CHMP2B

Summary

CHMP2B (charged multivesicular body protein 2B, HGNC:24537) is a protein-coding gene on chromosome 3p11.2, encoding Charged multivesicular body protein 2b (Q9UQN3). Probable core component of the endosomal sorting required for transport complex III (ESCRT-III) which is involved in multivesicular bodies (MVBs) formation and sorting of endosomal cargo proteins into MVBs.

This gene encodes a component of the heteromeric ESCRT-III complex (Endosomal Sorting Complex Required for Transport III) that functions in the recycling or degradation of cell surface receptors. ESCRT-III functions in the concentration and invagination of ubiquitinated endosomal cargos into intralumenal vesicles. The protein encoded by this gene is found as a monomer in the cytosol or as an oligomer in ESCRT-III complexes on endosomal membranes. It is expressed in neurons of all major regions of the brain. Mutations in this gene result in one form of familial frontotemporal lobar degeneration.

Source: NCBI Gene 25978 — RefSeq curated summary.

At a glance

• Gene–disease (curated): frontotemporal dementia and/or amyotrophic lateral sclerosis 7 (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 204 total — 4 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 111
• MANE Select transcript: NM_014043

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24537
Approved symbol	CHMP2B
Name	charged multivesicular body protein 2B
Location	3p11.2
Locus type	gene with protein product
Status	Approved
Aliases	DKFZP564O123, CHMP2.5, VPS2B
Ensembl gene	ENSG00000083937
Ensembl biotype	protein_coding
OMIM	609512
Entrez	25978

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 5 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000263780, ENST00000466696, ENST00000471660, ENST00000472024, ENST00000494980, ENST00000676705, ENST00000676947, ENST00000677929, ENST00000678818, ENST00000678859

RefSeq mRNA: 3 — MANE Select: NM_014043 NM_001244644, NM_001410777, NM_014043

CCDS: CCDS2918, CCDS58840

Canonical transcript exons

ENST00000263780 — 6 exons

Exon	Start	End
ENSE00001209407	87253404	87253510
ENSE00001828224	87227309	87227556
ENSE00001945124	87253712	87255556
ENSE00003711959	87245714	87245908
ENSE00003713804	87249875	87249977
ENSE00003716534	87240699	87240790

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 97.75.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 49.5228 / max 490.1281, expressed in 1819 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
37441	48.4725	1818
37442	1.0504	547

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
medial globus pallidus	UBERON:0002477	97.75	gold quality
amniotic fluid	UBERON:0000173	97.72	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.43	gold quality
colonic mucosa	UBERON:0000317	97.33	gold quality
jejunal mucosa	UBERON:0000399	97.13	gold quality
globus pallidus	UBERON:0001875	97.02	gold quality
esophagus squamous epithelium	UBERON:0006920	96.34	gold quality
palpebral conjunctiva	UBERON:0001812	95.98	gold quality
pons	UBERON:0000988	95.96	gold quality
oocyte	CL:0000023	95.77	gold quality
secondary oocyte	CL:0000655	95.72	gold quality
subthalamic nucleus	UBERON:0001906	95.71	gold quality
germinal epithelium of ovary	UBERON:0001304	95.34	gold quality
inferior vagus X ganglion	UBERON:0005363	95.31	gold quality
tongue squamous epithelium	UBERON:0006919	95.29	gold quality
cartilage tissue	UBERON:0002418	95.25	gold quality
calcaneal tendon	UBERON:0003701	95.03	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	94.92	gold quality
jejunum	UBERON:0002115	94.86	gold quality
tendon	UBERON:0000043	94.80	gold quality
spinal cord	UBERON:0002240	94.78	gold quality
eye	UBERON:0000970	94.76	gold quality
rectum	UBERON:0001052	94.76	gold quality
epithelium of esophagus	UBERON:0001976	94.62	gold quality
substantia nigra pars reticulata	UBERON:0001966	94.54	gold quality
superior vestibular nucleus	UBERON:0007227	94.48	gold quality
squamous epithelium	UBERON:0006914	94.45	gold quality
parietal pleura	UBERON:0002400	94.38	gold quality
mammalian vulva	UBERON:0000997	94.37	gold quality
substantia nigra pars compacta	UBERON:0001965	94.32	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

114 targeting CHMP2B, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4282	99.99	75.36	6408
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-4789-3P	99.99	70.75	2484
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-1250-3P	99.96	70.04	4038

Literature-anchored findings (GeneRIF, showing 40)

• there were no significant differences in the frequencies of the IVS4 + 44C/A, 1303C/A, 1254T/C and IVS15Ex16-16C/G polymorphism haplotypes in the patient cohorts (regardless of the degree of hepatic iron deposition) compared to the control cohort (PMID:15223008)
• identify a mutation in CHMP2B, encoding a component of the endosomal ESCRTIII complex, and show that it results in aberrant mRNA splicing in tissue samples from affected members of family with autosomal dominant frontotermporal dementia (PMID:16041373)
• Mutations in CHMP2B are a rare cause of familial FTLD and may be specific to the Danish pedigree. (PMID:16431024)
• This studyidentified mutations (Q206H; I29V) in two patients with non-SOD1 ALS. (PMID:16807408)
• CHMP2B mutations are not a cause of dementia in Dutch patients with familial and sporadic frontotemporal dementia. (PMID:16941655)
• CHMP2B can be excluded as a susceptibility gene conferring risk to sporadic forms of frontotemporal dementia. (PMID:16979267)
• These data suggest that C-truncating mutations in CHMP2B might underlie the pathogenic mechanism in frontotemporal lobar degeneration. (PMID:17956895)
• data indicates that CHMP2B mutations are a rare cause of ALS, and no mutations were found in classic ALS phenotypes. (PMID:18270236)
• These data suggest that SgIII, DMT-1 and HNP-1 are implicated in cell-mediated LDL oxidation. (PMID:19150442)
• The specificity of DMT1 inhibition by 4 molecules in a cell line is reported. (PMID:19179627)
• finding suggests that mutations in CHMP2B have widespread effects throughout the brain, leading to a neuro-anatomical signature distinct from other diseases in the frontotemporal lobar degeneration spectrum (PMID:19202337)
• Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons. (PMID:19706893)
• The fusion of endosomes with lysosomes is required for neuronal function suggesting a pathogenic mechanism for frontotemporal dementia caused by CHMP2B mutations. (PMID:20223751)
• analysis of CHMP2B mutations in lower motor neuron predominant amyotrophic lateral sclerosis (PMID:20352044)
• The results of this study confirmed that mutations in CHMP2B are not a common cause of frontotemporal lobar degeneration. (PMID:20412296)
• CHMP2B can be used as a reliable marker for GVD in neurons of the AD hippocampus. (PMID:20420883)
• A novel heterozygous variant p.Ser194Leu (c.581C>T) is found in exon 6 of the CHMP2B gene in one male patient with pure frontotemporal lobar degeneration. (PMID:20625756)
• CHMP2B is required for spine growth. Taken together, these results demonstrate that a mutant ESCRT-III subunit linked to a human neurodegenerative disease can disrupt the normal pattern of spine development. (PMID:20699355)
• recent advances in our understanding of the molecular basis of CHMP2B mutations indicate that the mechanisms involved may be broadly relevant to neurodegenerative processes.[review] (PMID:21222599)
• CHMP2B polymerization scaffolds membranes in vivo represents a first step toward demonstrating its structural role during outward membrane deformation (PMID:21926173)
• This study provided a better understanding of the cellular pathogenesis of neurodegenerative diseases associated with various missense mutations of CHMP2B as well as endocytic defects. (PMID:22521643)
• Direct link between disease-causing mutations and the cellular phenotype in cells originating from CHMP2B mutation patients with frontotemporal dementia. (PMID:22786763)
• These findings suggest that endosomal and autophagic pathway is associated with degradation or formation of alpha-synuclein aggregates in alpha-synucleinopathy. (PMID:22947304)
• CHMP2B immunoreactivity was increased in the dorsal motor nucleus of the vagus nerve in Parkinson’s disease and incidental Lewy body disease brains (PMID:22989140)
• Subjects with CHMP2B mutation show cognitive changes dominated by executive dysfunctions, years before they fulfil diagnostic criteria of FTD. (PMID:23142962)
• Data indicate that knockdown of syntaxin 13 (syx13) further increased the cellular toxicity caused by muaant CHMP2B (CHMP2BIntron5) expression. (PMID:24095276)
• Protein kinase CK2 alpha is involved in the phosphorylation of the ESCRT-III subunits CHMP3 and CHMP2B, as well as of VPS4B/SKD1, an ATPase that mediates ESCRT-III disassembly. (PMID:24440309)
• Study showed that mutant CHMP2B causes the pathological accumulation of endolysosomal components early in the frontotemporal dementia disease course (PMID:26358247)
• Endogenous TMEM106B was partly sequestered in CHMP2B-positive structures. SNP T185 was more associated with CHMP2B than SNP S185, and it enhanced neurotoxicity caused by CHMP2B(Intron5) compared to S185-expressing cells. (PMID:26651479)
• these data indicate that the neuronal expression of human CHMP2B(intron5) in areas involved in motor and cognitive functions induces progressive motor alterations associated with dementia symptoms and with histopathological hallmarks reminiscent of both amyotrophic lateral sclerosis and frontotemporal dementia. (PMID:27329763)
• We directly link TDP-43 loss of function toxicity to two genes with rare amyotrophic lateral sclerosis and frontotemporal lobar degeneration-causing mutations, CHMP2B and ErbB4 (PMID:27621269)
• Results suggest dysregulation of CHMP2B together with tau-pathology and possibly a disturbance of the regulation of vesicular compartments. The absence of combined Abeta- and tau-associated pathology in the transgenic mice may account for the difference in CHMP2B-immunoreactivity between the transgenic mice and human hippocampus. (PMID:30414727)
• Expression of a human variant of CHMP2B linked to neurodegeneration in Drosophila external sensory organs leads to cell fate transformations associated with increased Notch activity. (PMID:31587468)
• Retrovirus reactivation in CHMP2BIntron5 models of frontotemporal dementia. (PMID:32628265)
• Differential levels of CHMP2B, LLPH, and SLC25A51 proteins in secondary renal amyloidosis. (PMID:33583303)
• Serum Neurofilament Light in Patients with Frontotemporal Dementia Caused by CHMP2B Mutation. (PMID:33626531)
• The ESCRT-III isoforms CHMP2A and CHMP2B display different effects on membranes upon polymerization. (PMID:33832485)
• The ESCRT-III protein VPS4, but not CHMP4B or CHMP2B, is pathologically increased in familial and sporadic ALS neuronal nuclei. (PMID:34281622)
• Astrocytic reactivity triggered by defective autophagy and metabolic failure causes neurotoxicity in frontotemporal dementia type 3. (PMID:34678206)
• Six generations of CHMP2B-mediated Frontotemporal Dementia: Clinical features, predictive testing, progression, and survival. (PMID:34997757)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	chmp2bb	ENSDARG00000002190
danio_rerio	chmp2ba	ENSDARG00000068683
mus_musculus	Chmp2b	ENSMUSG00000004843
rattus_norvegicus	Chmp2b	ENSRNOG00000040257
drosophila_melanogaster	CHMP2B	FBGN0035589
caenorhabditis_elegans	C01A2.4	WBGENE00007216

Paralogs (4): CHMP3 (ENSG00000115561), CHMP2A (ENSG00000130724), CHMP1A (ENSG00000131165), CHMP1B (ENSG00000255112)

Protein

Protein identifiers

Charged multivesicular body protein 2b — Q9UQN3 (reviewed: Q9UQN3)

Alternative names: CHMP2.5, Chromatin-modifying protein 2b, Vacuolar protein sorting-associated protein 2-2

All UniProt accessions (4): Q9UQN3, A0A087WW88, B2RE76, C9J0A7

UniProt curated annotations — full annotation on UniProt →

Function. Probable core component of the endosomal sorting required for transport complex III (ESCRT-III) which is involved in multivesicular bodies (MVBs) formation and sorting of endosomal cargo proteins into MVBs. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. The MVB pathway appears to require the sequential function of ESCRT-O, -I,-II and -III complexes. ESCRT-III proteins mostly dissociate from the invaginating membrane before the ILV is released. The ESCRT machinery also functions in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis and the budding of enveloped viruses (HIV-1 and other lentiviruses). ESCRT-III proteins are believed to mediate the necessary vesicle extrusion and/or membrane fission activities, possibly in conjunction with the AAA ATPase VPS4.

Subunit / interactions. Probable core component of the endosomal sorting required for transport complex III (ESCRT-III). ESCRT-III components are thought to multimerize to form a flat lattice on the perimeter membrane of the endosome. Several assembly forms of ESCRT-III may exist that interact and act sequentially. Interacts with CHMP2A. Interacts with VPS4A. Interacts with VPS4B; the interaction is direct.

Subcellular location. Cytoplasm. Cytosol. Late endosome membrane.

Tissue specificity. Widely expressed. Expressed in brain, heart, skeletal muscle, spleen, kidney, liver, small intestine, pancreas, lung, placenta and leukocytes. In brain, it is expressed in cerebellum, cerebral cortex, medulla, spinal cord, occipital lobe, frontal lobe, temporal lobe and putamen.

Disease relevance. Frontotemporal dementia and/or amyotrophic lateral sclerosis 7 (FTDALS7) [MIM:600795] A neurodegenerative disorder characterized by frontotemporal dementia and/or amyotrophic lateral sclerosis in affected individuals. There is high intrafamilial variation. Frontotemporal dementia (FTD) is characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Amyotrophic lateral sclerosis (ALS) is characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. FTDALS7 is an autosomal dominant form characterized by onset of ALS or FTD in adulthood. A few patients may have both phenotypes. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The acidic C-terminus and the basic N-termminus are thought to render the protein in a closed, soluble and inactive conformation through an autoinhibitory intramolecular interaction. The open and active conformation, which enables membrane binding and oligomerization, is achieved by interaction with other cellular binding partners, probably including other ESCRT components.

Similarity. Belongs to the SNF7 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UQN3-1	1	yes
Q9UQN3-2	2

RefSeq proteins (3): NP_001231573, NP_001397706, NP_054762* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005024	Snf7_fam	Family

Pfam: PF03357

UniProt features (17 total): sequence variant 4, sequence conflict 3, modified residue 2, initiator methionine 1, chain 1, helix 1, region of interest 1, coiled-coil region 1, short sequence motif 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2JQK	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UQN3-F1	80.26	0.48

Functional residue map

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

Post-translational modifications (2): 2, 199

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-162588	Budding and maturation of HIV virion
R-HSA-1632852	Macroautophagy
R-HSA-5620971	Pyroptosis
R-HSA-917729	Endosomal Sorting Complex Required For Transport (ESCRT)
R-HSA-9610379	HCMV Late Events
R-HSA-9615710	Late endosomal microautophagy
R-HSA-9668328	Sealing of the nuclear envelope (NE) by ESCRT-III
R-HSA-9679504	Translation of Replicase and Assembly of the Replication Transcription Complex
R-HSA-9694676	Translation of Replicase and Assembly of the Replication Transcription Complex

MSigDB gene sets: 482 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, GOBP_MITOTIC_CYTOKINESIS, REACTOME_ENDOSOMAL_SORTING_COMPLEX_REQUIRED_FOR_TRANSPORT_ESCRT, GOBP_CHROMOSOME_ORGANIZATION, GOBP_NUCLEAR_MEMBRANE_REASSEMBLY, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_COGNITION, GOBP_LYSOSOMAL_TRANSPORT, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, GOBP_ENDOSOME_ORGANIZATION, TGCGCANK_UNKNOWN, GOBP_VACUOLE_ORGANIZATION, MORF_RAB5A, GOBP_MEMBRANE_BIOGENESIS

GO Biological Process (31): plasma membrane repair (GO:0001778), autophagy (GO:0006914), nucleus organization (GO:0006997), endosome organization (GO:0007032), mitotic metaphase chromosome alignment (GO:0007080), regulation of centrosome duplication (GO:0010824), protein transport (GO:0015031), macroautophagy (GO:0016236), viral release from host cell (GO:0019076), nuclear membrane reassembly (GO:0031468), endosome transport via multivesicular body sorting pathway (GO:0032509), multivesicular body assembly (GO:0036258), viral budding via host ESCRT complex (GO:0039702), ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway (GO:0043162), late endosome to vacuole transport (GO:0045324), viral budding from plasma membrane (GO:0046761), modulation of chemical synaptic transmission (GO:0050804), cognition (GO:0050890), vesicle fusion with vacuole (GO:0051469), multivesicular body-lysosome fusion (GO:0061763), midbody abscission (GO:0061952), neuron cellular homeostasis (GO:0070050), multivesicular body sorting pathway (GO:0071985), membrane fission (GO:0090148), autophagosome maturation (GO:0097352), regulation of modification of postsynaptic structure (GO:0099159), regulation of postsynapse organization (GO:0099175), regulation of mitotic spindle assembly (GO:1901673), late endosome to lysosome transport (GO:1902774), ESCRT III complex disassembly (GO:1904903), vacuolar transport (GO:0007034)

GO Molecular Function (3): protein domain specific binding (GO:0019904), cadherin binding (GO:0045296), protein binding (GO:0005515)

GO Cellular Component (21): autophagosome membrane (GO:0000421), kinetochore (GO:0000776), ESCRT III complex (GO:0000815), nuclear pore (GO:0005643), cytoplasm (GO:0005737), lysosomal membrane (GO:0005765), multivesicular body (GO:0005771), kinetochore microtubule (GO:0005828), cytosol (GO:0005829), plasma membrane (GO:0005886), postsynaptic density (GO:0014069), midbody (GO:0030496), multivesicular body membrane (GO:0032585), extracellular exosome (GO:0070062), glutamatergic synapse (GO:0098978), amphisome membrane (GO:1904930), lysosome (GO:0005764), endosome (GO:0005768), late endosome (GO:0005770), membrane (GO:0016020), late endosome membrane (GO:0031902)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Autophagy	2
Late Phase of HIV Life Cycle	1
Regulated Necrosis	1
Membrane Trafficking	1
HCMV Infection	1
Nuclear Envelope (NE) Reassembly	1
SARS-CoV-1 Infection	1
Early SARS-CoV-2 Infection Events	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
multivesicular body sorting pathway	2
viral budding	2
vesicle fusion	2
plasma membrane organization	1
wound healing	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
organelle organization	1
endomembrane system organization	1
vesicle organization	1
mitotic sister chromatid segregation	1
mitotic cell cycle	1
metaphase chromosome alignment	1
mitotic cell cycle process	1
regulation of centrosome cycle	1
centrosome duplication	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
autophagosome assembly	1
autophagy	1
viral process	1
viral life cycle	1
exit from host cell	1
membrane assembly	1
nuclear membrane organization	1
endosomal transport	1
multivesicular body organization	1
organelle assembly	1
ubiquitin-dependent protein catabolic process	1
protein catabolic process in the vacuole	1
vacuolar transport	1
intercellular transport	1
vesicle-mediated transport	1
non-lytic viral release	1
chemical synaptic transmission	1
regulation of trans-synaptic signaling	1
nervous system process	1

Protein interactions and networks

STRING

1318 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CHMP2B	CHMP1A	Q9HD42	957
CHMP2B	VPS4A	Q9UN37	955
CHMP2B	CHMP4A	Q9BY43	922
CHMP2B	VPS4B	O75351	921
CHMP2B	CHMP1B	Q7LBR1	918
CHMP2B	A0A140T963	A0A140T963	887
CHMP2B	CHMP3	Q9Y3E7	887
CHMP2B	TARDBP	Q13148	852
CHMP2B	VCP	P55072	849
CHMP2B	CHMP4C	Q96CF2	832
CHMP2B	C9orf72	Q96LT7	826
CHMP2B	GRN	P23781	820
CHMP2B	ALS2	Q96Q42	790
CHMP2B	CHMP6	Q96FZ7	782
CHMP2B	FUS	P35637	778

IntAct

84 interactions, top by confidence:

A	B	Type	Score
CHMP4B	CHMP2B	psi-mi:“MI:0407”(direct interaction)	0.590
CHMP2B	CHMP3	psi-mi:“MI:0407”(direct interaction)	0.590
CHMP2B	CHMP3	psi-mi:“MI:0915”(physical association)	0.590
INSR	PIK3R2	psi-mi:“MI:2364”(proximity)	0.570
SYNGAP1	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
TERF2IP	CHMP2B	psi-mi:“MI:0915”(physical association)	0.510
CHMP2B	rep	psi-mi:“MI:0915”(physical association)	0.510
USP8	CHMP2B	psi-mi:“MI:0407”(direct interaction)	0.440
CHMP2B	USP54	psi-mi:“MI:0407”(direct interaction)	0.440
ATP5ME	CHMP2B	psi-mi:“MI:0915”(physical association)	0.400
CHMP2B	CADPS	psi-mi:“MI:0915”(physical association)	0.400
CHMP2B	VTA1	psi-mi:“MI:0915”(physical association)	0.400
GPC1	SNAP23	psi-mi:“MI:0915”(physical association)	0.400
GPC1	GANAB	psi-mi:“MI:0915”(physical association)	0.400
CHMP2B	CHMP2B	psi-mi:“MI:0915”(physical association)	0.370
PNMA1	CHMP2B	psi-mi:“MI:0915”(physical association)	0.370
DPY30	CHMP2B	psi-mi:“MI:0915”(physical association)	0.370
MALSU1	CHMP2B	psi-mi:“MI:0915”(physical association)	0.370
CENPF	CHMP2B	psi-mi:“MI:0915”(physical association)	0.370
PHGDH	CHMP2B	psi-mi:“MI:0915”(physical association)	0.370
CHMP2B	CFTR	psi-mi:“MI:0915”(physical association)	0.370
CHMP2B	TRAF2	psi-mi:“MI:0915”(physical association)	0.370
Tipin	NEMF	psi-mi:“MI:0914”(association)	0.350
Nup98	POM121C	psi-mi:“MI:0914”(association)	0.350
Papss1	TCOF1	psi-mi:“MI:0914”(association)	0.350

BioGRID (125): CHMP2B (Two-hybrid), CHMP2A (Co-fractionation), CHMP2B (Co-fractionation), CHMP4B (Co-fractionation), CHMP2B (Affinity Capture-MS), CHMP2B (Affinity Capture-MS), CHMP2B (Affinity Capture-MS), CHMP2B (Affinity Capture-MS), CHMP2B (Affinity Capture-MS), CHMP2B (Affinity Capture-MS), CHMP2B (Affinity Capture-MS), CHMP2B (Affinity Capture-MS), CHMP2B (Affinity Capture-MS), CHMP2B (Affinity Capture-MS), CHMP2B (Affinity Capture-MS)

ESM2 similar proteins: O14177, O14296, O43633, O60074, O74422, P0C149, P0CR54, P0CR55, P36095, P36108, Q3SX42, Q4R574, Q54DB1, Q54GK9, Q54JK4, Q54P63, Q58CS7, Q5BKM3, Q5E994, Q5F3A2, Q5RAU5, Q5RAV2, Q5ZHN1, Q5ZKX1, Q66IV6, Q6CBS3, Q6DF27, Q6DFS6, Q6IP52, Q6NRM7, Q6NVL7, Q6NXD2, Q6NY88, Q7LBR1, Q7SYR0, Q7SZB5, Q7ZVB1, Q7ZW25, Q84VG1, Q871Y8

Diamond homologs: O14177, O43633, P36108, Q0WTY4, Q3SX42, Q54DB1, Q54GK9, Q54P63, Q5F3A2, Q5RAV2, Q5ZHN1, Q66IV6, Q6DFS6, Q6IP52, Q6NVL7, Q6NXD2, Q7SYR0, Q7ZW25, Q8BJF9, Q941D5, Q9DB34, Q9SKI2, Q9UQN3, Q6NY88, Q4R574, Q58CS7, Q5BKM3, Q5RAU5, Q6NRM7, Q8CGS4, Q9CQ10, Q9LXH5, Q9Y3E7

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CHMP2B	“form complex”	ESCRT-III	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 109 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
Amplification of signal from the kinetochores	5	13.7×	4e-03
RHOQ GTPase cycle	5	12.6×	4e-03
Mitotic Spindle Checkpoint	5	11.0×	6e-03
RHO GTPase Effectors	10	9.4×	5e-05
Signaling by Rho GTPases	11	5.2×	2e-03
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	11	5.1×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein transport	11	5.8×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	2
Uncertain significance	118
Likely benign	39
Benign	18

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
1654	NM_014043.4(CHMP2B):c.618A>C (p.Gln206His)	Pathogenic
1655	NM_014043.4(CHMP2B):c.493C>T (p.Gln165Ter)	Pathogenic
35472	NM_014043.4(CHMP2B):c.311C>A (p.Thr104Asn)	Pathogenic
98003	NM_014043.4(CHMP2B):c.532-1G>C	Pathogenic
2684154	NM_014043.4(CHMP2B):c.618A>T (p.Gln206His)	Likely pathogenic
3896799	NM_014043.4(CHMP2B):c.617A>C (p.Gln206Pro)	Likely pathogenic

SpliceAI

917 predictions. Top by Δscore:

Variant	Effect	Δscore
3:87240698:GAT:G	acceptor_gain	1.0000
3:87240787:GCTG:G	donor_gain	1.0000
3:87240790:GGTA:G	donor_loss	1.0000
3:87240791:G:GG	donor_gain	1.0000
3:87240791:G:T	donor_loss	1.0000
3:87240792:T:A	donor_loss	1.0000
3:87240793:AAGTA:A	donor_loss	1.0000
3:87245699:T:A	acceptor_gain	1.0000
3:87245712:A:AG	acceptor_gain	1.0000
3:87245712:AG:A	acceptor_gain	1.0000
3:87245713:G:A	acceptor_gain	1.0000
3:87245713:G:GA	acceptor_gain	1.0000
3:87245713:GGA:G	acceptor_gain	1.0000
3:87245713:GGAA:G	acceptor_gain	1.0000
3:87245713:GGAAT:G	acceptor_gain	1.0000
3:87245904:CAAAA:C	donor_gain	1.0000
3:87245905:AAAA:A	donor_gain	1.0000
3:87245906:AAA:A	donor_gain	1.0000
3:87245906:AAAGT:A	donor_loss	1.0000
3:87245907:AA:A	donor_gain	1.0000
3:87245908:AG:A	donor_loss	1.0000
3:87245909:GTAA:G	donor_gain	1.0000
3:87245910:T:G	donor_loss	1.0000
3:87245913:G:GG	donor_gain	1.0000
3:87249822:GTAAA:G	acceptor_gain	1.0000
3:87249867:A:AG	acceptor_gain	1.0000
3:87249868:T:G	acceptor_gain	1.0000
3:87249973:AATGA:A	donor_gain	1.0000
3:87249974:ATGA:A	donor_gain	1.0000
3:87249975:TGA:T	donor_gain	1.0000

AlphaMissense

1420 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:87245781:T:C	L65P	1.000
3:87240759:G:C	R32P	0.999
3:87240789:T:C	L42P	0.999
3:87245772:C:A	A62D	0.999
3:87245790:T:C	L68P	0.999
3:87245793:G:C	R69P	0.999
3:87245837:T:C	S84P	0.999
3:87245867:T:C	S94P	0.999
3:87245882:G:C	A99P	0.999
3:87245903:G:C	A106P	0.999
3:87253479:T:C	L167P	0.999
3:87253800:T:C	L207P	0.999
3:87245761:C:G	C58W	0.998
3:87245825:T:C	S80P	0.998
3:87245832:T:A	V82D	0.998
3:87245888:G:C	A101P	0.998
3:87249936:T:C	F128S	0.998
3:87249936:T:G	F128C	0.998
3:87253476:T:A	V166D	0.998
3:87245771:G:C	A62P	0.997
3:87245843:T:C	S86P	0.997
3:87245880:T:G	M98R	0.997
3:87245892:T:A	M102K	0.997
3:87249935:T:C	F128L	0.997
3:87249937:C:A	F128L	0.997
3:87249937:C:G	F128L	0.997
3:87240729:G:C	R22P	0.996
3:87240742:G:C	R26S	0.996
3:87240742:G:T	R26S	0.996
3:87245799:A:C	Q71P	0.996

dbSNP variants (sampled 300 via entrez): RS1000103120 (3:87249249 T>A), RS1000246398 (3:87231784 T>G), RS1000345303 (3:87225450 C>A,T), RS1000639267 (3:87231465 C>A), RS1000740631 (3:87235392 A>G), RS1000890484 (3:87230244 T>C), RS1000979891 (3:87242687 G>A,C), RS1001095662 (3:87236623 G>A), RS1001287531 (3:87242436 G>A), RS1001321361 (3:87248928 T>C), RS1001321655 (3:87249547 A>C,G), RS1001389205 (3:87242796 G>A), RS1001490187 (3:87243111 C>T), RS1001574731 (3:87225836 G>A,T), RS1001584722 (3:87226157 C>A)

Disease associations

OMIM: gene MIM:609512 | disease phenotypes: MIM:600795, MIM:614696

GenCC curated gene-disease

Disease	Classification	Inheritance
frontotemporal dementia and/or amyotrophic lateral sclerosis 7	Definitive	Autosomal dominant
amyotrophic lateral sclerosis type 17	Moderate	Autosomal dominant
amyotrophic lateral sclerosis	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
frontotemporal dementia and/or amyotrophic lateral sclerosis 7	Definitive	AD

Mondo (5): frontotemporal dementia and/or amyotrophic lateral sclerosis 7 (MONDO:0010936), parkinsonian disorder (MONDO:0021095), vascular dementia (MONDO:0004648), amyotrophic lateral sclerosis (MONDO:0004976), (MONDO:0013861)

Orphanet (3): Behavioral variant of frontotemporal dementia (Orphanet:275864), Frontotemporal dementia (Orphanet:282), Amyotrophic lateral sclerosis (Orphanet:803)

HPO phenotypes

111 total (30 of 111 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000020	Urinary incontinence
HP:0000217	Xerostomia
HP:0000474	Thickened nuchal skin fold
HP:0000708	Atypical behavior
HP:0000709	Psychosis
HP:0000710	Hyperorality
HP:0000711	Restlessness
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000718	Aggressive behavior
HP:0000719	Inappropriate behavior
HP:0000723	Restrictive behavior
HP:0000726	Dementia
HP:0000733	Motor stereotypy
HP:0000734	Disinhibition
HP:0000737	Irritability
HP:0000739	Anxiety
HP:0000741	Apathy
HP:0000743	Frontal release signs
HP:0000751	Personality changes
HP:0000757	Lack of insight
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001268	Mental deterioration
HP:0001288	Gait disturbance
HP:0001297	Stroke
HP:0001300	Parkinsonism
HP:0001308	Tongue fasciculations
HP:0001332	Dystonia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST002682_4	Tourette’s syndrome or obsessive-compulsive disorder	4.000000e-07

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
D015140	Dementia, Vascular	C10.228.140.300.400; C10.228.140.300.510.800.500; C10.228.140.380.230; C10.228.140.695.500; C14.907.137.126.372.500; C14.907.253.560.350.500; F03.615.400.350
D020734	Parkinsonian Disorders	C10.228.140.079.862; C10.228.662.600
C579991	Chromosome 3-Linked Frontotemporal Dementia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, affects cotreatment, increases abundance	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
glycidyl methacrylate	increases expression	1
cobaltous chloride	increases expression	1
perfluorooctanoic acid	increases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
ICG 001	decreases expression	1
abrine	increases expression	1
jinfukang	decreases expression	1
Temozolomide	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Arsenic	increases abundance, increases expression, affects cotreatment	1
Caffeine	decreases phosphorylation	1
Carbamazepine	affects expression	1
Cisplatin	decreases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Ozone	affects expression, increases abundance	1
Phenobarbital	affects expression	1
Testosterone	decreases expression	1
Thiram	increases expression	1
Tretinoin	increases expression	1
Aflatoxin B1	decreases methylation	1

Cellosaurus cell lines

16 cell lines: 12 induced pluripotent stem cell, 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1EW	Abcam A-549 CHMP2B KO	Cancer cell line	Male
CVCL_B6JX	U2OS CHMP2B KO	Cancer cell line	Female
CVCL_C7HH	HAP1 CHMP2B (-) 1	Cancer cell line	Male
CVCL_C7HI	HAP1 CHMP2B (-) 2	Cancer cell line	Male
CVCL_E3Y0	KOLF2.1J AAVS1-TREG3-NGN2 CHMP2B-/-	Induced pluripotent stem cell	Male
CVCL_E3Y1	KOLF2.1J AAVS1-TREG3-NGN2 CHMP2B Q165X/+	Induced pluripotent stem cell	Male
CVCL_E3Y2	KOLF2.1J AAVS1-TREG3-NGN2 CHMP2B I29V/I29V	Induced pluripotent stem cell	Male
CVCL_E4TZ	KOLF2.1J CHMP2B 26.3kbdel DEL/DEL	Induced pluripotent stem cell	Male
CVCL_E7JX	KOLF2.1J CHMP2B I29V REV/WT	Induced pluripotent stem cell	Male
CVCL_E7JY	KOLF2.1J CHMP2B I29V SNV/SNV	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00542412	PHASE4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	PHASE4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	PHASE4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	PHASE4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	PHASE4	RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT01662414	PHASE4	COMPLETED	Effect of Undenatured Cysteine-Rich Whey Protein Isolate (HMS 90®) in Patients With Parkinson’s Disease
NCT04871464	PHASE4	UNKNOWN	Role and Mechanism of Probiotics in Improving Motor Symptoms in Mild to Moderate Parkinson’s Disease
NCT00165763	PHASE4	COMPLETED	Efficacy and Safety of Donepezil Hydrochloride (Aricept) in Vascular Dementia
NCT00847860	PHASE4	COMPLETED	Cilostazol Verse Asprin for Vascular Dementia in Poststroke Patients With White Matter Lesions
NCT00947531	PHASE4	COMPLETED	A Clinical Trial to Evaluate the Safety and Efficacy of 20 ml Cerebrolysin in Patients With Vascular Dementia
NCT00950430	PHASE4	ENROLLING_BY_INVITATION	Imaging of Brain Amyloid Plaques in the Aging Population
NCT00021697	PHASE3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	PHASE3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	PHASE3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	PHASE3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00136110	PHASE3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	PHASE3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00372879	PHASE3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
NCT00415519	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III
NCT00424463	PHASE3	COMPLETED	Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00868166	PHASE3	COMPLETED	Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
NCT00965497	PHASE3	COMPLETED	Escitalopram (Lexapro) for Depression MS or ALS
NCT01016522	PHASE3	TERMINATED	Safety and Tolerability of the Ketogenic Diet in Amyotrophic Lateral Sclerosis (ALS)
NCT01160263	PHASE3	COMPLETED	Study of Dopamine and Serotonin Transporters in Patients With Amyotrophic Lateral Sclerosis and Controls
NCT01281189	PHASE3	COMPLETED	Phase 3 Study of Dexpramipexole in ALS
NCT01492686	PHASE3	COMPLETED	Phase 3 Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis
NCT01583088	PHASE3	TERMINATED	Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation
NCT01622088	PHASE3	TERMINATED	Phase 3 Extension Study of Dexpramipexole in ALS
NCT02496767	PHASE3	COMPLETED	Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
NCT02623699	PHASE3	COMPLETED	An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
NCT02936635	PHASE3	COMPLETED	A Study for Patients Who Completed VITALITY-ALS (CY 4031)
NCT03127267	PHASE3	RECRUITING	Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients
NCT03280056	PHASE3	COMPLETED	Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients
NCT03491462	PHASE3	COMPLETED	Arimoclomol in Amyotropic Lateral Sclerosis
NCT03505021	PHASE3	COMPLETED	Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
NCT03548311	PHASE3	COMPLETED	Clinical Trial of Ultra-high Dose Methylcobalamin for ALS
NCT03690791	PHASE3	UNKNOWN	Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease