MAGI3

Summary

MAGI3 (membrane associated guanylate kinase, WW and PDZ domain containing 3, HGNC:29647) is a protein-coding gene on chromosome 1p13.2, encoding Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 3 (Q5TCQ9). Acts as a scaffolding protein at cell-cell junctions, thereby regulating various cellular and signaling processes.

Predicted to enable frizzled binding activity. Predicted to be involved in signal transduction. Predicted to act upstream of or within positive regulation of JUN kinase activity. Located in cell junction.

Source: NCBI Gene 260425 — RefSeq curated summary.

At a glance

• GWAS associations: 20
• Clinical variants (ClinVar): 186 total
• Druggable target: yes
• MANE Select transcript: NM_001142782

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29647
Approved symbol	MAGI3
Name	membrane associated guanylate kinase, WW and PDZ domain containing 3
Location	1p13.2
Locus type	gene with protein product
Status	Approved
Aliases	MAGI-3
Ensembl gene	ENSG00000081026
Ensembl biotype	protein_coding
OMIM	615943
Entrez	260425

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000307546, ENST00000369611, ENST00000369615, ENST00000369617, ENST00000477955, ENST00000486456, ENST00000875357, ENST00000912117, ENST00000955188

RefSeq mRNA: 2 — MANE Select: NM_001142782 NM_001142782, NM_152900

CCDS: CCDS44196, CCDS860

Canonical transcript exons

ENST00000307546 — 21 exons

Exon	Start	End
ENSE00000784804	113659080	113659265
ENSE00000799981	113646486	113646642
ENSE00000957969	113590484	113590658
ENSE00000957970	113594481	113594560
ENSE00000957971	113614601	113614658
ENSE00000957972	113619736	113619830
ENSE00001068696	113585387	113585596
ENSE00001159158	113622806	113622994
ENSE00001237680	113653830	113654018
ENSE00001237692	113651014	113651206
ENSE00001237702	113649237	113649328
ENSE00001237719	113643743	113643774
ENSE00001333316	113641911	113642516
ENSE00001356727	113681198	113681336
ENSE00001356728	113673322	113673465
ENSE00001356730	113672615	113672741
ENSE00001356733	113671734	113671836
ENSE00001690552	113580542	113580661
ENSE00001940018	113390515	113391349
ENSE00003509045	113682897	113685923
ENSE00003554234	113549515	113549631

Expression profiles

Bgee: expression breadth ubiquitous, 250 present calls, max score 92.79.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.4982 / max 117.3024, expressed in 1393 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
4720	4.8265	1354
4721	0.6717	365

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower lobe of lung	UBERON:0008949	92.79	gold quality
nasal cavity epithelium	UBERON:0005384	92.57	gold quality
ileal mucosa	UBERON:0000331	92.09	gold quality
jejunal mucosa	UBERON:0000399	89.55	gold quality
kidney epithelium	UBERON:0004819	89.24	silver quality
colonic mucosa	UBERON:0000317	88.92	gold quality
palpebral conjunctiva	UBERON:0001812	88.56	gold quality
mucosa of sigmoid colon	UBERON:0004993	88.20	gold quality
corpus epididymis	UBERON:0004359	87.34	gold quality
substantia nigra pars compacta	UBERON:0001965	87.15	gold quality
pharyngeal mucosa	UBERON:0000355	87.06	gold quality
pancreatic ductal cell	CL:0002079	86.92	gold quality
esophagus squamous epithelium	UBERON:0006920	86.80	gold quality
epithelial cell of pancreas	CL:0000083	86.52	silver quality
sperm	CL:0000019	86.08	gold quality
postcentral gyrus	UBERON:0002581	85.78	gold quality
eye	UBERON:0000970	85.71	gold quality
epithelium of nasopharynx	UBERON:0001951	85.65	gold quality
pons	UBERON:0000988	85.61	gold quality
parietal lobe	UBERON:0001872	85.22	gold quality
substantia nigra pars reticulata	UBERON:0001966	85.20	gold quality
ventricular zone	UBERON:0003053	85.20	gold quality
mucosa of paranasal sinus	UBERON:0005030	85.02	gold quality
amniotic fluid	UBERON:0000173	84.84	gold quality
superior frontal gyrus	UBERON:0002661	84.28	gold quality
visceral pleura	UBERON:0002401	84.15	gold quality
Brodmann (1909) area 23	UBERON:0013554	84.11	gold quality
superior vestibular nucleus	UBERON:0007227	84.08	gold quality
cardia of stomach	UBERON:0001162	83.97	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.95	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-119	yes	23.61
E-ANND-3	yes	16.89
E-GEOD-130148	yes	5.58

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

213 targeting MAGI3, 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-5692A	100.00	74.40	6850
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-12136	99.98	72.81	5713
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192

Literature-anchored findings (GeneRIF, showing 12)

• Oncogenic human papillomavirus E6 proteins target the MAGI-2 and MAGI-3 proteins for degradation [MAGI-2, MAGI-3] (PMID:12140759)
• In epithelial cells, MAGI-3 was localized with ZO-1 and cingulin at tight junctions, whereas in primary cultured astrocytes it was found in E-cadherin-based cell-cell contacts and in focal adhesion sites. (PMID:12615970)
• These results demonstrate that MAGI-3 interacts directly with LPA(2) and regulates the ability of LPA(2) to activate Erk and RhoA. (PMID:16904289)
• All of the E6 genes from different HPV types displayed similar abilities to mediate the degradation of both p53 and MAGI-3 (PMID:18518978)
• MAGI-3 competes with NHERF-2 to negatively regulate LPA2 receptor signaling in colon cancer cells. (PMID:21134377)
• Expression levels of MAGI3 and PTEN were significantly downregulated in gliomas. (PMID:26248734)
• Results identify MAGI3 as a novel tumor suppressor and provide insight into the pathogenesis of glioma. (PMID:26452219)
• The altered mRNA isoform, called MAGI3(pPA), produces a truncated protein that acts in a dominant-negative manner to prevent full-length MAGI3 from interacting with the YAP oncoprotein, thereby relieving YAP inhibition and promoting malignant transformation of human mammary epithelial cells. (PMID:27205883)
• Our findings lend support to a genetic basis for modulation of intestinal epithelial barrier in IBD, and we have identified MAGI3 as a new candidate gene for IBD. (PMID:28545409)
• Study shows that MAGI3 undergoes premature polyadenylation (pPA) at the intron immediately downstream of its large internal exon, which is normally highly modified by N(6)-methyladenosine (m(6)A). In breast cancer cells that upregulate MAGI3 (pPA) , m(6)A levels in the large internal exon of MAGI3 are significantly reduced compared to cells that do not express MAGI3 (pPA). MAGI3 (pPA) transcripts are depleted of m(6)A. (PMID:29362392)
• Integrated analyses identify miR-34c-3p/MAGI3 axis for the Warburg metabolism in hepatocellular carcinoma. (PMID:32080912)
• Reduced MAGI3 level by HPV18E6 contributes to Wnt/beta-catenin signaling activation and cervical cancer progression. (PMID:34510826)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	magi3b	ENSDARG00000025974
danio_rerio	magi3a	ENSDARG00000101869
mus_musculus	Magi3	ENSMUSG00000052539
rattus_norvegicus	Magi3	ENSRNOG00000019885

Paralogs (6): GRIP2 (ENSG00000144596), MAGI1 (ENSG00000151276), SAV1 (ENSG00000151748), GRIP1 (ENSG00000155974), MAGI2 (ENSG00000187391), MAGIX (ENSG00000269313)

Protein

Protein identifiers

Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 3 — Q5TCQ9 (reviewed: Q5TCQ9)

Alternative names: Membrane-associated guanylate kinase inverted 3

All UniProt accessions (1): Q5TCQ9

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a scaffolding protein at cell-cell junctions, thereby regulating various cellular and signaling processes. Cooperates with PTEN to modulate the kinase activity of AKT1. Its interaction with PTPRB and tyrosine phosphorylated proteins suggests that it may link receptor tyrosine phosphatase with its substrates at the plasma membrane. In polarized epithelial cells, involved in efficient trafficking of TGFA to the cell surface. Regulates the ability of LPAR2 to activate ERK and RhoA pathways. Regulates the JNK signaling cascade via its interaction with FZD4 and VANGL2.

Subunit / interactions. Interacts with ADRB1, FZD4, FZD7, PTPRB, TGFA and VANGL2. Interacts with unidentified tyrosine phosphorylated proteins. Interacts with ADGRB1, LPAR2/EDG4, GRIN2B and PTEN. Does not interact with HTLV TAX2 or TAX3 proteins. Interacts with DLL1. Interacts with PRRG4 (via cytoplasmic domain). (Microbial infection) Interacts with HTLV1 Tax protein, possibly affecting the transformation ability of Tax. (Microbial infection) Interacts with human papillomavirus/HPV type 16 and 18 E6 proteins.

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

Tissue specificity. Widely expressed.

Post-translational modifications. Ubiquitinated following interaction with HPV E6 protein, leading to its degradation by the proteasome. Degradation is independent of E6AP ubiquitin ligase complex.

Miscellaneous. MAGI3 PDZ domains are used to design peptide ligands that bind and inhibit PDZ domains.

Similarity. Belongs to the MAGUK family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q5TCQ9-4	1	yes
Q5TCQ9-1	4
Q5TCQ9-2	2
Q5TCQ9-3	3

RefSeq proteins (2): NP_001136254, NP_690864 (=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

UniProt features (59 total): sequence conflict 13, compositionally biased region 11, domain 9, region of interest 9, modified residue 5, strand 5, splice variant 3, helix 2, chain 1, binding site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3SOE	X-RAY DIFFRACTION	1.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5TCQ9-F1	59.39	0.21

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): 121–128

Post-translational modifications (5): 234, 595, 699, 832, 915

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 201 (showing top): GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, KEGG_TIGHT_JUNCTION, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, IWANAGA_E2F1_TARGETS_INDUCED_BY_SERUM, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_GDP_METABOLIC_PROCESS, GOMF_G_PROTEIN_COUPLED_RECEPTOR_BINDING, GOBP_NUCLEOSIDE_MONOPHOSPHATE_METABOLIC_PROCESS, GOBP_GMP_METABOLIC_PROCESS, GOMF_SIGNALING_RECEPTOR_BINDING, GOCC_CELL_CELL_JUNCTION, GOBP_PURINE_CONTAINING_COMPOUND_METABOLIC_PROCESS

GO Biological Process (5): apoptotic process (GO:0006915), signal transduction (GO:0007165), intracellular signal transduction (GO:0035556), GMP metabolic process (GO:0046037), GDP metabolic process (GO:0046710)

GO Molecular Function (5): GMP kinase activity (GO:0004385), frizzled binding (GO:0005109), ATP binding (GO:0005524), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (8): nucleus (GO:0005634), cytoplasm (GO:0005737), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), bicellular tight junction (GO:0005923), membrane (GO:0016020), cell junction (GO:0030054), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
intracellular anatomical structure	2
purine ribonucleotide metabolic process	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
signal transduction	1
purine ribonucleoside monophosphate metabolic process	1
purine ribonucleoside diphosphate metabolic process	1
GMP metabolic process	1
GDP metabolic process	1
nucleoside monophosphate kinase activity	1
G protein-coupled receptor binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
anchoring junction	1
apical junction complex	1
tight junction	1
cell junction	1

Protein interactions and networks

STRING

3055 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAGI3	PTEN	P60484	962
MAGI3	LPAR2	Q9HBW0	918
MAGI3	FZD4	Q9ULV1	890
MAGI3	MAST3	O60307	763
MAGI3	PHTF1	Q9UMS5	729
MAGI3	VANGL2	Q9ULK5	696
MAGI3	FZD7	O75084	655
MAGI3	PTPN22	Q9Y2R2	600
MAGI3	AMOT	Q4VCS5	594
MAGI3	CNTN2	P78432	589
MAGI3	DLG1	Q12959	568
MAGI3	ARHGEF12	Q9NZN5	537
MAGI3	MARVELD2	Q8N4S9	535
MAGI3	SCRIB	Q14160	526
MAGI3	SDCBP	O00560	520

IntAct

578 interactions, top by confidence:

A	B	Type	Score
PTPN14	YAP1	psi-mi:“MI:0914”(association)	0.810
RNF146	TNKS	psi-mi:“MI:0914”(association)	0.790
PTEN	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.750
MAGI3	PTEN	psi-mi:“MI:0915”(physical association)	0.750
PTEN	MAGI3	psi-mi:“MI:0915”(physical association)	0.750
ADRB1	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.740
CIT	TAX1BP3	psi-mi:“MI:0914”(association)	0.690
USP43	YWHAB	psi-mi:“MI:0914”(association)	0.640
TGFA	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.620
DLGAP4	LIN7A	psi-mi:“MI:0914”(association)	0.590
Tax	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.590
Tax	MAGI3	psi-mi:“MI:0915”(physical association)	0.590
RNF146	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.590
PRRG4	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.540
PRRG4	MAGI3	psi-mi:“MI:0915”(physical association)	0.540
E6	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.540
LDLRAD4	WWP2	psi-mi:“MI:0914”(association)	0.530
CAVIN1	ZZEF1	psi-mi:“MI:0914”(association)	0.530
TCL1B	MED14	psi-mi:“MI:0914”(association)	0.530
RHBDL1	ITGB8	psi-mi:“MI:0914”(association)	0.530
ORF putative E6	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.520
E6	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.520
	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.440
MAGI3	E6	psi-mi:“MI:0407”(direct interaction)	0.440
E6	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (92): MAGI3 (Affinity Capture-MS), MAGI3 (Protein-peptide), MAGI3 (Affinity Capture-MS), MAGI3 (Affinity Capture-MS), MAGI3 (Affinity Capture-MS), PCBP2 (Co-fractionation), RPE (Co-fractionation), MAGI3 (Two-hybrid), MAGI3 (Proximity Label-MS), MAGI3 (Affinity Capture-MS), MAGI3 (Affinity Capture-MS), MAGI3 (Affinity Capture-MS), MAGI3 (Affinity Capture-MS), MAGI3 (Affinity Capture-MS), MAGI3 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2K2P5, A0JNJ1, B1WAP7, G9CGD6, O14640, O75122, O88382, O95049, O97758, P34908, P39447, P51141, P54792, P70175, Q05AS8, Q07157, Q16825, Q5F488, Q5IS48, Q5SGD7, Q5TCQ9, Q5XI81, Q61062, Q62136, Q62728, Q62936, Q6DKE2, Q6P9H4, Q6ZM86, Q812E4, Q86UL8, Q8BMA3, Q8IVH8, Q8JHI3, Q8TDW5, Q920B0, Q924I2, Q925T6, Q92997, Q95168

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

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 184 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
Trafficking of AMPA receptors	5	21.9×	7e-04
Neurexins and neuroligins	8	12.7×	1e-04
Class B/2 (Secretin family receptors)	6	9.2×	3e-03
RHOB GTPase cycle	6	7.5×	7e-03
Cardiac conduction	8	7.0×	2e-03
Cell-Cell communication	6	6.7×	1e-02
Neurotransmitter receptors and postsynaptic signal transmission	8	6.5×	2e-03
Muscle contraction	8	5.0×	9e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of synaptic transmission, glutamatergic	8	29.4×	2e-07
non-canonical Wnt signaling pathway	5	17.1×	1e-03
positive regulation of excitatory postsynaptic potential	5	15.5×	2e-03
synapse assembly	10	13.6×	2e-06
social behavior	6	9.6×	3e-03
sodium ion transmembrane transport	7	8.4×	2e-03
regulation of membrane potential	6	8.2×	6e-03
cell-cell adhesion	12	7.2×	4e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	147
Likely benign	5
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

5101 predictions. Top by Δscore:

Variant	Effect	Δscore
1:113391350:G:GA	donor_loss	1.0000
1:113549501:T:TA	acceptor_gain	1.0000
1:113549507:T:TA	acceptor_gain	1.0000
1:113549513:A:AG	acceptor_gain	1.0000
1:113549513:AG:A	acceptor_gain	1.0000
1:113549514:G:GT	acceptor_gain	1.0000
1:113549514:GG:G	acceptor_gain	1.0000
1:113549514:GGC:G	acceptor_gain	1.0000
1:113549514:GGCA:G	acceptor_gain	1.0000
1:113549514:GGCAA:G	acceptor_gain	1.0000
1:113549627:TCCAT:T	donor_gain	1.0000
1:113549629:CAT:C	donor_gain	1.0000
1:113549630:AT:A	donor_gain	1.0000
1:113549631:TGTA:T	donor_loss	1.0000
1:113549632:G:GA	donor_loss	1.0000
1:113549632:G:GG	donor_gain	1.0000
1:113549633:T:A	donor_loss	1.0000
1:113549636:G:GG	donor_gain	1.0000
1:113580537:CTTA:C	acceptor_loss	1.0000
1:113580539:TA:T	acceptor_loss	1.0000
1:113580540:A:AG	acceptor_gain	1.0000
1:113580540:AG:A	acceptor_gain	1.0000
1:113580541:G:GT	acceptor_gain	1.0000
1:113580541:GG:G	acceptor_gain	1.0000
1:113580541:GGC:G	acceptor_gain	1.0000
1:113580541:GGCA:G	acceptor_gain	1.0000
1:113580739:G:GG	donor_gain	1.0000
1:113585382:TTCA:T	acceptor_loss	1.0000
1:113585385:A:AG	acceptor_gain	1.0000
1:113585385:AG:A	acceptor_gain	1.0000

AlphaMissense

9750 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:113391064:T:A	W11R	1.000
1:113391064:T:C	W11R	1.000
1:113391158:T:C	F42S	1.000
1:113391269:T:A	V79D	1.000
1:113391274:G:A	G81R	1.000
1:113391274:G:C	G81R	1.000
1:113391274:G:T	G81W	1.000
1:113391275:G:A	G81E	1.000
1:113391278:T:C	L82P	1.000
1:113391302:T:A	V90D	1.000
1:113549536:T:C	L113S	1.000
1:113549548:T:C	L117P	1.000
1:113549559:T:C	F121L	1.000
1:113549560:T:C	F121S	1.000
1:113549561:T:A	F121L	1.000
1:113549561:T:G	F121L	1.000
1:113549599:T:A	I134N	1.000
1:113549611:T:C	L138P	1.000
1:113580551:G:T	R148M	1.000
1:113580611:T:C	F168S	1.000
1:113580641:T:C	L178S	1.000
1:113585398:G:A	G189R	1.000
1:113585398:G:C	G189R	1.000
1:113585399:G:A	G189E	1.000
1:113590615:T:A	W299R	1.000
1:113590615:T:C	W299R	1.000
1:113590652:T:C	F311S	1.000
1:113594503:T:A	W321R	1.000
1:113594503:T:C	W321R	1.000
1:113614615:T:A	W345R	1.000

dbSNP variants (sampled 300 via entrez): RS1000005515 (1:113423268 G>GA), RS1000018729 (1:113667289 G>A,C), RS1000019495 (1:113609216 A>G), RS1000020687 (1:113535714 C>A,T), RS1000036806 (1:113589525 A>G), RS1000046109 (1:113643283 C>A,T), RS1000050439 (1:113452505 C>G), RS1000074806 (1:113461819 A>G), RS1000077955 (1:113475165 T>A,C), RS1000080173 (1:113433090 T>C), RS1000092974 (1:113444250 G>A), RS1000099500 (1:113395633 C>T), RS1000105294 (1:113684084 T>A,C), RS1000111356 (1:113665333 T>C), RS1000113581 (1:113536102 A>G)

Disease associations

OMIM: gene MIM:615943 | disease phenotypes: MIM:617468, MIM:208150

GenCC curated gene-disease

Mondo (3): RASopathy (MONDO:0021060), arthrogryposis multiplex congenita (MONDO:0015168), fetal akinesia deformation sequence 1 (MONDO:0100101)

Orphanet (3): RASopathy (Orphanet:536391), Arthrogryposis multiplex congenita (Orphanet:1037), Fetal akinesia deformation sequence (Orphanet:994)

HPO phenotypes

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

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST001762_676	Obesity-related traits	2.000000e-06
GCST001958_8	Bulimia nervosa	6.000000e-06
GCST002876_8	Type 1 diabetes and autoimmune thyroid diseases	4.000000e-07
GCST003075_73	Cognitive decline rate in late mild cognitive impairment	7.000000e-07
GCST003075_79	Cognitive decline rate in late mild cognitive impairment	5.000000e-07
GCST003075_98	Cognitive decline rate in late mild cognitive impairment	4.000000e-07
GCST003075_99	Cognitive decline rate in late mild cognitive impairment	5.000000e-07
GCST003134_3	Cerebrospinal fluid clusterin levels	1.000000e-06
GCST003650_1	Bacteremia	5.000000e-06
GCST003855_2	Gut microbiota (bacterial taxa)	5.000000e-06
GCST004132_97	Crohn’s disease	4.000000e-06
GCST004866_5	Alopecia areata	7.000000e-07
GCST009856_27	Leukocyte telomere length	1.000000e-06
GCST009890_1	Parental lifespan	6.000000e-09
GCST010152_2	Neuroblastoma or malignant cutaneous melanoma	5.000000e-08
GCST010571_6	Autoimmune thyroid disease	2.000000e-12
GCST011100_2	Aging traits (healthspan, parental lifespan or longevity) (multivariate analysis)	2.000000e-09
GCST011365_83	Myocardial infarction	3.000000e-07
GCST011656_1	Lung cancer	9.000000e-08
GCST012490_199	Femur bone mineral density x serum urate levels interaction	1.000000e-09

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0005134	amino acid measurement
EFO:0007710	cognitive decline measurement
EFO:0007874	gut microbiome measurement
EFO:0007796	parental longevity
EFO:0009762	healthspan
EFO:0004531	urate measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5212 (SINGLE PROTEIN)

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

ChEMBL bioactivities

8 potent at pChembl≥5 of 15 total, top 8 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.70	Kd	20	nM	CHEMBL266681
6.13	IC50	740	nM	CHEMBL266681
6.00	Kd	1000	nM	CHEMBL411352
5.39	IC50	4100	nM	CHEMBL311026
5.35	IC50	4500	nM	CHEMBL2369910
5.29	IC50	5100	nM	CHEMBL2369613
5.28	IC50	5200	nM	CHEMBL310546
5.01	IC50	9800	nM	CHEMBL1790641

PubChem BioAssay actives

8 with measured affinity, of 21 total; 7 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(4S)-5-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-5-amino-1-[[(2S,3S)-1-[[(2S,3R)-1-[[(2S)-1-[[(1S)-1-carboxy-2-methylpropyl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-4-[[(2S)-3-carboxy-2-[[(2S)-3-phenyl-2-[[(2S)-pyrrolidine-2-carbonyl]amino]propanoyl]amino]propanoyl]amino]-5-oxopentanoic acid	102397: Dissociation constant for binding to MAGI-3 PDZ2 domain	kd	0.0200	uM
(4S)-5-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-5-amino-1-[[(2S,3S)-1-[[(2S,3R)-1-[[(2S)-6-amino-1-[[(1S)-1-carboxy-2-methylpropyl]amino]-1-oxohexan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-4-[[(2S)-3-carboxy-2-[[(2S)-3-phenyl-2-[[(2S)-pyrrolidine-2-carbonyl]amino]propanoyl]amino]propanoyl]amino]-5-oxopentanoic acid	102397: Dissociation constant for binding to MAGI-3 PDZ2 domain	kd	1.0000	uM
(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-acetamido-3-(1H-imidazol-5-yl)propanoyl]amino]-3-hydroxybutanoyl]amino]-5-amino-5-oxopentanoyl]amino]-3-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-methylbutanoic acid	102395: Inhibitory concentration for MAGI-3 PDZ2 domain	ic50	4.1000	uM
(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S,3S)-2-[[(2S)-2-acetamido-5-amino-5-oxopentanoyl]amino]-3-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-methylbutanoic acid	102395: Inhibitory concentration for MAGI-3 PDZ2 domain	ic50	4.5000	uM
(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S,3R)-2-acetamido-3-hydroxybutanoyl]amino]-5-amino-5-oxopentanoyl]amino]-3-methylpentanoyl]amino]-3,4-dihydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-methylbutanoic acid	102395: Inhibitory concentration for MAGI-3 PDZ2 domain	ic50	5.1000	uM
(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S,3R)-2-acetamido-3-hydroxybutanoyl]amino]-5-amino-5-oxopentanoyl]amino]-3-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-methylbutanoic acid	102395: Inhibitory concentration for MAGI-3 PDZ2 domain	ic50	5.2000	uM
(2S)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S,3S)-2-acetamido-3-hydroxybutanoyl]-methylamino]-5-amino-5-oxopentanoyl]amino]-3-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-methylbutanoic acid	102395: Inhibitory concentration for MAGI-3 PDZ2 domain	ic50	9.8000	uM

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	decreases expression, decreases methylation, affects expression	3
entinostat	affects cotreatment, decreases expression	2
Benzo(a)pyrene	decreases expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
Particulate Matter	increases abundance, increases expression	2
FR900359	decreases phosphorylation	1
sulforaphane	decreases expression	1
sodium arsenite	decreases expression	1
nickel sulfate	decreases 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
dorsomorphin	affects cotreatment, decreases expression	1
asparanin A	decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
Vorinostat	decreases expression	1
Leflunomide	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Caffeine	decreases phosphorylation	1
Cisplatin	decreases expression, affects cotreatment	1
Doxorubicin	decreases expression	1
Phthalic Acids	decreases methylation	1
Quercetin	decreases expression	1
Urethane	increases expression	1
Valproic Acid	affects expression	1
Cyclosporine	decreases expression	1
Asbestos, Crocidolite	increases methylation	1
Lactic Acid	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
CHEMBL3880037	Binding	Inhibition of fluorescein labeled PFDEDQHTQITWV-COOH interaction with GST-fused MAGI-3 second PDZ domain (unknown origin) expressed in Escherichia coli BL21 (DE3) by fluorescence polarization assay	Small molecule inhibition of PDZ-domain interaction

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_D7TZ	Ubigene A-549 MAGI3 KO	Cancer cell line	Male
CVCL_D8PN	Ubigene HCT 116 MAGI3 KO	Cancer cell line	Male
CVCL_D9J0	Ubigene HEK293 MAGI3 KO	Transformed cell line	Female
CVCL_E0GW	Ubigene HeLa MAGI3 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04888936	Not specified	RECRUITING	Clinical, Genetic, and Epidemiologic Study of Children and Adults With RASopathies
NCT05761314	Not specified	RECRUITING	Solid Tumors in RASopathies
NCT06331117	Not specified	UNKNOWN	Effect of RAS/MAPK Pathway Hyperactivation on Growth’ and Bone’ Profile of the RASopathies
NCT06355622	Not specified	UNKNOWN	Prevalence and Characterization of Pain in RASopathies
NCT06489067	Not specified	RECRUITING	Study of the Thyroid Function and Echostructural Morphology in Patients Affected With Rasopathies (ECORAS2023)
NCT06776380	Not specified	RECRUITING	Pubertal Development in Patients with RASopathies
NCT07005297	Not specified	NOT_YET_RECRUITING	Clinical Genetics Branch Eligibility Screening Survey
NCT07344480	Not specified	RECRUITING	Retrospective Natural History Study of RASopathy-associated Cardiomyopathy (RAS-CM)
NCT07464821	Not specified	RECRUITING	National Multicentre Study on Lipid Profile in Noonan Syndrome and Related Disorders: Trends by Age, Gender and Genotype
NCT05393375	Not specified	COMPLETED	Arthrogryposis Multiplex Congenita in Pediatric Age: Correlation Between MUScular MRI and Functional Evaluation
NCT05673265	Not specified	UNKNOWN	Pediatric and Adult Registry for Patients With ARThrogryposis
NCT06130592	Not specified	UNKNOWN	Technical Feasibility Study of Ultrasound Muscle Imaging in Antenatal Ultrasound
NCT07360574	Not specified	NOT_YET_RECRUITING	Piezo2-related Arthrogryposis & physiopathOLOgy 3