MIB2

Summary

MIB2 (MIB E3 ubiquitin protein ligase 2, HGNC:30577) is a protein-coding gene on chromosome 1p36.33, encoding E3 ubiquitin-protein ligase MIB2 (Q96AX9). E3 ubiquitin-protein ligase that mediates ubiquitination of Delta receptors, which act as ligands of Notch proteins.

The protein encoded by this gene is an E3 ubiquitin protein ligase that mediates ubiquitination of proteins in the Notch signaling pathway. The encoded protein may be a suppressor of melanoma invasion.

Source: NCBI Gene 142678 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 292 total — 1 pathogenic
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• MANE Select transcript: NM_001170687

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30577
Approved symbol	MIB2
Name	MIB E3 ubiquitin protein ligase 2
Location	1p36.33
Locus type	gene with protein product
Status	Approved
Aliases	skeletrophin, ZZZ5, FLJ39787
Ensembl gene	ENSG00000197530
Ensembl biotype	protein_coding
OMIM	611141
Entrez	142678

Gene structure

Transcript identifiers

Ensembl transcripts: 163 — 142 protein_coding, 13 retained_intron, 6 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000355826, ENST00000378708, ENST00000378712, ENST00000463492, ENST00000464570, ENST00000467597, ENST00000470373, ENST00000473511, ENST00000477990, ENST00000479659, ENST00000483015, ENST00000486072, ENST00000487053, ENST00000489635, ENST00000502470, ENST00000503789, ENST00000504599, ENST00000505370, ENST00000505820, ENST00000506488, ENST00000507082, ENST00000507229, ENST00000508148, ENST00000508455, ENST00000510793, ENST00000511502, ENST00000511910, ENST00000512004, ENST00000514234, ENST00000514363, ENST00000518681, ENST00000520777, ENST00000889171, ENST00000889172, ENST00000889173, ENST00000889174, ENST00000889175, ENST00000889176, ENST00000889177, ENST00000889178, ENST00000889179, ENST00000889180, ENST00000889181, ENST00000889182, ENST00000889183, ENST00000889184, ENST00000889185, ENST00000889186, ENST00000889187, ENST00000889188, ENST00000889189, ENST00000889190, ENST00000889191, ENST00000889192, ENST00000889193, ENST00000889194, ENST00000889195, ENST00000889196, ENST00000889197, ENST00000889198, ENST00000889199, ENST00000889200, ENST00000889201, ENST00000889202, ENST00000889203, ENST00000889204, ENST00000889205, ENST00000933979, ENST00000933980, ENST00000933981, ENST00000933982, ENST00000933983, ENST00000958537, ENST00000958538, ENST00000958539, ENST00000958540, ENST00000958541, ENST00000958542, ENST00000958543, ENST00000958544, ENST00000958545, ENST00000958546, ENST00000958547, ENST00000958548, ENST00000958549, ENST00000958551, ENST00000958552, ENST00000958554, ENST00000958559, ENST00000958560, ENST00000958561, ENST00000958562, ENST00000958563, ENST00000958564, ENST00000958565, ENST00000958566, ENST00000958567, ENST00000958568, ENST00000958569, ENST00000958570, ENST00000958571, ENST00000958572, ENST00000958573, ENST00000958574, ENST00000958575, ENST00000958576, ENST00000958577, ENST00000958578, ENST00000958579, ENST00000958580, ENST00000958581, ENST00000958582, ENST00000958583, ENST00000958584, ENST00000958585, ENST00000958586, ENST00000958587, ENST00000958588, ENST00000958589, ENST00000958590, ENST00000958591, ENST00000958592, ENST00000958593, ENST00000958594, ENST00000958595, ENST00000958596, ENST00000958597, ENST00000958598, ENST00000958599, ENST00000958600, ENST00000958601, ENST00000958602, ENST00000958603, ENST00000958604, ENST00000958605, ENST00000958606, ENST00000958607, ENST00000958608, ENST00000958609, ENST00000958610, ENST00000958611, ENST00000958612, ENST00000958613, ENST00000958614, ENST00000958615, ENST00000958616, ENST00000958617, ENST00000958618, ENST00000958619, ENST00000958620, ENST00000958621, ENST00000958622, ENST00000958623, ENST00000958624, ENST00000958625, ENST00000958626, ENST00000958627, ENST00000958628, ENST00000958629, ENST00000958630, ENST00000958631, ENST00000958632, ENST00000958633

RefSeq mRNA: 5 — MANE Select: NM_001170687 NM_001170686, NM_001170687, NM_001170688, NM_001170689, NM_080875

CCDS: CCDS41224, CCDS53261, CCDS53262, CCDS53264

Canonical transcript exons

ENST00000355826 — 20 exons

Exon	Start	End
ENSE00002129565	1615500	1615633
ENSE00003502987	1629639	1629704
ENSE00003506180	1623431	1623699
ENSE00003508056	1625286	1625428
ENSE00003509279	1616508	1616614
ENSE00003525913	1626650	1626754
ENSE00003537484	1623774	1623945
ENSE00003548099	1624991	1625185
ENSE00003554681	1630292	1630605
ENSE00003590159	1627673	1627829
ENSE00003601252	1628489	1628722
ENSE00003646402	1625546	1625653
ENSE00003650046	1627296	1627444
ENSE00003653398	1628273	1628399
ENSE00003656004	1627074	1627207
ENSE00003658755	1629385	1629566
ENSE00003667001	1626837	1626999
ENSE00003667800	1629133	1629311
ENSE00003674348	1628019	1628179
ENSE00003785943	1624795	1624901

Expression profiles

Bgee: expression breadth ubiquitous, 214 present calls, max score 98.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.2346 / max 119.5832, expressed in 1792 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
125	6.3207	1687
124	4.6550	1678
130	0.8602	202
131	0.4211	172
129	0.3755	154
132	0.1923	80
133	0.1739	83
127	0.1206	53
126	0.0646	33
128	0.0507	18

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	98.43	gold quality
apex of heart	UBERON:0002098	98.40	gold quality
adenohypophysis	UBERON:0002196	98.19	gold quality
right ovary	UBERON:0002118	98.05	gold quality
lower esophagus mucosa	UBERON:0035834	97.97	gold quality
left ovary	UBERON:0002119	97.92	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.81	gold quality
right uterine tube	UBERON:0001302	97.36	gold quality
cerebellar hemisphere	UBERON:0002245	97.17	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.07	gold quality
cerebellar cortex	UBERON:0002129	97.04	gold quality
left uterine tube	UBERON:0001303	96.76	gold quality
skin of abdomen	UBERON:0001416	96.69	gold quality
right frontal lobe	UBERON:0002810	96.65	gold quality
endocervix	UBERON:0000458	96.51	gold quality
pituitary gland	UBERON:0000007	96.45	gold quality
body of uterus	UBERON:0009853	96.45	gold quality
right lobe of thyroid gland	UBERON:0001119	96.37	gold quality
ascending aorta	UBERON:0001496	96.37	gold quality
thoracic aorta	UBERON:0001515	96.28	gold quality
mucosa of transverse colon	UBERON:0004991	96.28	gold quality
right testis	UBERON:0004534	96.16	gold quality
skin of leg	UBERON:0001511	96.15	gold quality
right coronary artery	UBERON:0001625	96.12	gold quality
ectocervix	UBERON:0012249	96.05	gold quality
descending thoracic aorta	UBERON:0002345	96.00	gold quality
gastrocnemius	UBERON:0001388	95.95	gold quality
left lobe of thyroid gland	UBERON:0001120	95.92	gold quality
left testis	UBERON:0004533	95.80	gold quality
transverse colon	UBERON:0001157	95.59	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.20
E-CURD-112	no	3.17

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 14)

• Mib2 has functional similarities to Mib1, but might have distinct roles in Notch signaling as an E3 ubiquitin ligase (PMID:15824097)
• Skeletrophin, a novel RING molecule controlled by the chromatin remodeling complex, is down-regulated in melanoma. (PMID:15869411)
• skeletrophin is a novel ubiquitin ligase that targets the intracellular region of Jagged-2 and is aberrantly overexpressed in multiple myeloma cells. (PMID:15920166)
• skeletrophin might be a novel suppressor factor for melanoma invasion (PMID:16715130)
• Data identify Mind bomb-2 as an E3 ubiquitin ligase that interacts with and ubiquitinates the NR2B subunit of the NMDAR in mammalian cells. (PMID:17962190)
• identify MIB2 as a novel component of the activated BCL10 signaling complex and a missing link in the BCL10-dependent NF-kappaB signaling pathway. (PMID:21896478)
• The DLAIS motif in MAVS was found to be critical for MIB2 binding, the ligation of K63-linked ubiquitin to TANK-binding kinase 1, and phosphorylation-mediated IRF3/7 activation. (PMID:25142606)
• Here, we report a novel interaction between CYLD and MIB2 that supports the hypothesis that the CYLD/MIB2 interaction might play a pathogenic role in human cancer. (PMID:25565632)
• Missense p.V742G variant in MIB2 is associated with left ventricle hypertrabeculation/non-compaction and Menetrier-like gastropathy. (PMID:28013292)
• MIB2 represses the cytotoxic potential of RIPK1 by ubiquitylating lysine residues in the C-terminal portion of RIPK1. Disruption of MIB2-mediated ubiquitylation, either by mutation of MIB2’s E3 activity or RIPK1’s ubiquitin-acceptor lysines, sensitizes cells to RIPK1-mediated cell death. (PMID:29642005)
• Results suggest that MIB2 enhances NF-kappaB signaling in inflammation by promoting the ubiquitin-dependent degradation of CYLD. (PMID:31366726)
• MIND bomb 2 prevents RIPK1 kinase activity-dependent and -independent apoptosis through ubiquitylation of cFLIPL. (PMID:33469115)
• E3 ubiquitin-protein ligase 2 inhibits cell proliferation, migration, and invasion of non-small cell lung cancer through ubiquitination of Notch1. (PMID:34971948)
• MIB2 promotes the progression of non-small cell lung cancer by regulating cell cycle control pathways. (PMID:37436668)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mib2	ENSDARG00000103609
mus_musculus	Mib2	ENSMUSG00000029060
rattus_norvegicus	Mib2	ENSRNOG00000017564
drosophila_melanogaster	mib2	FBGN0086442
caenorhabditis_elegans		WBGENE00012933

Paralogs (1): MIB1 (ENSG00000101752)

Protein

Protein identifiers

E3 ubiquitin-protein ligase MIB2 — Q96AX9 (reviewed: Q96AX9)

Alternative names: Mind bomb homolog 2, Novel zinc finger protein, Putative NF-kappa-B-activating protein 002N, RING-type E3 ubiquitin transferase MIB2, Skeletrophin, Zinc finger ZZ type with ankyrin repeat domain protein 1

All UniProt accessions (15): A0A8C8N694, A0A8C8USR6, D6R9Q6, D6RAZ0, D6RDI1, D6RE96, D6RED3, D6RFJ2, D6RHY5, E9PD12, Q96AX9, F2Z2L2, H0YAM8, J3QLE0, J3QR95

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that mediates ubiquitination of Delta receptors, which act as ligands of Notch proteins. Positively regulates the Delta-mediated Notch signaling by ubiquitinating the intracellular domain of Delta, leading to endocytosis of Delta receptors.

Subunit / interactions. Interacts with actin monomer.

Subcellular location. Cytoplasm. Endosome.

Tissue specificity. Expressed in skeletal muscle, and to a lesser extent in heart, brain and kidney.

Post-translational modifications. Ubiquitinated. Possibly via autoubiquitination.

Induction. Down-regulated in many primary skin melanomas. Treatment with a demethylating agent, 5’-aza-2-deoxycytidine, restores expression, suggesting that down-regulation is the result of methylation of the gene.

Pathway. Protein modification; protein ubiquitination.

Isoforms (9)

UniProt ID	Names	Canonical?
Q96AX9-1	1	yes
Q96AX9-3	3, Gamma
Q96AX9-4	4, Beta
Q96AX9-5	5
Q96AX9-10	10
Q96AX9-7	7
Q96AX9-8	8
Q96AX9-9	9
Q96AX9-6	6

RefSeq proteins (5): NP_001164157, NP_001164158, NP_001164159, NP_001164160, NP_543151 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000433	Znf_ZZ	Domain
IPR001841	Znf_RING	Domain
IPR002110	Ankyrin_rpt	Repeat
IPR010606	Mib_Herc2	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR037252	Mib_Herc2_sf	Homologous_superfamily
IPR040847	SH3_15	Domain
IPR042056	MIB1/2_ZZ	Domain
IPR043145	Znf_ZZ_sf	Homologous_superfamily

Pfam: PF00023, PF00569, PF06701, PF12796, PF13920, PF18346

UniProt features (46 total): sequence conflict 11, repeat 9, splice variant 9, binding site 8, zinc finger region 3, modified residue 3, domain 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96AX9-F1	85.74	0.58

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 (8): 91; 94; 106; 109; 115; 118; 124; 128

Post-translational modifications (3): 251, 1, 1

Function

Pathways and Gene Ontology

Reactome pathways

26 pathways

ID	Pathway
R-HSA-2122948	Activated NOTCH1 Transmits Signal to the Nucleus
R-HSA-2644606	Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2691232	Constitutive Signaling by NOTCH1 HD Domain Mutants
R-HSA-2894862	Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-2979096	NOTCH2 Activation and Transmission of Signal to the Nucleus
R-HSA-5357786	TNFR1-induced proapoptotic signaling
R-HSA-5357905	Regulation of TNFR1 signaling
R-HSA-9013507	NOTCH3 Activation and Transmission of Signal to the Nucleus
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-9931295	PD-L1(CD274) glycosylation and translocation to plasma membrane
R-HSA-1280218	Adaptive Immune System
R-HSA-157118	Signaling by NOTCH
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-168256	Immune System
R-HSA-1980143	Signaling by NOTCH1
R-HSA-1980145	Signaling by NOTCH2
R-HSA-2644602	Signaling by NOTCH1 PEST Domain Mutants in Cancer
R-HSA-2644603	Signaling by NOTCH1 in Cancer
R-HSA-2691230	Signaling by NOTCH1 HD Domain Mutants in Cancer
R-HSA-2894858	Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-73887	Death Receptor Signaling
R-HSA-75893	TNF signaling
R-HSA-9012852	Signaling by NOTCH3
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 130 (showing top): REACTOME_SIGNALING_BY_NOTCH, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_TUMOR_NECROSIS_FACTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_REGULATION_OF_TUMOR_NECROSIS_FACTOR_MEDIATED_SIGNALING_PATHWAY, GOMF_ACTIN_BINDING, GOBP_POSITIVE_REGULATION_OF_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_REGULATION_OF_RESPONSE_TO_CYTOKINE_STIMULUS, GOBP_RESPONSE_TO_TUMOR_NECROSIS_FACTOR, GOCC_TRANSFERASE_COMPLEX

GO Biological Process (4): Notch signaling pathway (GO:0007219), regulation of tumor necrosis factor-mediated signaling pathway (GO:0010803), protein ubiquitination (GO:0016567), positive regulation of canonical NF-kappaB signal transduction (GO:0043123)

GO Molecular Function (7): actin binding (GO:0003779), ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (6): ubiquitin ligase complex (GO:0000151), cytoplasm (GO:0005737), early endosome (GO:0005769), cytosol (GO:0005829), plasma membrane (GO:0005886), endosome (GO:0005768)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
TNF signaling	2
Signaling by NOTCH	2
Signaling by NOTCH1 in Cancer	2
Signaling by NOTCH1	1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1
Signaling by NOTCH1 HD Domain Mutants in Cancer	1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1
Signaling by NOTCH2	1
Signaling by NOTCH3	1
Class I MHC mediated antigen processing & presentation	1
Regulation of PD-L1(CD274) Post-translational modification	1
Immune System	1
Signal Transduction	1
Diseases of signal transduction by growth factor receptors and second messengers	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
cell surface receptor signaling pathway	1
regulation of cytokine-mediated signaling pathway	1
tumor necrosis factor-mediated signaling pathway	1
protein modification by small protein conjugation	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
cytoskeletal protein binding	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular protein-containing complex	1
transferase complex	1
intracellular anatomical structure	1
endosome	1
cytoplasm	1
membrane	1
cell periphery	1
endomembrane system	1
cytoplasmic vesicle	1

Protein interactions and networks

STRING

3184 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MIB2	BCL10	O95999	916
MIB2	ARID1A	O14497	669
MIB2	JAG2	Q9Y219	658
MIB2	TFAP2A	P05549	584
MIB2	UBE2D2	P51669	569
MIB2	MED12	Q93074	518
MIB2	ACTA1	P02568	517
MIB2	NEURL1B	A8MQ27	510
MIB2	NEURL1	O76050	508
MIB2	SNAI1	O95863	499
MIB2	RNF41	Q9H4P4	486
MIB2	ERICH1	Q86X53	462
MIB2	SNW1	Q13573	416
MIB2	RNF128	Q8TEB7	404
MIB2	DMD	P11532	386

IntAct

43 interactions, top by confidence:

A	B	Type	Score
CCT2	TXNDC9	psi-mi:“MI:0914”(association)	0.730
CCT3	TXNDC9	psi-mi:“MI:0914”(association)	0.640
CCT5	TXNDC9	psi-mi:“MI:0914”(association)	0.640
P2RY1	SLC19A2	psi-mi:“MI:0914”(association)	0.530
ELANE	ITIH2	psi-mi:“MI:0914”(association)	0.530
TRIP6	WTIP	psi-mi:“MI:0914”(association)	0.530
CCT7	PEX7	psi-mi:“MI:0914”(association)	0.530
MIB2	TBK1	psi-mi:“MI:0915”(physical association)	0.500
MIB2	NCL	psi-mi:“MI:0915”(physical association)	0.400
UBE2U	MIB2	psi-mi:“MI:0915”(physical association)	0.370
NAF1	C1orf226	psi-mi:“MI:0914”(association)	0.350
HIF1AN	CNOT1	psi-mi:“MI:0914”(association)	0.350
rep	CNK3/IPCEF1	psi-mi:“MI:0914”(association)	0.350
RIPK1	H2AZ1	psi-mi:“MI:0914”(association)	0.350
SRP14	RPSA2	psi-mi:“MI:0914”(association)	0.350
TMEM74	KLRG2	psi-mi:“MI:0914”(association)	0.350
CHRNB4	GPR89A	psi-mi:“MI:0914”(association)	0.350
F9	APBB1	psi-mi:“MI:0914”(association)	0.350
DEFB125	ZZEF1	psi-mi:“MI:0914”(association)	0.350
PMCH	B4GALT5	psi-mi:“MI:0914”(association)	0.350
C6orf15	TIMM8A	psi-mi:“MI:0914”(association)	0.350
NUP58	RNF40	psi-mi:“MI:0914”(association)	0.350
IKZF5	PEX14	psi-mi:“MI:0914”(association)	0.350
IKZF1	MTA2	psi-mi:“MI:0914”(association)	0.350
PI15	GLS	psi-mi:“MI:0914”(association)	0.350
MACC1	MARK3	psi-mi:“MI:0914”(association)	0.350
PLAAT3	OCLN	psi-mi:“MI:0914”(association)	0.350
PLPPR4	FAM91A1	psi-mi:“MI:0914”(association)	0.350
KCNH2	KLHDC10	psi-mi:“MI:0914”(association)	0.350

BioGRID (100): MIB2 (Affinity Capture-MS), MIB2 (Affinity Capture-Western), MIB2 (Affinity Capture-MS), CYLD (Biochemical Activity), MIB2 (Co-fractionation), MIB2 (Biochemical Activity), MIB2 (Proximity Label-MS), MIB2 (Affinity Capture-MS), MIB2 (Affinity Capture-MS), MIB2 (Affinity Capture-MS), MIB2 (Affinity Capture-MS), MIB2 (Affinity Capture-MS), MIB2 (Affinity Capture-MS), MIB2 (Affinity Capture-MS), MIB2 (Affinity Capture-MS)

ESM2 similar proteins: A2AAJ9, A2ABU4, A2RUH7, B4GBH0, D3ZGQ5, O09127, O70468, O75038, O88599, O95382, P16419, P21709, P22455, P22607, P29322, P54760, P54761, P55144, P55146, P56741, P70218, P70402, Q00653, Q06418, Q13203, Q13308, Q13425, Q14896, Q15746, Q290N5, Q32P44, Q4LDD4, Q5FW53, Q5PQM4, Q5VST9, Q5VTT5, Q60750, Q61851, Q68LP1, Q80UW5

Diamond homologs: A2AWP0, A5D8Q0, A9JTP3, A9ULZ2, D3ZDI6, O14064, O62640, O88738, P41437, Q05AK5, Q13075, Q24307, Q28H51, Q5BKL8, Q5E9J6, Q5NVC7, Q60989, Q68LP1, Q6AYH3, Q6GNY1, Q6R7D0, Q6R7I2, Q6TEM9, Q804S5, Q80SY4, Q86YT6, Q8JGN5, Q8JHV9, Q8R516, Q8WY64, Q969K3, Q96AX9, Q96CA5, Q96P09, Q99KR6, Q9JIB3, Q9JIB6, Q9LY87, Q9NR09, Q9QUK4

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
MIB2	up-regulates	JAG2	ubiquitination
Ub:E2	“up-regulates activity”	MIB2	ubiquitination
MIB2	“down-regulates activity”	RIPK1	polyubiquitination
MIB2	“down-regulates quantity by destabilization”	RIPK1	ubiquitination
MIB2	“down-regulates quantity”	GRIN2B	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 70 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.

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of telomere maintenance via telomerase	5	64.3×	3e-06
binding of sperm to zona pellucida	5	37.0×	2e-05

Disease & clinical

Cancer significance

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

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	213
Likely benign	31
Benign	8

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
152807	GRCh38/hg38 1p36.33-36.32(chr1:821713-5099990)x1	Pathogenic

SpliceAI

3862 predictions. Top by Δscore:

Variant	Effect	Δscore
1:1623942:GCCC:G	donor_gain	1.0000
1:1624793:A:AG	acceptor_gain	1.0000
1:1624794:G:GA	acceptor_gain	1.0000
1:1624794:GT:G	acceptor_gain	1.0000
1:1625427:AGGT:A	donor_loss	1.0000
1:1625428:GGTGA:G	donor_loss	1.0000
1:1625429:GTGAG:G	donor_loss	1.0000
1:1625430:T:G	donor_loss	1.0000
1:1625544:A:AG	acceptor_gain	1.0000
1:1625545:G:GG	acceptor_gain	1.0000
1:1626648:A:AG	acceptor_gain	1.0000
1:1626649:G:GA	acceptor_gain	1.0000
1:1626649:GC:G	acceptor_gain	1.0000
1:1626649:GCA:G	acceptor_gain	1.0000
1:1626649:GCAC:G	acceptor_gain	1.0000
1:1626649:GCACC:G	acceptor_gain	1.0000
1:1626750:CCCCT:C	donor_gain	1.0000
1:1626751:CCCT:C	donor_gain	1.0000
1:1626752:CCT:C	donor_gain	1.0000
1:1626753:CT:C	donor_gain	1.0000
1:1626753:CTG:C	donor_loss	1.0000
1:1626754:TGT:T	donor_loss	1.0000
1:1626755:G:GG	donor_gain	1.0000
1:1626755:GTG:G	donor_loss	1.0000
1:1626756:TGAG:T	donor_loss	1.0000
1:1626757:GAGTC:G	donor_loss	1.0000
1:1626954:G:GT	donor_gain	1.0000
1:1626957:G:GT	donor_gain	1.0000
1:1626969:G:GT	donor_gain	1.0000
1:1626989:G:GT	donor_gain	1.0000

AlphaMissense

6794 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000005080 (1:1620208 T>A), RS1000045042 (1:1629852 A>C,G), RS1000066132 (1:1614974 C>A), RS1000071654 (1:1621197 G>T), RS1000171516 (1:1620014 G>A), RS1000385433 (1:1626959 T>C), RS1000486332 (1:1630594 A>C,T), RS1000561667 (1:1615335 C>T), RS1000615266 (1:1618889 C>G), RS1000671975 (1:1619996 T>C), RS1000715897 (1:1627135 A>G), RS1000762972 (1:1627522 C>A,T), RS1000822115 (1:1630600 C>A,G,T), RS1000934524 (1:1630689 G>A,C,T), RS1001148577 (1:1619356 C>A,T)

Disease associations

OMIM: gene MIM:611141 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST005951_34	Body mass index	3.000000e-08
GCST007740_1	Iris color (a* coordinate)	4.000000e-06
GCST007741_1	Iris color (b* coordinate)	7.000000e-06
GCST008839_353	Height	1.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0009764	eye colour measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects cotreatment, decreases expression	5
Ozone	affects expression, affects cotreatment, increases expression, increases oxidation, increases abundance	3
sodium arsenite	increases expression	2
methacrylaldehyde	affects cotreatment, increases expression, increases oxidation, increases abundance	2
Acetaminophen	decreases expression, increases expression	2
Acrolein	affects cotreatment, increases expression, increases oxidation, increases abundance	2
Air Pollutants	increases expression, increases oxidation, affects expression, affects cotreatment, increases abundance	2
Aflatoxin B1	increases expression, decreases methylation	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
alpha-pinene	affects cotreatment, increases expression, increases oxidation, increases abundance	1
pirinixic acid	decreases expression, increases activity, affects binding	1
bisphenol A	decreases methylation	1
trichostatin A	decreases expression	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	increases reaction, affects binding	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, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
enzalutamide	affects expression	1
jinfukang	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Ethanol	increases abundance, increases expression, affects cotreatment	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation	1
Camptothecin	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Diethylhexyl Phthalate	increases methylation, increases abundance	1

Clinical trials (associated diseases)

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