE3	COMPLETED	Survival Study Of Oncophage® vs. Observation In Patients With Kidney Cancer
NCT00126178	PHASE3	TERMINATED	Clinical Trial Studying a Personalized Cancer Vaccine in Patients With Non-metastatic Kidney Cancer
NCT00291369	PHASE3	COMPLETED	Cytokines in Patients With Metastatic Renal Cell Carcinoma of Intermediate Prognosis
NCT00410124	PHASE3	COMPLETED	RAD001 Plus Best Supportive Care (BSC) Versus BSC Plus Placebo in Patients With Metastatic Carcinoma of the Kidney Which Has Progressed After Treatment With Sorafenib and/or Sunitinib
NCT00474786	PHASE3	COMPLETED	Temsirolimus Versus Sorafenib As Second-Line Therapy In Patients With Advanced RCC Who Have Failed First-Line Sunitinib
NCT00478114	PHASE3	COMPLETED	Efficacy and Safety of Sorafenib in Advanced Renal Cell Carcinoma (RCC)
NCT00606632	PHASE3	COMPLETED	Pre-surgical Detection of Clear Cell Renal Cell Carcinoma (ccRCC) Using Radiolabeled G250-Antibody
NCT00606866	PHASE3	COMPLETED	MRI Study of BAY 43-9006 in Metastatic Renal Cell Carcinoma
NCT00631371	PHASE3	COMPLETED	Study Comparing Bevacizumab + Temsirolimus vs. Bevacizumab + Interferon-Alfa In Advanced Renal Cell Carcinoma Subjects
NCT00732914	PHASE3	COMPLETED	Sequential Study to Treat Renal Cell Carcinoma
NCT00869011	PHASE3	UNKNOWN	Exercise for Patients With Renal Cell Cancer Receiving Sunitinib
NCT00930033	PHASE3	COMPLETED	Clinical Trial to Assess the Importance of Nephrectomy
NCT01030783	PHASE3	COMPLETED	A Study to Compare Tivozanib (AV-951) to Sorafenib in Subjects With Advanced Renal Cell Carcinoma
NCT01076010	PHASE3	COMPLETED	An Extension Treatment Protocol for Subjects Who Have Participated in a Study of Tivozanib Versus Sorafenib in Kidney Carcinoma (Protocol AV-951-09-301).
NCT01198158	PHASE3	TERMINATED	Everolimus With or Without Bevacizumab in Treating Patients With Advanced Kidney Cancer That Progressed After First-Line Therapy
NCT01223027	PHASE3	COMPLETED	Study of Dovitinib Versus Sorafenib in Patients With Metastatic Renal Cell Carcinoma
NCT01224288	PHASE3	ACTIVE_NOT_RECRUITING	Dynamic Contrast Enhancement Computed Tomography for Evaluating Tumor Perfusion in Patients With Metastatic Renal Cell Carcinoma Receiving Targeted Therapies: Renal Cell Carcinoma (RCC) Scramble
NCT01235962	PHASE3	COMPLETED	A Study to Evaluate Pazopanib as an Adjuvant Treatment for Localized Renal Cell Carcinoma (RCC)
NCT01265810	PHASE3	COMPLETED	Caphosol in Oral Mucositis Due to Targeted Therapy
NCT01265901	PHASE3	COMPLETED	IMA901 in Patients Receiving Sunitinib for Advanced/Metastatic Renal Cell Carcinoma
NCT01481870	PHASE3	UNKNOWN	Comparison of Sequential Therapies With Sunitinib and Sorafenib in Advanced Renal Cell Carcinoma
NCT01582672	PHASE3	TERMINATED	Phase 3 Trial of Autologous Dendritic Cell Immunotherapy Plus Standard Treatment of Advanced Renal Cell Carcinoma
NCT01613846	PHASE3	COMPLETED	Phase III Sequential Open-label Study to Evaluate the Efficacy and Safety of Sorafenib Followed by Pazopanib Versus Pazopanib Followed by Sorafenib in the Treatment of Advanced / Metastatic Renal Cell Carcinoma (SWITCH-II)
NCT01762592	PHASE3	WITHDRAWN	REDECT 2: REnal Masses: Pivotal Trial to DEteCT Clear Cell Renal Cell Carcinoma With PET/CT
NCT01865747	PHASE3	COMPLETED	A Study of Cabozantinib (XL184) vs Everolimus in Subjects With Metastatic Renal Cell Carcinoma
NCT02231749	PHASE3	COMPLETED	Nivolumab Combined With Ipilimumab Versus Sunitinib in Previously Untreated Advanced or Metastatic Renal Cell Carcinoma (CheckMate 214)