BEX2

Summary

BEX2 (brain expressed X-linked 2, HGNC:30933) is a protein-coding gene on chromosome Xq22.2, encoding Protein BEX2 (Q9BXY8). Regulator of mitochondrial apoptosis and G1 cell cycle in breast cancer.

This gene belongs to the brain expressed X-linked gene family. The encoded protein interacts with the transcription factor LIM domain only 2 in a DNA-binding complex that recognizes the E-box element and promotes transcription. This gene has been found to be a tumor suppressor that is silenced in human glioma. In breast cancer cells, this gene product modulates apoptosis in response to estrogen and tamoxifen, and enhances the anti-proliferative effect of tamoxifen. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 84707 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 40 total — 1 pathogenic
• GTEx eGene: eQTL in 45 tissues, sQTL in 21 (q < 0.05)
• MANE Select transcript: NM_032621

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30933
Approved symbol	BEX2
Name	brain expressed X-linked 2
Location	Xq22.2
Locus type	gene with protein product
Status	Approved
Aliases	DJ79P11.1
Ensembl gene	ENSG00000133134
Ensembl biotype	protein_coding
OMIM	300691
Entrez	84707

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 16 protein_coding

MANE Select: ENST00000372677

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 2, TSL 3: 1

ENST00000372677, ENST00000372674, ENST00000449185, ENST00000536889, ENST00000880036, ENST00000880037, ENST00000880038, ENST00000911968, ENST00000911969, ENST00000911970, ENST00000911971, ENST00000911972, ENST00000911973, ENST00000911974, ENST00000946186, ENST00001132118

RefSeq mRNA: 4 — MANE Select: NM_032621 NM_001168399, NM_001168400, NM_001168401, NM_032621

CCDS: CCDS14505, CCDS55467

Canonical transcript exons

ENST00000372677 — 3 exons

Exon	Start	End
ENSE00001458371	103309346	103309981
ENSE00001458422	103310860	103310990
ENSE00003591930	103310358	103310433

Expression profiles

Bgee: expression breadth ubiquitous, 249 present calls, max score 99.15.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 58.1837 / max 3327.7631, expressed in 1313 samples.

Highest expression (Bgee): endothelial cell, Brodmann (1909) area 23, pons, adenohypophysis, prefrontal cortex.

Genetic regulation across tissues (GTEx eQTL / sQTL)

BEX2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 45 tissues and its splicing (sQTL) in 21 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 66 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Nerve Tibial	eqtl	4.7e-50	+0.65	X:103318605:T:C
Whole Blood	eqtl	1.3e-42	+0.31	X:103310966:C:A
Esophagus Muscularis	eqtl	9.1e-41	+0.63	X:103310966:C:A
Colon Transverse	eqtl	8.1e-40	+0.54	X:103310966:C:A
Heart Atrial Appendage	eqtl	8.6e-37	+0.53	X:103310966:C:A
Thyroid	eqtl	5.8e-35	+0.27	X:103318605:T:C
Testis	eqtl	3.8e-31	+0.29	X:103310966:C:A
Testis	sqtl	5.6e-30	+0.76	X:103310966:C:A
Thyroid	sqtl	1.9e-29	-0.65	X:103310966:C:A
Artery Tibial	eqtl	4.6e-29	+0.43	X:103310966:C:A
Spleen	eqtl	2.5e-26	+0.55	X:103310966:C:A
Adipose Subcutaneous	eqtl	2.9e-25	+0.48	X:103310966:C:A
Artery Aorta	eqtl	8.9e-25	+0.46	X:103310966:C:A
Colon Sigmoid	eqtl	5.5e-24	+0.38	X:103310966:C:A
Adipose Visceral Omentum	eqtl	7.2e-23	+0.27	X:103310966:C:A
Breast Mammary Tissue	eqtl	4.5e-22	+0.23	X:103310966:C:A
Pituitary	sqtl	7.9e-22	-0.83	X:103310966:C:A
Pancreas	eqtl	7.9e-22	+0.68	X:103295292:A:G
Esophagus Gastroesophageal Junction	eqtl	1.2e-20	+0.38	X:103310966:C:A
Lung	eqtl	4.1e-19	+0.21	X:103310966:C:A

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
199992	55.5748	1293
199993	2.6090	672

Top tissues by expression

showing 100 of 254 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.15	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.12	gold quality
pons	UBERON:0000988	99.08	gold quality
adenohypophysis	UBERON:0002196	98.95	gold quality
prefrontal cortex	UBERON:0000451	98.94	gold quality
nucleus accumbens	UBERON:0001882	98.93	gold quality
middle temporal gyrus	UBERON:0002771	98.93	gold quality
superior vestibular nucleus	UBERON:0007227	98.93	gold quality
cerebellar vermis	UBERON:0004720	98.89	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.89	gold quality
superior frontal gyrus	UBERON:0002661	98.88	gold quality
frontal cortex	UBERON:0001870	98.86	gold quality
pituitary gland	UBERON:0000007	98.84	gold quality
hypothalamus	UBERON:0001898	98.83	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	98.83	gold quality
occipital lobe	UBERON:0002021	98.77	gold quality
entorhinal cortex	UBERON:0002728	98.74	gold quality
primary visual cortex	UBERON:0002436	98.72	gold quality
right frontal lobe	UBERON:0002810	98.72	gold quality
cerebral cortex	UBERON:0000956	98.71	gold quality
neocortex	UBERON:0001950	98.71	gold quality
parietal lobe	UBERON:0001872	98.68	gold quality
kidney epithelium	UBERON:0004819	98.62	gold quality
temporal lobe	UBERON:0001871	98.61	gold quality
forebrain	UBERON:0001890	98.61	gold quality
postcentral gyrus	UBERON:0002581	98.61	gold quality
cerebellum	UBERON:0002037	98.59	gold quality
ventral tegmental area	UBERON:0002691	98.58	gold quality
cerebellar cortex	UBERON:0002129	98.57	gold quality
cerebellar hemisphere	UBERON:0002245	98.57	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.57	gold quality
anterior cingulate cortex	UBERON:0009835	98.56	gold quality
brain	UBERON:0000955	98.53	gold quality
amygdala	UBERON:0001876	98.51	gold quality
medulla oblongata	UBERON:0001896	98.51	gold quality
Ammon’s horn	UBERON:0001954	98.51	gold quality
Brodmann (1909) area 46	UBERON:0006483	98.50	gold quality
substantia nigra pars compacta	UBERON:0001965	98.44	gold quality
caudate nucleus	UBERON:0001873	98.41	gold quality
putamen	UBERON:0001874	98.38	gold quality
cortical plate	UBERON:0005343	98.25	gold quality
corpus epididymis	UBERON:0004359	98.14	gold quality
germinal epithelium of ovary	UBERON:0001304	98.06	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.04	gold quality
midbrain	UBERON:0001891	97.93	gold quality
lateral globus pallidus	UBERON:0002476	97.87	gold quality
substantia nigra	UBERON:0002038	97.85	gold quality
pigmented layer of retina	UBERON:0001782	97.68	gold quality
dorsal plus ventral thalamus	UBERON:0001897	97.52	gold quality
islet of Langerhans	UBERON:0000006	97.46	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.37	gold quality
left lobe of thyroid gland	UBERON:0001120	96.95	gold quality
adult organism	UBERON:0007023	96.88	gold quality
caput epididymis	UBERON:0004358	96.86	gold quality
thyroid gland	UBERON:0002046	96.74	gold quality
inferior vagus X ganglion	UBERON:0005363	96.70	gold quality
globus pallidus	UBERON:0001875	96.66	gold quality
subthalamic nucleus	UBERON:0001906	96.62	gold quality
spinal cord	UBERON:0002240	96.50	gold quality
medial globus pallidus	UBERON:0002477	96.44	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.40	gold quality
right lobe of thyroid gland	UBERON:0001119	96.06	gold quality
renal medulla	UBERON:0000362	95.86	gold quality
ganglionic eminence	UBERON:0004023	95.83	gold quality
cardiac muscle of right atrium	UBERON:0003379	95.82	gold quality
palpebral conjunctiva	UBERON:0001812	95.00	gold quality
left adrenal gland cortex	UBERON:0035825	94.96	gold quality
dorsal root ganglion	UBERON:0000044	94.92	gold quality
adrenal cortex	UBERON:0001235	94.84	gold quality
left adrenal gland	UBERON:0001234	94.76	gold quality
corpus callosum	UBERON:0002336	94.69	gold quality
epithelial cell of pancreas	CL:0000083	94.56	gold quality
right adrenal gland	UBERON:0001233	94.47	gold quality
right adrenal gland cortex	UBERON:0035827	94.41	gold quality
metanephros	UBERON:0000081	94.36	gold quality
left ovary	UBERON:0002119	94.17	gold quality
adrenal gland	UBERON:0002369	94.13	gold quality
thymus	UBERON:0002370	94.00	gold quality
kidney	UBERON:0002113	93.72	gold quality
adult mammalian kidney	UBERON:0000082	93.71	gold quality
cortex of kidney	UBERON:0001225	93.46	gold quality
ventricular zone	UBERON:0003053	93.19	gold quality
right testis	UBERON:0004534	92.83	gold quality
trigeminal ganglion	UBERON:0001675	92.78	gold quality
pancreas	UBERON:0001264	92.65	gold quality
cauda epididymis	UBERON:0004360	92.60	gold quality
adrenal tissue	UBERON:0018303	92.43	gold quality
seminal vesicle	UBERON:0000998	92.41	gold quality
left testis	UBERON:0004533	92.25	gold quality
metanephros cortex	UBERON:0010533	92.23	gold quality
ovary	UBERON:0000992	92.22	gold quality
testis	UBERON:0000473	91.78	gold quality
upper arm skin	UBERON:0004263	91.16	gold quality
body of pancreas	UBERON:0001150	90.80	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	90.56	gold quality
right ovary	UBERON:0002118	90.05	gold quality
tibialis anterior	UBERON:0001385	89.93	silver quality
lower lobe of lung	UBERON:0008949	89.93	gold quality
nasal cavity mucosa	UBERON:0001826	89.85	gold quality
cardiac atrium	UBERON:0002081	89.22	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	871.07
E-GEOD-134144	yes	39.90
E-HCAD-10	yes	35.87
E-HCAD-6	yes	34.81
E-CURD-114	yes	20.42
E-ANND-3	yes	17.69
E-MTAB-5061	yes	14.50
E-MTAB-7316	yes	13.98
E-MTAB-9388	yes	11.71
E-GEOD-84465	yes	6.68
E-GEOD-125970	yes	4.68
E-MTAB-6524	no	209.17
E-HCAD-31	no	1.95

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 64 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Pituitary gland	tissue	199.0
Hypothalamus	tissue	134.7
Cerebral cortex	tissue	121.4	medium
Postcentral gyrus	tissue	121.4
Epididymis	tissue	116.8	medium
Parathyroid gland	tissue	115.6	low
Thyroid gland	tissue	96.7	medium
Basal ganglia	tissue	93.8	low
Hippocampal formation	tissue	86.2
Retina	tissue	77.4
Midbrain	tissue	77.1
Nucleus accumbens	tissue	76.2
Retrosplenial cortex	tissue	76.0
Pons	tissue	73.3
Locus coeruleus	tissue	73.3
Occipital cortex	tissue	72.2
Amygdala	tissue	70.3
Hippocampus	tissue	70.2	low
Thalamus	tissue	69.6
Adrenal gland	tissue	69.4	medium
Putamen	tissue	62.2
Medulla oblongata	tissue	61.7
Cerebellum	tissue	61.7	medium
Spinal cord	tissue	59.8
Substantia nigra	tissue	53.1
Kidney	tissue	48.0	medium
Ovary	tissue	39.4	medium
Endometrium 1	tissue	25.8	medium
Pancreas	tissue	23.3	medium
Testis	tissue	22.9	medium
Prostate	tissue	20.4	low
Seminal vesicle	tissue	19.8	medium
Thymus	tissue	19.6
Salivary gland	tissue	19.1	low
Choroid plexus	tissue	18.4
Breast	tissue	18.1	medium
Tonsil	tissue	15.8	medium
Fallopian tube	tissue	14.6	medium
Spleen	tissue	13.7	not detected
Lymph node	tissue	13.3	medium
Heart muscle	tissue	12.9	low
Bone marrow	tissue	12.9	low
Vagina	tissue	11.0	low
Tongue	tissue	10.8
Stomach 1	tissue	10.6	medium
Lung	tissue	10.6	medium
Cervix	tissue	8.5	low
Smooth muscle	tissue	8.1	not detected
Urinary bladder	tissue	8.1	medium
Placenta	tissue	7.6	medium
Gallbladder	tissue	7.1	medium
Colon	tissue	7.0	medium
Appendix	tissue	6.4	medium
Skin 1	tissue	6.2	medium
Small intestine	tissue	6.1	medium
Rectum	tissue	5.6	medium
Esophagus	tissue	3.8	medium
Duodenum	tissue	3.2	medium
Skeletal muscle	tissue	3.1	not detected
Adipose tissue	tissue	1.2	not detected

Brain sub-regions (HPA Brain Atlas): detected in 187; highest nTPM — Arcuate nucleus (134.7), Ventromedial nucleus (102.2), Lateral hypothalamic area (96.2), Nucleus of the diagonal band (93.8), Perirhinal gyrus (93.1).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): JUN, LMO2, RELA

miRNA regulators (miRDB)

Targeting BEX2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 31 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5011-5P	100.00	83.46	5820
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-511-3P	99.99	68.85	1467
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-452-5P	99.65	69.63	1762
HSA-MIR-4676-3P	99.65	69.31	1733
HSA-MIR-892C-3P	99.65	69.38	1745
HSA-MIR-543	99.52	69.03	2595
HSA-MIR-548G-3P	99.48	68.67	2159
HSA-MIR-133A-5P	99.28	69.13	941
HSA-MIR-5581-3P	98.55	70.31	1161
HSA-MIR-7114-3P	98.42	66.53	569
HSA-MIR-1180-5P	98.16	65.32	460
HSA-MIR-6893-3P	97.79	64.91	1238
HSA-MIR-320E	97.49	65.96	865
HSA-MIR-370-3P	97.09	64.92	1221
HSA-MIR-6872-3P	97.08	66.99	750

Functional genomics

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000372677 — one region, missense o/e 0.94.

Literature-anchored findings (GeneRIF, showing 17)

• hBex2 may act as a specific regulator during embryonic development by modulating the transcriptional activity of a novel E-box sequence-binding complex that contains hBex2, LMO2, NSCL2 and LDB1. (PMID:16314316)
• Two novel brain expressed genes, BEX1 and BEX2 are identified; they are silenced in all glioma specimens and exhibit extensive promoter hypermethylation. (PMID:16818640)
• Correlation between BEX2 expression and mixed lineage leukemia chromosomal aberrations are shown in the cell lines. (PMID:17251904)
• a NGF/BEX2/NF-kappaB pathway is involved in regulating apoptosis in breast cancer cells and in modulating response to tamoxifen in primary tumors (PMID:17638883)
• BEX2 is implicated in oligodendroglioma biology. (PMID:19412433)
• These results suggest that the conspicuous expression of the tumor suppressor genes BEX2, IGSF4 and TIMP3 in MLLmu acute myeloid leukemias cell lines is the consequence of altered epigenetic properties of MLL fusion proteins. (PMID:19835597)
• BEX2 has a functional interplay with c-Jun and p65/RelA in breast cancer. (PMID:20482821)
• BEX2 overexpression was associated with breast cancer. (PMID:21384344)
• Both BEX2 and INI1/hSNF5 mainly localized in cell nucleus. (PMID:22698742)
• Bex2 overexpression promoted cell migration and invasion in glioma cell lines. (PMID:22907646)
• Bex2 may be an important player during the development of glioma (PMID:23022184)
• The study reveals that BEX2 promotes colorectal cancer cell proliferation via the JNK/c-Jun pathway, suggesting BEX2 as a potential candidate target for the treatment of CRC. (PMID:28367093)
• MiR-370 could downregulate BEX2 gene. (PMID:31530937)
• Induced pluripotent stem cells established from a female patient with Xq22 deletion confirm that BEX2 escapes from X-chromosome inactivation. (PMID:33244819)
• BEX2 suppresses mitochondrial activity and is required for dormant cancer stem cell maintenance in intrahepatic cholangiocarcinoma. (PMID:33299012)
• BEX2 is required for maintaining dormant cancer stem cell in hepatocellular carcinoma. (PMID:34424582)
• Crotonylated BEX2 interacts with NDP52 and enhances mitophagy to modulate chemotherapeutic agent-induced apoptosis in non-small-cell lung cancer cells. (PMID:37777549)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Bex2	ENSMUSG00000042750
mus_musculus	Bex1	ENSMUSG00000050071
rattus_norvegicus	Bex2	ENSRNOG00000032729
rattus_norvegicus	Bex1	ENSRNOG00000033844
rattus_norvegicus	Bex5l1	ENSRNOG00000082512

Paralogs (3): BEX1 (ENSG00000133169), BEX3 (ENSG00000166681), BEX5 (ENSG00000184515)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1328321) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 2 distinct phenotype terms.

Mouse phenotype (MP)	Records
impaired exercise endurance	1
abnormal skeletal muscle regeneration	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pongo abelii	Q5R590	97.5%	Diamond
Macaca fascicularis	Q2PG52	92.2%	Diamond
Bos taurus	Q3ZBJ6	81.5%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
TCEAL5	protein-coding	340543
BEX4	protein-coding	56271
TCEAL8	protein-coding	90843
LL0XNC01-250H12.3	ncRNA	100506901
RAB40A	protein-coding	142684
BEX3	protein-coding	27018
TCEAL9	protein-coding	51186
TCEAL7	protein-coding	56849

Protein

Protein identifiers

Protein BEX2 — Q9BXY8 (reviewed: Q9BXY8)

Alternative names: Brain-expressed X-linked protein 2

All UniProt accessions (2): Q9BXY8, X6RDN0

UniProt curated annotations — full annotation on UniProt →

Function. Regulator of mitochondrial apoptosis and G1 cell cycle in breast cancer. Protects the breast cancer cells against mitochondrial apoptosis and this effect is mediated through the modulation of BCL2 protein family, which involves the positive regulation of anti-apoptotic member BCL2 and the negative regulation of pro-apoptotic members BAD, BAK1 and PUMA. Required for the normal cell cycle progression during G1 in breast cancer cells through the regulation of CCND1 and CDKN1A. Regulates the level of PP2A regulatory subunit B and PP2A phosphatase activity. In absence of reductive stress, acts as a pseudosubstrate for the CRL2(FEM1B) complex: associates with FEM1B via zinc, thereby preventing association between FEM1B and its substrates.

Subunit / interactions. Interacts with LMO2, possibly leading to regulate the transcriptional activity of a DNA-binding complex containing LMO2. Interacts with OMP.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Expressed in central nervous system, with high level in pituitary, cerebellum and temporal lobe. Widely expressed in breast cancer cell lines.

Domain organisation. The histidine cluster (His cluster) and Cys-125 mediate zinc-binding.

Similarity. Belongs to the BEX family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BXY8-1	1	yes
Q9BXY8-2	2

RefSeq proteins (4): NP_001161871, NP_001161872, NP_001161873, NP_116010* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007623	BEX	Family
IPR021156	TF_A-like/BEX	Family

Pfam: PF04538

UniProt features (7 total): region of interest 2, chain 1, compositionally biased region 1, binding site 1, modified residue 1, splice variant 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BXY8-F1	68.93	0.08

Human Protein Atlas

Protein class: Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol

Antibody reliability (HPA): IH uncertain · IF uncertain

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)

Position	Role
125	Zn(2+)

Post-translational modifications (1)

Type	Positions
Omega-n-methylarginine	50

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

MSigDB gene sets: 126 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GCANCTGNY_MYOD_Q6, GCM_ZNF198, CAGCTG_AP4_Q5, LINDGREN_BLADDER_CANCER_CLUSTER_2A_DN, PATIL_LIVER_CANCER, GOBP_REGULATION_OF_CELL_CYCLE, HFH8_01, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, MYOD_Q6, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_METABOLIC_PROCESS, NRF2_Q4, JAATINEN_HEMATOPOIETIC_STEM_CELL_UP, VECCHI_GASTRIC_CANCER_EARLY_DN, FREAC7_01

GO Biological Process (5): apoptotic process (GO:0006915), signal transduction (GO:0007165), negative regulation of protein ubiquitination (GO:0031397), regulation of apoptotic process (GO:0042981), regulation of cell cycle (GO:0051726)

GO Molecular Function (4): signaling receptor binding (GO:0005102), metal ion binding (GO:0046872), molecular function inhibitor activity (GO:0140678), protein binding (GO:0005515)

GO Cellular Component (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

GO top-level categories

21 GO namespaces:

Category	Terms
regulation of cellular process	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell communication	1
cellular process	1
signaling	1
cellular response to stimulus	1
protein ubiquitination	1
regulation of protein ubiquitination	1
negative regulation of protein modification by small protein conjugation or removal	1
apoptotic process	1
regulation of programmed cell death	1
cell cycle	1
protein binding	1
cation binding	1
molecular function regulator activity	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 2 of 11 annotations. The rest are phylogenetic / computational / electronic (IEA).

2 experimentally-supported GO terms:

GO term	NS	Evidence
regulation of apoptotic process	BP	direct assay
regulation of cell cycle	BP	direct assay

Protein interactions and networks

STRING

showing 15 of 548 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BEX2	NHLH2	Q02577	834
BEX2	LDB2	O43679	785
BEX2	LDB1	Q86U70	780
BEX2	LMO2	P25791	717
BEX2	TCEAL5	Q5H9L2	508
BEX2	TCEAL3	Q969E4	481
BEX2	NGF	P01138	474
BEX2	GPRASP1	Q5JY77	463
BEX2	BEX5	Q5H9J7	460
BEX2	GPRASP2	Q96D09	452
BEX2	TCEAL8	Q8IYN2	449
BEX2	TCEAL2	Q9H3H9	449
BEX2	NGFR	P08138	439
BEX2	KDM5A	P29375	429
BEX2	TCEAL9	Q9UHQ7	423

IntAct

Human interaction partners of BEX2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 90 partners by confidence:

Partner	Interaction type	MIscore	Records
BLZF1	physical association	0.720	6
CEP70	physical association	0.720	6
KRT31	physical association	0.720	6
KRTAP10-8	physical association	0.720	6
MKRN3	physical association	0.720	6
TRAF2	physical association	0.720	6
MDFI	physical association	0.600	4
CTAG1A	physical association	0.560	5
MAGEA11	physical association	0.560	4
AKAP9	physical association	0.560	3
BORCS6	physical association	0.560	3
CALCOCO2	physical association	0.560	3
CCDC197	physical association	0.560	3
CCDC57	physical association	0.560	3
CCDC88B	physical association	0.560	3
CDR2	physical association	0.560	3
COG4	physical association	0.560	3
CYSRT1	physical association	0.560	3
DYNC1H1	physical association	0.560	3
EXOC8	physical association	0.560	3
FSD2	physical association	0.560	3
FST	physical association	0.560	3
GPRASP3	physical association	0.560	3
HSF2BP	physical association	0.560	3
HSPB2	physical association	0.560	3
KLHL20	physical association	0.560	3
KLK6	physical association	0.560	3
KNSTRN	physical association	0.560	3
KRT15	physical association	0.560	3
KRT19	physical association	0.560	3

BioGRID (122 interactions; top human partners by supporting records): CALCOCO2 (Two-hybrid; 3 records), LMO2 (Two-hybrid; 3 records), BLZF1 (Two-hybrid; 2 records), CEP70 (Two-hybrid; 2 records), FEM1B (Affinity Capture-MS; 2 records), KRT31 (Two-hybrid; 2 records), KRTAP10-8 (Two-hybrid; 2 records), LDB1 (Affinity Capture-Western; 2 records), MAGEA11 (Two-hybrid; 2 records), MAP1LC3B (Affinity Capture-Western; 2 records), MKRN3 (Two-hybrid; 2 records), TRAF2 (Two-hybrid; 2 records), ACAD11 (Affinity Capture-MS), AKAP9 (Two-hybrid), AURKA (Two-hybrid)

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
E-box sequence-binding complex	4	BEX2, LDB1, LMO2, NHLH2

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 90 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
Keratinization	19	20.4×	4e-18
Formation of the cornified envelope	10	16.9×	3e-08

GO biological processes:

GO term	Partners	Fold	FDR
morphogenesis of an epithelium	9	40.2×	3e-10
intermediate filament organization	10	31.3×	3e-10
epithelial cell differentiation	9	20.5×	1e-07

Disease & clinical

Genetic variants

Variant evidence for BEX2: 40 ClinVar records (1 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	29
Likely benign	2
Benign	2

Top pathogenic / likely-pathogenic (1)

Showing all 1 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
1077188	Single allele	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore BEX2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 28 predictions of 196):

Position(s)	Effect	Δscore	Sites
X:103309982–103309983	acceptor_loss	1.0000	6
X:103310357	donor_loss	1.0000	3
X:103310356	donor_loss	0.9900	2
X:103310442	acceptor_gain	0.9900
X:103310445–103310446	acceptor_gain	0.9900	2
X:103309991	acceptor_gain	0.9800
X:103310434–103310435	acceptor_loss	0.9700	6
X:103310632	donor_gain	0.9400
X:103310858–103310859	donor_loss	0.9400	5
X:103310858	donor_loss	0.9200

AlphaMissense

136 missense substitutions predicted likely pathogenic (of 865 scored), across 35 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
F124	7	0.945	0.992
C125	7	0.854	0.939
M127	7	0.832	0.943
P128	6	0.897	0.952
L126	6	0.779	0.933
D114	6	0.694	0.786
D122	6	0.655	0.675
S112	5	0.878	0.950
S107	5	0.819	0.929
V111	5	0.734	0.887
A110	5	0.720	0.842
K102	5	0.708	0.839
E123	5	0.694	0.819
W67	4	0.726	0.775
R59	4	0.713	0.798
K98	4	0.652	0.700
Q103	4	0.634	0.696
P61	4	0.611	0.655
L99	3	0.793	0.922
L95	3	0.748	0.938

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Thyroid Carcinoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Papillary Cell Carcinoma (TCGA)	favorable	1.03e-07
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	2.98e-07

Disease associations

OMIM: gene MIM:300691 | disease phenotypes: MIM:312080, MIM:312920

GenCC curated gene-disease

Mondo (2): Pelizaeus-Merzbacher spectrum disorder (MONDO:0010714), hereditary spastic paraplegia 2 (MONDO:0010733)

Orphanet (2): Pelizaeus-Merzbacher disease (Orphanet:702), Spastic paraplegia type 2 (Orphanet:99015)

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
D020371	Pelizaeus-Merzbacher Disease	C10.228.140.163.100.362.775; C10.228.140.695.625.775; C10.314.400.775; C16.320.322.906; C16.320.565.189.362.775; C18.452.132.100.362.775; C18.452.648.189.362.775

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases methylation, affects cotreatment, increases expression	6
Cyclosporine	increases expression	3
bisphenol A	affects expression, increases expression	2
trichostatin A	affects cotreatment, decreases expression	2
sodium arsenite	decreases expression, increases expression	2
Estradiol	affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	increases expression	2
aristolochic acid I	increases expression	1
sotorasib	affects cotreatment, decreases expression	1
propionaldehyde	increases expression	1
terbufos	increases methylation	1
tris(2-butoxyethyl) phosphate	affects expression	1
dimethylselenide	increases expression, increases oxidation	1
beta-lapachone	increases expression	1
o,p’-DDT	increases expression	1
boron nitride	increases expression	1
butyraldehyde	increases expression	1
3,4,3’,4’-tetrachlorobiphenyl	affects expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
cupric oxide	increases expression	1
beta-methylcholine	affects expression	1
pentanal	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment, decreases expression	1
nutlin 3	affects cotreatment, increases expression	1
ICG 001	increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
licochalcone B	increases expression	1
NSC 689534	affects binding, increases expression	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

9 trials:

NCT	Phase	Status	Title
NCT07382739	Phase 2	RECRUITING	A Phase 2 Study of Radiotherapy-induced Immune Priming to Enhance Elranatamab (Elra) in Relapsed Refractory Multiple Myeloma (RRMM) With Extramedullary Disease (EMD) and Paramedullary Disease (PMD) PRIME-EMD-PMD
NCT01005004	Phase 1	COMPLETED	Study of Human Central Nervous System (CNS) Stem Cells Transplantation in Pelizaeus-Merzbacher Disease (PMD) Subjects
NCT02254863	Phase 1	RECRUITING	UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells
NCT06150716	Phase 1	RECRUITING	Orbit Study: A Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Intrathecally Administered ION356 in Participants With Pelizaeus Merzbacher Disease (PMD)
NCT01391637	Not specified	COMPLETED	Long-Term Follow-Up Study of Human Stem Cells Transplanted in Subjects With Connatal Pelizaeus-Merzbacher Disease (PMD)
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT05659901	Not specified	RECRUITING	Rocket Study: A Study to Characterize Biomarkers and Disease Progression in Participants With Pelizaeus-Merzbacher Disease