MYCBP2

Summary

MYCBP2 (MYC binding protein 2, HGNC:23386) is a protein-coding gene on chromosome 13q22.3, encoding E3 ubiquitin-protein ligase MYCBP2 (O75592). Atypical E3 ubiquitin-protein ligase which specifically mediates ubiquitination of threonine and serine residues on target proteins, instead of ubiquitinating lysine residues.

This gene encodes an E3 ubiquitin-protein ligase and member of the PHR (Phr1/MYCBP2, highwire and RPM-1) family of proteins. The encoded protein plays a role in axon guidance and synapse formation in the developing nervous system. In mammalian cells, this protein regulates the cAMP and mTOR signaling pathways, and may additionally regulate autophagy. Reduced expression of this gene has been observed in acute lymphoblastic leukemia patients and a mutation in this gene has been identified in patients with a rare inherited vision defect.

Source: NCBI Gene 23077 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Strong, GenCC)
• GWAS associations: 7
• Clinical variants (ClinVar): 832 total — 12 pathogenic, 7 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_015057

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23386
Approved symbol	MYCBP2
Name	MYC binding protein 2
Location	13q22.3
Locus type	gene with protein product
Status	Approved
Aliases	PAM, KIAA0916, FLJ10106, PHR1
Ensembl gene	ENSG00000005810
Ensembl biotype	protein_coding
OMIM	610392
Entrez	23077

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 15 retained_intron, 11 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000357337, ENST00000429715, ENST00000466564, ENST00000474882, ENST00000485061, ENST00000486679, ENST00000544440, ENST00000682321, ENST00000683697, ENST00000683823, ENST00000684354, ENST00000695078, ENST00000695079, ENST00000695080, ENST00000695081, ENST00000695082, ENST00000695083, ENST00000695084, ENST00000695085, ENST00000695086, ENST00000695087, ENST00000695088, ENST00000695089, ENST00000695090, ENST00000695091, ENST00000695092, ENST00000695093, ENST00000695094, ENST00000695095, ENST00000932841

RefSeq mRNA: 1 — MANE Select: NM_015057 NM_015057

Canonical transcript exons

ENST00000544440 — 83 exons

Exon	Start	End
ENSE00000500626	77051811	77051918
ENSE00000684253	77087484	77087633
ENSE00000802466	77050997	77051162
ENSE00000802468	77055558	77055767
ENSE00000802469	77056986	77057093
ENSE00000802472	77059523	77059626
ENSE00000802473	77061169	77061301
ENSE00000802476	77064615	77064734
ENSE00000802485	77077148	77077387
ENSE00000802506	77097370	77099013
ENSE00000923746	77078824	77078889
ENSE00001155129	77044657	77045493
ENSE00001252517	77076751	77076849
ENSE00001252856	77093165	77093332
ENSE00001252865	77095358	77095602
ENSE00001253400	77061662	77061790
ENSE00001253408	77062596	77062697
ENSE00001253421	77065992	77066088
ENSE00001253430	77067581	77067864
ENSE00001253437	77068565	77068831
ENSE00001253446	77070631	77070711
ENSE00001253496	77083032	77083192
ENSE00001344954	77058218	77058406
ENSE00001345001	77081427	77081651
ENSE00001345003	77081837	77081993
ENSE00001345170	77088832	77089031
ENSE00001345174	77090106	77090263
ENSE00003461789	77225435	77225554
ENSE00003466820	77166329	77166554
ENSE00003486833	77206653	77206825
ENSE00003487290	77262053	77262129
ENSE00003492520	77161906	77161955
ENSE00003496601	77188951	77189047
ENSE00003498217	77191679	77191813
ENSE00003500996	77243059	77243160
ENSE00003503707	77176497	77176628
ENSE00003503881	77146162	77146217
ENSE00003513135	77180127	77180318
ENSE00003520575	77140047	77140163
ENSE00003529354	77140846	77140943
ENSE00003529501	77288161	77288376
ENSE00003536157	77233156	77233263
ENSE00003545730	77121373	77121495
ENSE00003550078	77169614	77169714
ENSE00003550734	77177748	77177954
ENSE00003552107	77260428	77260592
ENSE00003556598	77125336	77125468
ENSE00003558835	77263929	77264002
ENSE00003564856	77261171	77261375
ENSE00003572122	77205473	77205598
ENSE00003574811	77211167	77211320
ENSE00003576444	77150734	77150949
ENSE00003580147	77267841	77267937
ENSE00003582625	77257671	77257829
ENSE00003591877	77194153	77194244
ENSE00003592421	77205256	77205383
ENSE00003593419	77168428	77168646
ENSE00003601110	77181701	77181922
ENSE00003604169	77096312	77096481
ENSE00003607223	77263651	77263789
ENSE00003613890	77296599	77296674
ENSE00003618145	77185103	77185377
ENSE00003625966	77165273	77165391
ENSE00003630175	77251151	77251355
ENSE00003632568	77164454	77164541
ENSE00003634945	77217840	77217957
ENSE00003641125	77224451	77224532
ENSE00003644046	77139196	77139336
ENSE00003645245	77126318	77126542
ENSE00003645817	77171492	77171634
ENSE00003647168	77185871	77186063
ENSE00003648687	77174311	77174489
ENSE00003648760	77278758	77278911
ENSE00003648902	77156058	77156202
ENSE00003651771	77273472	77273668
ENSE00003656738	77269992	77270063
ENSE00003657972	77243806	77243951
ENSE00003660392	77211956	77212160
ENSE00003662355	77190252	77190335
ENSE00003674946	77157937	77158109
ENSE00003680322	77270296	77270538
ENSE00003692353	77144445	77144560
ENSE00003848740	77326474	77327094

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.74.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.4096 / max 385.0156, expressed in 1789 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
137689	22.7183	1789
137688	0.5139	255
137687	0.1774	87

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	99.74	gold quality
middle temporal gyrus	UBERON:0002771	99.60	gold quality
hair follicle	UBERON:0002073	98.98	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.95	gold quality
Brodmann (1909) area 10	UBERON:0013541	98.92	gold quality
frontal pole	UBERON:0002795	98.89	gold quality
cerebellar vermis	UBERON:0004720	98.79	gold quality
nipple	UBERON:0002030	98.77	gold quality
pons	UBERON:0000988	98.76	gold quality
substantia nigra pars compacta	UBERON:0001965	98.67	gold quality
entorhinal cortex	UBERON:0002728	98.60	gold quality
occipital lobe	UBERON:0002021	98.59	gold quality
primary visual cortex	UBERON:0002436	98.58	gold quality
orbitofrontal cortex	UBERON:0004167	98.52	gold quality
superior vestibular nucleus	UBERON:0007227	98.52	gold quality
gingival epithelium	UBERON:0001949	98.50	gold quality
Brodmann (1909) area 46	UBERON:0006483	98.49	gold quality
gingiva	UBERON:0001828	98.46	gold quality
parietal lobe	UBERON:0001872	98.43	gold quality
superior frontal gyrus	UBERON:0002661	98.42	gold quality
tongue squamous epithelium	UBERON:0006919	98.38	gold quality
penis	UBERON:0000989	98.37	gold quality
substantia nigra pars reticulata	UBERON:0001966	98.37	gold quality
postcentral gyrus	UBERON:0002581	98.34	gold quality
lateral globus pallidus	UBERON:0002476	98.27	gold quality
mammalian vulva	UBERON:0000997	98.26	gold quality
parietal pleura	UBERON:0002400	98.19	gold quality
pericardium	UBERON:0002407	98.16	gold quality
medulla oblongata	UBERON:0001896	98.14	gold quality
oral cavity	UBERON:0000167	98.12	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	419.03
E-MTAB-8142	yes	138.87
E-CURD-112	yes	19.76
E-ANND-3	yes	12.79
E-GEOD-137537	yes	6.66

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DOT1L, MYC

miRNA regulators (miRDB)

119 targeting MYCBP2, 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-3646	100.00	73.56	5283
HSA-MIR-4262	100.00	73.26	3931
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
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-568	99.98	69.86	2084
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882

Literature-anchored findings (GeneRIF, showing 15)

• Pam, through its interaction with tuberin, could regulate the ubiquitination and proteasomal degradation of the tuberin-hamartin complex particularly in the CNS (PMID:14559897)
• PAM the longest lasting nontranscriptional regulator of adenylyl cyclase activity known to date and presents a novel mechanism for the temporal regulation of cAMP signaling (PMID:15257286)
• Identifies the region in PAM that inhibits the domain of type V adenylyl cyclase. (PMID:15470080)
• PAM protein activated by facilitating the GDP/GTP-exchange of RHEBL1 protein which is an activator of mTOR protein. (PMID:19000755)
• Arf-bp1 and Pam are novel regulators of circadian gene expression that target Rev-erb alpha for degradation (PMID:20534529)
• Data show that epithelial-mesenchymal transition (EMT)-transcription factors can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45). (PMID:25460509)
• We describe a distinct excavated optic disc anomaly associated with high myopia and increased axial length. The condition appears to follow an autosomal dominant pattern and segregate with a deletion in MYCBP2. (PMID:25634536)
• In castration resistant prostate cancer, MYCBP2 is down-regulated at the mRNA and protein levels. (PMID:25731699)
• Data indicate an oncogenic role for an Ikaros protein/MYCBP2 protein/proto-oncogene protein c-MYC axis in adult acute lymphoblastic leukemia (ALL), providing a mechanism of target therapies that activate Ikaros in ALL. (PMID:26517351)
• identification of the neuron-associated E3 ligase MYCBP2 (also known as PHR1) as the apparent single member of a class of RING-linked E3 ligase with esterification activity and intrinsic selectivity for threonine over serine (PMID:29643511)
• MYCBP2, a member of the c-myc oncogene family, is a direct functional target of miR-1247. Furthermore, in colorectal cancer patients, MYCBP2 protein levels are associated with miR-1247 levels and survival (PMID:30318507)
• FBXO45-MYCBP2 regulates mitotic cell fate by targeting FBXW7 for degradation. (PMID:31285543)
• Loss-of-function variants in MYCBP2 cause neurobehavioural phenotypes and corpus callosum defects. (PMID:36200388)
• MYCBP2 expression correlated with inflammatory cell infiltration and prognosis immunotherapy in thyroid cancer patients. (PMID:36582246)
• Ubiquitin ligase and signalling hub MYCBP2 is required for efficient EPHB2 tyrosine kinase receptor function. (PMID:38289221)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	mycbp2	ENSDARG00000001220
mus_musculus	Mycbp2	ENSMUSG00000033004
rattus_norvegicus	Mycbp2	ENSRNOG00000010479

Paralogs (1): FBXO24 (ENSG00000106336)

Protein

Protein identifiers

E3 ubiquitin-protein ligase MYCBP2 — O75592 (reviewed: O75592)

Alternative names: Myc-binding protein 2, Protein associated with Myc

All UniProt accessions (10): O75592, A0A499FJI4, A0A804HIR9, A0A804HJ25, A0A804HKQ1, A0A804HL12, A0A8Q3SHK7, A0A8Q3SHQ2, A0A8Q3SHQ6, H7C3U4

UniProt curated annotations — full annotation on UniProt →

Function. Atypical E3 ubiquitin-protein ligase which specifically mediates ubiquitination of threonine and serine residues on target proteins, instead of ubiquitinating lysine residues. Shows esterification activity towards both threonine and serine, with a preference for threonine, and acts via two essential catalytic cysteine residues that relay ubiquitin to its substrate via thioester intermediates. Interacts with the E2 enzymes UBE2D1, UBE2D3, UBE2E1 and UBE2L3. Plays a key role in neural development, probably by mediating ubiquitination of threonine residues on target proteins. Involved in different processes such as regulation of neurite outgrowth, synaptic growth, synaptogenesis and axon degeneration. Required for the formation of major central nervous system axon tracts. Required for proper axon growth by regulating axon navigation and axon branching: acts by regulating the subcellular location and stability of MAP3K12/DLK. Required for proper localization of retinogeniculate projections but not for eye-specific segregation. Regulates axon guidance in the olfactory system. Involved in Wallerian axon degeneration, an evolutionarily conserved process that drives the loss of damaged axons: acts by promoting destabilization of NMNAT2, probably via ubiquitination of NMNAT2. Catalyzes ubiquitination of threonine and/or serine residues on NMNAT2, consequences of threonine and/or serine ubiquitination are however unknown. Regulates the internalization of TRPV1 in peripheral sensory neurons. Mediates ubiquitination and subsequent proteasomal degradation of TSC2/tuberin. Independently of the E3 ubiquitin-protein ligase activity, also acts as a guanosine exchange factor (GEF) for RAN in neurons of dorsal root ganglia. May function as a facilitator or regulator of transcriptional activation by MYC. Acts in concert with HUWE1 to regulate the circadian clock gene expression by promoting the lithium-induced ubiquitination and degradation of NR1D1.

Subunit / interactions. Interacts with MYC. Interacts with TSC2 (tuberin) when TSC2 is in complex with TSC1 (hamartin). Interacts with FBXO45. Interacts with RAE1. Interacts with CPNE1 (via VWFA domain) and CPNE4 (via VWFA domain). Interacts with (sumoylated) RANGAP1; interaction with sumoylated RANGAP1 inhibits E3 ubiquitin-protein ligase activity and promotes MYCBP2 translocation to the nucleus. Interacts with RAN. Interacts with ATP13A2; the interaction inhibits the ubiquitination of TSC2 by MYCBP2. Interacts with USP11.

Subcellular location. Nucleus. Cell projection. Axon. Cytoplasm. Cytoskeleton.

Tissue specificity. Expressed in all tissues examined, expression is exceptionally abundant in brain and thymus. Colocalizes with TSC1 and TSC2 along the neurites and in the growth cones. Highly expressed in peripheral and central neurons. Colocalized with TSC1 in one of the filopodial extensions at the tip of a growth cone.

Post-translational modifications. Autoubiquitinated.

Domain organisation. The PHR domains are compact beta-sandwich folds composed of 11 antiparallel strands and decorated with conserved apical loops. They are likely to play a structural role and mediate interactions with substrates or partners. The tandem cysteine domain region confers threonine specificity and contains the two essential catalytic cysteine residues that relay ubiquitin. It binds four zinc ions in a C5HC7HC2 configuration.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the RING-Cys relay (RCR) family.

Isoforms (2)

UniProt ID	Names	Canonical?
O75592-1	1	yes
O75592-2	2

RefSeq proteins (1): NP_055872* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000408	Reg_chr_condens	Repeat
IPR001841	Znf_RING	Domain
IPR004939	APC_su10/DOC_dom	Domain
IPR008979	Galactose-bd-like_sf	Homologous_superfamily
IPR009091	RCC1/BLIP-II	Homologous_superfamily
IPR012983	PHR	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR014756	Ig_E-set	Homologous_superfamily
IPR017868	Filamin/ABP280_rpt-like	Repeat
IPR038648	PHR_sf	Homologous_superfamily

Pfam: PF00415, PF03256, PF08005, PF13540

Enzyme classification (BRENDA):

• EC 2.3.2.33 — RCR-type E3 ubiquitin transferase (BRENDA: 3 organisms, 13 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

UniProt features (143 total): binding site 24, modified residue 21, region of interest 16, helix 14, strand 13, compositionally biased region 12, sequence conflict 9, turn 8, mutagenesis site 8, repeat 6, site 3, active site 2, sequence variant 2, chain 1, domain 1, zinc finger region 1, disulfide bond 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
5O6C	X-RAY DIFFRACTION	1.75
6T7F	X-RAY DIFFRACTION	2.58

Predicted structure (AlphaFold)

No AlphaFold model available for O75592 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

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

Catalytic / active sites (5): 4558; 4610; 4611 (important for catalysis); 4616 (important for catalysis); 4624 (important for catalysis)

Ligand- & substrate-binding residues (24): 4428; 4431; 4446; 4448; 4451; 4454; 4475; 4478; 4544; 4547; 4575; 4578 …

Post-translational modifications (21): 127, 178, 181, 183, 1624, 2683, 2769, 2787, 2789, 2833, 2839, 2869, 2871, 2920, 2985, 3090, 3478, 3505, 3921, 3931 …

Disulfide bonds (1): 1748–1863

Mutagenesis-validated functional residues (8):

Position	Phenotype
4558	abolished e3 ubiquitin-protein ligase activity.
4572	does not affect e3 ubiquitin-protein ligase activity.
4610	increased thiol-sensitive adduct formation.
4610	retains activity while also forming a discrete monoubiquitin adduct that is resistant to thiolysis but is reversible aft
4611	reduced e3 ubiquitin-protein ligase activity in threonine discharge assay.
4616	reduced e3 ubiquitin-protein ligase activity in threonine discharge assay.
4621	abolished e3 ubiquitin-protein ligase activity in threonine discharge assay, associated with enhanced thiol-sensitive ub
4624	reduced e3 ubiquitin-protein ligase activity in threonine discharge assay.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 664 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GOBP_CIRCADIAN_RHYTHM, GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, GGGACCA_MIR133A_MIR133B, VERHAAK_AML_WITH_NPM1_MUTATED_DN, MODULE_93, ZHAN_LATE_DIFFERENTIATION_GENES_UP, GOBP_RESPONSE_TO_ZINC_ION, GGTGTGT_MIR329, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_SYNAPSE_ASSEMBLY, GOCC_SECRETORY_GRANULE, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GCANCTGNY_MYOD_Q6, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP

GO Biological Process (17): axon guidance (GO:0007411), regulation of synaptic assembly at neuromuscular junction (GO:0008582), protein ubiquitination (GO:0016567), branchiomotor neuron axon guidance (GO:0021785), central nervous system projection neuron axonogenesis (GO:0021952), positive regulation of protein ubiquitination (GO:0031398), regulation of protein localization (GO:0032880), circadian regulation of gene expression (GO:0032922), negative regulation of protein catabolic process (GO:0042177), neuromuscular process (GO:0050905), regulation of cytoskeleton organization (GO:0051493), protein K48-linked ubiquitination (GO:0070936), regulation of axon guidance (GO:1902667), motor neuron axon guidance (GO:0008045), rhythmic process (GO:0048511), cell morphogenesis involved in neuron differentiation (GO:0048667), axon development (GO:0061564)

GO Molecular Function (8): guanyl-nucleotide exchange factor activity (GO:0005085), zinc ion binding (GO:0008270), small GTPase binding (GO:0031267), identical protein binding (GO:0042802), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (10): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), microtubule cytoskeleton (GO:0015630), membrane (GO:0016020), axon (GO:0030424), cytoskeleton (GO:0005856), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
axon guidance	2
axonogenesis	1
neuron projection guidance	1
regulation of developmental growth	1
synaptic assembly at neuromuscular junction	1
regulation of synapse assembly	1
regulation of neuromuscular junction development	1
protein modification by small protein conjugation	1
motor neuron axon guidance	1
central nervous system neuron axonogenesis	1
protein ubiquitination	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
intracellular protein localization	1
regulation of localization	1
circadian rhythm	1
regulation of gene expression	1
negative regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
negative regulation of protein metabolic process	1
nervous system process	1
cytoskeleton organization	1
regulation of organelle organization	1
protein polyubiquitination	1
regulation of neuron projection development	1
regulation of chemotaxis	1
biological_process	1
cell morphogenesis	1
neuron differentiation	1
neuron development	1
neuron projection development	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
transition metal ion binding	1
GTPase binding	1
protein binding	1
ubiquitin-protein transferase activity	1

Protein interactions and networks

STRING

1656 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MYCBP2	FBXO45	P0C2W1	989
MYCBP2	LRPAP1	P30533	850
MYCBP2	MYC	P01106	831
MYCBP2	SKP1	P34991	810
MYCBP2	NASP	P49321	767
MYCBP2	TSC2	P49815	692
MYCBP2	HUWE1	Q7Z6Z7	654
MYCBP2	UNC13A	Q9UPW8	643
MYCBP2	UNC13B	O14795	638
MYCBP2	OPN1LW	P04000	585
MYCBP2	CUL1	Q13616	556
MYCBP2	BIRC6	Q9NR09	514
MYCBP2	ADCY5	O95622	512
MYCBP2	RBX1	P62877	498
MYCBP2	SLBP	Q14493	490

IntAct

281 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:2364”(proximity)	0.900
YWHAQ	WDR62	psi-mi:“MI:0914”(association)	0.830
YWHAH	FAM83G	psi-mi:“MI:0914”(association)	0.710
VCP	UBXN8	psi-mi:“MI:0914”(association)	0.690
FBXW7	MYCBP2	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
CETN1	SFI1	psi-mi:“MI:0914”(association)	0.640
CRIPTO	AIP	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
PLK1	C1orf226	psi-mi:“MI:0914”(association)	0.560
rep	SBNO1	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
IGFBP4	MYCBP2	psi-mi:“MI:0914”(association)	0.530
CLEC11A	VWA8	psi-mi:“MI:0914”(association)	0.530
PGBD1	ZNF213	psi-mi:“MI:0914”(association)	0.530
STAT2	INPPL1	psi-mi:“MI:0914”(association)	0.530
TXNIP	PER1	psi-mi:“MI:0914”(association)	0.530
PDGFB	DKC1	psi-mi:“MI:0914”(association)	0.530
GDF10	LRP4	psi-mi:“MI:0914”(association)	0.530
EPHB2	MYCBP2	psi-mi:“MI:0914”(association)	0.530
POGLUT1	CLGN	psi-mi:“MI:0914”(association)	0.530

BioGRID (330): MYCBP2 (Affinity Capture-MS), MYCBP2 (Affinity Capture-Western), FBXO45 (Affinity Capture-Western), MYCBP2 (Affinity Capture-MS), MYCBP2 (Affinity Capture-MS), MYCBP2 (Affinity Capture-MS), MYCBP2 (Affinity Capture-MS), MYCBP2 (Affinity Capture-MS), MYCBP2 (Affinity Capture-MS), MYCBP2 (Affinity Capture-MS), MYCBP2 (Affinity Capture-MS), MYCBP2 (Affinity Capture-MS), MYCBP2 (Affinity Capture-MS), MYCBP2 (Affinity Capture-MS), MYCBP2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4I9Y1, A0A0R4IBK5, A2AN08, A2ARZ3, A5WUT8, A6NKT7, B1WBT0, B8RJM0, C9JQI7, E9Q3L2, E9Q555, H2QII6, O08662, O14715, O15050, O43310, O75592, O75969, P0DJD0, P0DJD1, P13864, P42356, P49792, Q0V9S3, Q0VF22, Q24K09, Q2TL32, Q4R6W9, Q4V847, Q63HN8, Q6PB60, Q6PEE2, Q71HP2, Q7TPH6, Q7TPV2, Q7Z3J3, Q80930, Q80TA9, Q810N5, Q811D2

Diamond homologs: A6NED2, F1RD40, F2Z461, O74881, O75592, O95714, P18754, P23800, Q15034, Q4R828, Q4U2R1, Q52KW8, Q5GLZ8, Q5PQN1, Q6NRS1, Q6PAV2, Q7TPH6, Q80YD6, Q8BTU7, Q8IVU3, Q8VE37, Q9FN03, Q9NB71, Q9P2D0, Q9UII4, A0A2R8Q1W5, A4IFG2, A9JRD8, B7U179, F7ASZ0, G3X9X1, M3XQV7, P57790, P58544, P58545, Q0V9W6, Q14145, Q17551, Q2LE78, Q5R774

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
MYC	“down-regulates quantity by repression”	MYCBP2	“transcriptional regulation”
MYCBP2	“down-regulates quantity by destabilization”	MYC	ubiquitination
MYCBP2	“down-regulates quantity by destabilization”	AR	ubiquitination
DOT1L	“down-regulates quantity by repression”	MYCBP2	“transcriptional regulation”
Ub:E2	“up-regulates activity”	MYCBP2	ubiquitination
MYCBP2	“form complex”	“Skp1-Pam E3”	binding
MYCBP2	“down-regulates quantity by destabilization”	TSC2	ubiquitination
MYCBP2	“down-regulates quantity”	ULK1	ubiquitination
RANGAP1	“down-regulates quantity by destabilization”	MYCBP2	relocalization
MYCBP2	“up-regulates activity”	RAN	“guanine nucleotide exchange factor”
MYCBP2	down-regulates	TSC	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 225 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
Activation of BAD and translocation to mitochondria	7	38.6×	7e-08
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	34.1×	1e-07
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	34.1×	1e-07
Activation of BH3-only proteins	7	25.2×	8e-07
Intrinsic Pathway for Apoptosis	8	17.0×	2e-06
RHO GTPases activate PKNs	7	16.1×	2e-05
FOXO-mediated transcription	5	12.2×	1e-03
Translocation of SLC2A4 (GLUT4) to the plasma membrane	10	11.2×	2e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	7
Uncertain significance	645
Likely benign	59
Benign	31

Top pathogenic / likely-pathogenic (19)

Variant ID	HGVS	Classification
1074432	NC_000013.10:g.(?77566087)(78492734_?)del	Pathogenic
2573055	NM_015057.5(MYCBP2):c.2143C>T (p.Arg715Ter)	Pathogenic
3253097	NM_015057.5(MYCBP2):c.9896T>G (p.Val3299Gly)	Pathogenic
3340699	NM_015057.5(MYCBP2):c.13669C>T (p.Arg4557Cys)	Pathogenic
3343001	NM_015057.5(MYCBP2):c.2803C>T (p.Arg935Ter)	Pathogenic
3368075	NM_015057.5(MYCBP2):c.12463C>T (p.Arg4155Ter)	Pathogenic
3773644	NM_015057.5(MYCBP2):c.3983_3984del (p.Gly1328fs)	Pathogenic
3899545	NM_015057.5(MYCBP2):c.13528G>T (p.Glu4510Ter)	Pathogenic
4056817	NM_015057.5(MYCBP2):c.556G>T (p.Glu186Ter)	Pathogenic
4282410	NM_015057.5(MYCBP2):c.4118A>G (p.Asp1373Gly)	Pathogenic
4526917	NM_015057.5(MYCBP2):c.4939C>T (p.Gln1647Ter)	Pathogenic
503586	GRCh37/hg19 13q22.1-31.3(chr13:74459395-93481294)x1	Pathogenic
2575587	NM_015057.5(MYCBP2):c.7401G>A (p.Lys2467=)	Likely pathogenic
3340679	NM_015057.5(MYCBP2):c.11855T>C (p.Met3952Thr)	Likely pathogenic
3342347	NM_015057.5(MYCBP2):c.7188-2A>G	Likely pathogenic
3343417	NM_015057.5(MYCBP2):c.4942-2A>C	Likely pathogenic
3572747	NM_015057.5(MYCBP2):c.8146C>T (p.Arg2716Ter)	Likely pathogenic
3900389	NM_015057.5(MYCBP2):c.8867_8868insG (p.Phe2957fs)	Likely pathogenic
3900582	NM_015057.5(MYCBP2):c.1612C>T (p.Arg538Ter)	Likely pathogenic

SpliceAI

17219 predictions. Top by Δscore:

Variant	Effect	Δscore
13:77045504:T:C	acceptor_gain	1.0000
13:77050991:GCATA:G	donor_loss	1.0000
13:77050992:CATA:C	donor_loss	1.0000
13:77050993:ATACC:A	donor_loss	1.0000
13:77050994:TAC:T	donor_loss	1.0000
13:77050995:ACC:A	donor_loss	1.0000
13:77051084:C:CT	acceptor_gain	1.0000
13:77051158:CACAT:C	acceptor_gain	1.0000
13:77051159:ACAT:A	acceptor_gain	1.0000
13:77051160:CAT:C	acceptor_gain	1.0000
13:77051160:CATC:C	acceptor_gain	1.0000
13:77051161:AT:A	acceptor_gain	1.0000
13:77051163:C:CC	acceptor_gain	1.0000
13:77051165:A:C	acceptor_gain	1.0000
13:77051169:C:CT	acceptor_gain	1.0000
13:77051170:A:T	acceptor_gain	1.0000
13:77051808:TA:T	donor_loss	1.0000
13:77051809:A:AC	donor_gain	1.0000
13:77051809:A:T	donor_loss	1.0000
13:77051810:C:CC	donor_gain	1.0000
13:77051810:C:CG	donor_loss	1.0000
13:77051914:TATGC:T	acceptor_gain	1.0000
13:77051915:ATGC:A	acceptor_gain	1.0000
13:77051916:TGC:T	acceptor_gain	1.0000
13:77051917:GC:G	acceptor_gain	1.0000
13:77051918:CC:C	acceptor_gain	1.0000
13:77051919:C:CC	acceptor_gain	1.0000
13:77051920:T:A	acceptor_loss	1.0000
13:77053516:AAC:A	donor_gain	1.0000
13:77055763:TTGTT:T	acceptor_gain	1.0000

AlphaMissense

30710 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:77045399:G:C	C4672W	1.000
13:77045400:C:G	C4672S	1.000
13:77045401:A:G	C4672R	1.000
13:77045401:A:T	C4672S	1.000
13:77045409:C:T	C4669Y	1.000
13:77045410:A:G	C4669R	1.000
13:77045412:C:T	G4668E	1.000
13:77045460:C:G	C4652S	1.000
13:77045461:A:G	C4652R	1.000
13:77045461:A:T	C4652S	1.000
13:77051006:A:G	C4638R	1.000
13:77051057:G:C	H4621D	1.000
13:77051058:A:C	C4620W	1.000
13:77051059:C:T	C4620Y	1.000
13:77051060:A:G	C4620R	1.000
13:77051067:A:C	C4617W	1.000
13:77051068:C:A	C4617F	1.000
13:77051068:C:G	C4617S	1.000
13:77051068:C:T	C4617Y	1.000
13:77051069:A:G	C4617R	1.000
13:77051069:A:T	C4617S	1.000
13:77051070:A:C	F4616L	1.000
13:77051070:A:T	F4616L	1.000
13:77051072:A:G	F4616L	1.000
13:77051075:G:C	H4615D	1.000
13:77051085:A:C	F4611L	1.000
13:77051085:A:T	F4611L	1.000
13:77051087:A:G	F4611L	1.000
13:77051088:A:C	C4610W	1.000
13:77051089:C:T	C4610Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000003742 (13:77199934 G>C), RS1000004973 (13:77201890 A>C), RS1000009677 (13:77288743 A>C), RS1000022332 (13:77065414 C>G,T), RS1000051751 (13:77299853 A>T), RS1000052317 (13:77114584 T>C), RS1000057404 (13:77248884 G>A), RS1000065815 (13:77067803 A>G), RS1000070934 (13:77255758 C>A), RS1000077671 (13:77065068 T>G), RS1000088181 (13:77202828 T>C), RS1000092436 (13:77112190 T>C), RS1000097508 (13:77154037 A>T), RS1000134325 (13:77131843 A>C), RS1000134463 (13:77173794 A>G)

Disease associations

OMIM: gene MIM:610392 | disease phenotypes: MIM:256730, MIM:615834

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Strong	Autosomal dominant

Mondo (5): neuronal ceroid lipofuscinosis (MONDO:0016295), prostate cancer (MONDO:0008315), autism spectrum disorder due to AUTS2 deficiency (MONDO:0014361), MYCBP2-related developmental delay with corpus callosum defects (MONDO:1060117), neurodevelopmental disorder (MONDO:0700092)

Orphanet (4): Neuronal ceroid lipofuscinosis (Orphanet:216), OBSOLETE: Infantile neuronal ceroid lipofuscinosis (Orphanet:79263), Familial prostate cancer (Orphanet:1331), Autism spectrum disorder due to AUTS2 deficiency (Orphanet:352490)

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001949_10	Preeclampsia	1.000000e-06
GCST002682_13	Tourette’s syndrome or obsessive-compulsive disorder	1.000000e-06
GCST007565_101	Morning person	8.000000e-19
GCST007565_111	Morning person	4.000000e-19
GCST007565_119	Morning person	1.000000e-18
GCST007576_398	Chronotype	4.000000e-19
GCST007742_23	Iris heterochromicity	5.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement
EFO:0009764	eye colour measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067006 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.21	Kd	6.181	nM	CHEMBL5653589
8.21	ED50	6.181	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148803: Binding affinity to human MYCBP2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0062	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, decreases methylation, affects cotreatment	7
trichostatin A	affects cotreatment, increases expression	3
graphene oxide	increases expression	2
bisphenol A	decreases expression, affects cotreatment	2
Dexamethasone	decreases expression, increases expression, affects cotreatment	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	decreases expression	1
arsenite	affects binding, decreases reaction	1
tetrabromobisphenol A	decreases expression	1
manganese chloride	decreases expression, increases abundance	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
coumarin	affects phosphorylation	1
epigallocatechin gallate	decreases expression, increases expression, affects cotreatment	1
celastrol	decreases expression	1
gedunin	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol S	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
picoxystrobin	decreases expression	1
(+)-JQ1 compound	increases expression	1
EPZ004777	increases expression	1
Temozolomide	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651845	Binding	Binding affinity to human MYCBP2 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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,
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery