CHMP4B

Summary

CHMP4B (charged multivesicular body protein 4B, HGNC:16171) is a protein-coding gene on chromosome 20q11.22, encoding Charged multivesicular body protein 4b (Q9H444). 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. It is a selective cancer dependency (DepMap: 86.4% of cell lines).

This gene encodes a member of the chromatin-modifying protein/charged multivesicular body protein (CHMP) protein family. The protein is part of the endosomal sorting complex required for transport (ESCRT) complex III (ESCRT-III), which functions in the sorting of endocytosed cell-surface receptors into multivesicular endosomes. The ESCRT machinery also functions in the final abscisson stage of cytokinesis and in the budding of enveloped viruses such as HIV-1. The three proteins of the CHMP4 subfamily interact with programmed cell death 6 interacting protein (PDCD6IP, also known as ALIX), which also functions in the ESCRT pathway. The CHMP4 proteins assemble into membrane-attached 5-nm filaments that form circular scaffolds and promote or stabilize outward budding. These polymers are proposed to help generate the luminal vesicles of multivesicular bodies. Mutations in this gene result in autosomal dominant posterior polar cataracts.

Source: NCBI Gene 128866 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cataract 31 multiple types (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 48 total — 2 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 4
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 86.4% of screened cell lines
• MANE Select transcript: NM_176812

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16171
Approved symbol	CHMP4B
Name	charged multivesicular body protein 4B
Location	20q11.22
Locus type	gene with protein product
Status	Approved
Aliases	dJ553F4.4, Shax1, SNF7-2, VPS32B
Ensembl gene	ENSG00000101421
Ensembl biotype	protein_coding
OMIM	610897
Entrez	128866

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000217402, ENST00000873319

RefSeq mRNA: 1 — MANE Select: NM_176812 NM_176812

CCDS: CCDS13228

Canonical transcript exons

ENST00000217402 — 5 exons

Exon	Start	End
ENSE00000661352	33811348	33811658
ENSE00000661353	33848467	33848644
ENSE00000661354	33850952	33851066
ENSE00000860068	33852077	33852203
ENSE00001288764	33853496	33854366

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 99.50.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 89.2518 / max 1472.6062, expressed in 1824 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
184178	77.9988	1823
184180	6.0553	1716
184181	1.6813	1162
184179	1.5677	1012
184177	1.1812	636
184182	0.7675	404

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	99.50	gold quality
upper arm skin	UBERON:0004263	99.15	gold quality
tibialis anterior	UBERON:0001385	99.09	gold quality
nasal cavity epithelium	UBERON:0005384	99.00	gold quality
mucosa of transverse colon	UBERON:0004991	98.83	gold quality
kidney epithelium	UBERON:0004819	98.75	gold quality
cartilage tissue	UBERON:0002418	98.74	gold quality
cardiac muscle of right atrium	UBERON:0003379	98.70	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.45	gold quality
mucosa of stomach	UBERON:0001199	98.44	gold quality
popliteal artery	UBERON:0002250	98.40	gold quality
tibial artery	UBERON:0007610	98.40	gold quality
left ventricle myocardium	UBERON:0006566	98.39	gold quality
transverse colon	UBERON:0001157	98.37	gold quality
prefrontal cortex	UBERON:0000451	98.35	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	98.35	gold quality
monocyte	CL:0000576	98.32	gold quality
colonic mucosa	UBERON:0000317	98.31	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.31	gold quality
leukocyte	CL:0000738	98.26	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.26	gold quality
aorta	UBERON:0000947	98.25	gold quality
right coronary artery	UBERON:0001625	98.25	gold quality
gastrocnemius	UBERON:0001388	98.23	gold quality
colon	UBERON:0001155	98.16	gold quality
anterior cingulate cortex	UBERON:0009835	98.16	gold quality
large intestine	UBERON:0000059	98.14	gold quality
frontal cortex	UBERON:0001870	98.14	gold quality
myocardium	UBERON:0002349	98.12	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.08	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-3929	yes	591.95
E-HCAD-4	yes	32.73
E-ANND-3	yes	7.73
E-GEOD-110499	no	267.28
E-GEOD-125970	no	14.68

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NRG1

miRNA regulators (miRDB)

65 targeting CHMP4B, 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-548AW	99.99	72.57	3559
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-6715A-3P	99.83	68.05	1473
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-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-1251-3P	99.64	67.21	1408
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-4269	99.55	69.89	1373
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-548G-3P	99.48	68.67	2159
HSA-MIR-4519	99.48	66.10	859
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-135A-5P	99.36	71.85	1601

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 86.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 21)

• CHMP4b and Alix participate in formation of multivesicular bodies by cooperating with SKD1 (PMID:12860994)
• ALIX can have a dramatic effect on HIV-1 release by binding at the CHMP4B site; the ability to use ALIX may allow HIV-1 to replicate in cells that express only low levels of Tsg101 (PMID:17428861)
• These data provide the first evidence that CHMP4B plays a vital role the maintenance of lens transparency. (PMID:17701905)
• Results suggest that efficient interaction between CHMP4s and Brox requires Brox farnesylation. (PMID:18190528)
• Study demonstrates that CHMP4A and CHMP4B proteins form novel membrane-attached filaments that can promote or stabilize negative curvature and outward budding. (PMID:18209100)
• The Bro1 domain of ALIX binds specifically to C-terminal residues of the human CHMP4B. (PMID:18511562)
• The CHMP4b- and Src-docking sites in the Bro1 domain are autoinhibited in the native state of Alix. (PMID:19016654)
• hSnf7-1 and hSnf7-2 are preferentially associated with CHMP2A and CHMP2B, respectively, and regulate the turnover of distinct transmembrane cargos such as neurotransmitter receptors in human neurons. (PMID:21975012)
• CC2D1A interaction with CHMP4B/4A blocks HIV-1 budding. (PMID:22258254)
• CHMP4B interacts directly with CC2D1A and CC2D1B with nanomolar affinity by forming a 1:1 complex. (PMID:22406677)
• CHMP4B, through its association with chromatin, may participate in the autophagolysosomal degradation of micronuclei and other extranuclear chromatin. (PMID:24741567)
• our results implied that CHMP4B could be a promising prognostic biomarker as well as a potential therapeutic target of HCC. (PMID:25874485)
• homologous domain of human Bro1 domain-containing proteins, Alix and Brox, binds CHMP4B but not STAM2, despite their high structural similarity (PMID:26866605)
• The ESCRT-III subunit CHMP4B is a key effector in abscission, whereas its paralogue, CHMP4C, is a component in the abscission checkpoint that delays abscission until chromatin is cleared from the intercellular bridge. (PMID:26929449)
• Data (including data from studies using transgenic mice) suggest that the process leading to microparticle release from cardiac myocytes involves recruitment of CHMP4B protein to the forming microparticle membrane which also contains cBIN1; plasma cBIN1 is reduced in patients with heart failure as compared to control subjects. (CHMP4B = charged multivesicular body protein 4B; cBIN1 = cardiac bridging integrator 1) (PMID:28806752)
• CHMP4B was localized to primary cilia in mammalian cells. Knockdown of CHMP4B interfered with cilium assembly and also caused fragmentation of preexisting cilia. (PMID:31914703)
• Up-regulation of CHMP4B alleviates microglial necroptosis induced by traumatic brain injury. (PMID:32585748)
• ESCRT-III controls nuclear envelope deformation induced by progerin. (PMID:33139753)
• The ESCRT-III protein VPS4, but not CHMP4B or CHMP2B, is pathologically increased in familial and sporadic ALS neuronal nuclei. (PMID:34281622)
• HSP90beta prevents aging-related cataract formation through regulation of the charged multivesicular body protein (CHMP4B) and p53. (PMID:37487085)
• CHMP4B and VSP4A reverse GSDMD-mediated pyroptosis by cell membrane remodeling in endometrial carcinoma. (PMID:37931722)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	chmp4bb	ENSDARG00000007323
danio_rerio	chmp4ba	ENSDARG00000016255
mus_musculus	Chmp4b	ENSMUSG00000038467
rattus_norvegicus	Chmp4bl1	ENSRNOG00000034071
rattus_norvegicus	Chmp4b	ENSRNOG00000046585
drosophila_melanogaster	shrb	FBGN0086656
caenorhabditis_elegans		WBGENE00016961

Paralogs (5): CHMP5 (ENSG00000086065), CHMP7 (ENSG00000147457), CHMP4C (ENSG00000164695), CHMP4A (ENSG00000254505), CHMP4BP1 (ENSG00000258469)

Protein

Protein identifiers

Charged multivesicular body protein 4b — Q9H444 (reviewed: Q9H444)

Alternative names: Chromatin-modifying protein 4b, SNF7 homolog associated with Alix 1, SNF7-2, Vacuolar protein sorting-associated protein 32-2

All UniProt accessions (1): Q9H444

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. Together with SPAST, the ESCRT-III complex promotes nuclear envelope sealing and mitotic spindle disassembly during late anaphase. Plays a role in the endosomal sorting pathway. ESCRT-III proteins are believed to mediate the necessary vesicle extrusion and/or membrane fission activities, possibly in conjunction with the AAA ATPase VPS4. When overexpressed, membrane-assembled circular arrays of CHMP4B filaments can promote or stabilize negative curvature and outward budding. CHMP4A/B/C are required for the exosomal release of SDCBP, CD63 and syndecan. Majority of the protein exists in a folded closed conformation. (Microbial infection) The ESCRT machinery also functions in topologically equivalent membrane fission events, such as the budding of enveloped viruses (HIV-1 and other lentiviruses). Via its interaction with PDCD6IP involved in HIV-1 p6- and p9-dependent virus release.

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 CHMP6 and CHMP4C. Interacts with PDCD6IP; the interaction is direct. Interacts with VPS4A; the interaction is direct. Interacts with VPS4B; the interaction is direct. Interacts with CHMP7. Interacts with CFTR; the interaction requires misfolded CFTR. Interacts with PTPN23. Interacts with CC2D1B.

Subcellular location. Cytoplasm. Cytosol. Late endosome membrane. Midbody. Nucleus envelope.

Tissue specificity. Widely expressed. Expressed at higher level in heart and skeletal muscle. Also expressed in brain, colon, thymus, spleen, kidney, liver, small intestine, placenta, lung and peripheral blood lymphocytes.

Post-translational modifications. ISGylated. Isgylation weakens its interaction with VPS4A.

Disease relevance. Cataract 31, multiple types (CTRCT31) [MIM:605387] An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. In general, the more posteriorly located and dense an opacity, the greater the impact on visual function. CTRCT31 includes posterior polar, progressive posterior subcapsular, nuclear, and anterior subcapsular cataracts. 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.

Miscellaneous. Its overexpression strongly inhibits HIV-1 release.

Similarity. Belongs to the SNF7 family.

RefSeq proteins (1): NP_789782* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005024	Snf7_fam	Family

Pfam: PF03357

UniProt features (19 total): modified residue 5, helix 4, sequence variant 2, mutagenesis site 2, region of interest 2, initiator methionine 1, chain 1, coiled-coil region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
5MK2	X-RAY DIFFRACTION	1.7
4ABM	X-RAY DIFFRACTION	1.8
3C3Q	X-RAY DIFFRACTION	2.1
3UM3	X-RAY DIFFRACTION	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H444-F1	79.98	0.45

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 (5): 223, 2, 6, 114, 184

Mutagenesis-validated functional residues (2):

Position	Phenotype
54	no loss of interaction with cc2d1b and forms a disulfide bond locking the protein in its folded closed conformation when
180	no loss of interaction with cc2d1b and forms a disulfide bond locking the protein in its folded closed conformation when

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: 371 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, GOBP_MITOTIC_CYTOKINESIS, REACTOME_ENDOSOMAL_SORTING_COMPLEX_REQUIRED_FOR_TRANSPORT_ESCRT, GOBP_CHROMOSOME_ORGANIZATION, GOBP_NUCLEAR_MEMBRANE_REASSEMBLY, GOBP_LYSOSOMAL_TRANSPORT, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, GOBP_ENDOSOME_ORGANIZATION, GOBP_VACUOLE_ORGANIZATION, GOBP_MEMBRANE_BIOGENESIS, GOCC_VACUOLAR_MEMBRANE, GOBP_VESICLE_ORGANIZATION, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_CHROMOSOME_LOCALIZATION, AAGCCAT_MIR135A_MIR135B

GO Biological Process (31): mitotic cytokinesis (GO:0000281), plasma membrane repair (GO:0001778), post-translational protein targeting to endoplasmic reticulum membrane (GO:0006620), vesicle budding from membrane (GO:0006900), autophagy (GO:0006914), nucleus organization (GO:0006997), mitotic metaphase chromosome alignment (GO:0007080), exit from mitosis (GO:0010458), regulation of centrosome duplication (GO:0010824), protein transport (GO:0015031), macroautophagy (GO:0016236), nuclear membrane reassembly (GO:0031468), late endosome to vacuole transport via multivesicular body sorting pathway (GO:0032511), multivesicular body assembly (GO:0036258), maintenance of lens transparency (GO:0036438), viral budding via host ESCRT complex (GO:0039702), ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway (GO:0043162), viral budding (GO:0046755), viral budding from plasma membrane (GO:0046761), nervous system process (GO:0050877), protein polymerization (GO:0051258), vesicle fusion with vacuole (GO:0051469), multivesicular body-lysosome fusion (GO:0061763), midbody abscission (GO:0061952), multivesicular body sorting pathway (GO:0071985), membrane fission (GO:0090148), obsolete ubiquitin-independent protein catabolic process via the multivesicular body sorting pathway (GO:0090611), autophagosome maturation (GO:0097352), regulation of mitotic spindle assembly (GO:1901673), late endosome to lysosome transport (GO:1902774), vacuolar transport (GO:0007034)

GO Molecular Function (4): identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), cadherin binding (GO:0045296), protein binding (GO:0005515)

GO Cellular Component (22): autophagosome membrane (GO:0000421), kinetochore (GO:0000776), ESCRT III complex (GO:0000815), nucleus (GO:0005634), nuclear envelope (GO:0005635), nuclear pore (GO:0005643), cytoplasm (GO:0005737), lysosomal membrane (GO:0005765), endosome (GO:0005768), multivesicular body (GO:0005771), kinetochore microtubule (GO:0005828), cytosol (GO:0005829), plasma membrane (GO:0005886), cytoplasmic side of plasma membrane (GO:0009898), membrane coat (GO:0030117), midbody (GO:0030496), vesicle (GO:0031982), multivesicular body membrane (GO:0032585), extracellular exosome (GO:0070062), amphisome membrane (GO:1904930), 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	3
mitotic cell cycle	2
mitotic cell cycle process	2
viral budding	2
membrane protein complex	2
endomembrane system	2
cytoplasm	2
cytoskeleton-dependent cytokinesis	1
plasma membrane organization	1
wound healing	1
protein targeting to membrane	1
protein targeting to ER	1
vesicle organization	1
vesicle-mediated transport	1
membrane organization	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
organelle organization	1
mitotic sister chromatid segregation	1
metaphase chromosome alignment	1
mitotic cell cycle phase transition	1
mitotic nuclear division	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
membrane assembly	1
nuclear membrane organization	1
endosome transport via multivesicular body sorting pathway	1
late endosome to vacuole transport	1
multivesicular body organization	1
organelle assembly	1
tissue homeostasis	1
ubiquitin-dependent protein catabolic process	1
protein catabolic process in the vacuole	1
multivesicular body sorting pathway	1

Protein interactions and networks

STRING

1965 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CHMP4B	TMEM114	B3SHH9	736
CHMP4B	PTPN23	Q9H3S7	730
CHMP4B	CHMP2B	Q9UQN3	685
CHMP4B	CRYBB2	P43320	635
CHMP4B	CRYBA4	P53673	626
CHMP4B	CRYBB1	P53674	623
CHMP4B	CRYGD	P07320	617
CHMP4B	GJA3	Q9Y6H8	614
CHMP4B	GJA8	P48165	613
CHMP4B	HSF4	Q9ULV5	612
CHMP4B	LIM2	P55344	610
CHMP4B	TSG101	Q99816	606
CHMP4B	CRYBA1	P05813	605
CHMP4B	CRYGS	P22914	605
CHMP4B	BFSP2	Q13515	600

IntAct

239 interactions, top by confidence:

A	B	Type	Score
CHMP4B	PDCD6IP	psi-mi:“MI:0407”(direct interaction)	0.860
PDCD6IP	CHMP4B	psi-mi:“MI:0407”(direct interaction)	0.860
PDCD6IP	CHMP4B	psi-mi:“MI:0915”(physical association)	0.860
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CHMP4B	CHMP3	psi-mi:“MI:0407”(direct interaction)	0.690
CHMP3	CHMP4B	psi-mi:“MI:0915”(physical association)	0.690
CHMP4B	CHMP3	psi-mi:“MI:0915”(physical association)	0.690
HTT	CHMP4B	psi-mi:“MI:0915”(physical association)	0.670
CC2D1A	CHMP4B	psi-mi:“MI:0915”(physical association)	0.660
CHMP4B	PTPN23	psi-mi:“MI:0407”(direct interaction)	0.660
CHMP4B	CHMP4B	psi-mi:“MI:0915”(physical association)	0.640
CHMP4B	CHMP4B	psi-mi:“MI:0407”(direct interaction)	0.640
BROX	CHMP4B	psi-mi:“MI:0407”(direct interaction)	0.610
BROX	CHMP4B	psi-mi:“MI:0915”(physical association)	0.610

BioGRID (839): CHMP4B (Affinity Capture-MS), CHMP4B (Two-hybrid), CHMP2A (Co-localization), CHMP1B (Co-fractionation), CHMP4B (Co-fractionation), CHMP4B (Co-fractionation), CHMP4B (Co-fractionation), CHMP4B (Co-fractionation), CHMP4B (Co-fractionation), IMPDH2 (Co-fractionation), CHMP4B (Proximity Label-MS), ATP6V1A (Affinity Capture-MS), ATP6V1B2 (Affinity Capture-MS), ATP6V1E1 (Affinity Capture-MS), ATP6V0A1 (Affinity Capture-MS)

ESM2 similar proteins: A0JN61, B5FZ63, O14737, O43242, O82197, P02643, P13412, P27768, P48788, P49205, P50502, P50503, P56812, Q06364, Q08AG7, Q15691, Q2HJH9, Q3ZBD9, Q3ZBJ0, Q4QQV8, Q5R7Z5, Q5RBR3, Q5RBT0, Q5RF31, Q5SRX1, Q5XGW6, Q5XGY9, Q5ZHP5, Q5ZLF0, Q61166, Q66HR2, Q6DD52, Q6GL11, Q6IQ73, Q6PBL0, Q6ZVM7, Q7ZVC4, Q8K396, Q8NFI4, Q99L47

Diamond homologs: A2VDY3, O82197, P0C149, P0CR54, P0CR55, P39929, P59074, Q569C1, Q5ABD0, Q5B5E0, Q5XGW6, Q5ZHP5, Q6BSH2, Q6CBS3, Q6CJL0, Q6FW96, Q6GL11, Q6GNN8, Q6IQ73, Q753W3, Q7ZVC4, Q86H98, Q871Y8, Q8T0Q4, Q96CF2, Q9BY43, Q9D7F7, Q9D8B3, Q9H444, Q9P7F7, Q9SZE4, Q54KZ4, Q7T0X5, Q86K93, Q9VVI9, Q5R861, Q96FZ7, O74422, P0C0A3, Q54JK4

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
TTC19	“up-regulates activity”	CHMP4B	binding
CHMP4B	“form complex”	ESCRT-III	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 178 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
Budding and maturation of HIV virion	12	41.1×	2e-14
Endosomal Sorting Complex Required For Transport (ESCRT)	11	34.0×	3e-12
Sealing of the nuclear envelope (NE) by ESCRT-III	10	29.1×	2e-10
Pyroptosis	8	28.4×	2e-08
Late endosomal microautophagy	10	27.4×	3e-10
Lysosome Vesicle Biogenesis	5	13.7×	2e-03
SUMOylation of transcription cofactors	6	12.2×	6e-04
HCMV Late Events	11	9.1×	3e-06

GO biological processes:

GO term	Partners	Fold	FDR
nuclear membrane reassembly	11	73.7×	1e-16
viral budding via host ESCRT complex	12	65.1×	5e-17
late endosome to lysosome transport	9	60.3×	6e-13
multivesicular body sorting pathway	11	59.6×	1e-15
midbody abscission	11	54.5×	3e-15
multivesicular body assembly	13	46.3×	1e-16
vesicle budding from membrane	6	45.5×	1e-07
regulation of mitotic spindle assembly	9	44.6×	2e-11

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	15
Likely benign	9
Benign	11

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1085	NM_176812.5(CHMP4B):c.386A>T (p.Asp129Val)	Pathogenic
1086	NM_176812.5(CHMP4B):c.481G>A (p.Glu161Lys)	Pathogenic
2841293	NM_176812.5(CHMP4B):c.200A>G (p.Gln67Arg)	Likely pathogenic

SpliceAI

823 predictions. Top by Δscore:

Variant	Effect	Δscore
20:33811654:GCGCG:G	donor_gain	1.0000
20:33848461:AC:A	acceptor_gain	1.0000
20:33848462:C:CA	acceptor_gain	1.0000
20:33848462:C:G	acceptor_gain	1.0000
20:33848465:A:AG	acceptor_gain	1.0000
20:33848465:AGC:A	acceptor_gain	1.0000
20:33848465:AGCG:A	acceptor_gain	1.0000
20:33848466:G:GT	acceptor_gain	1.0000
20:33848466:GC:G	acceptor_gain	1.0000
20:33848466:GCG:G	acceptor_gain	1.0000
20:33848466:GCGG:G	acceptor_gain	1.0000
20:33848466:GCGGC:G	acceptor_gain	1.0000
20:33848640:AACAT:A	donor_gain	1.0000
20:33848641:ACAT:A	donor_gain	1.0000
20:33848641:ACATG:A	donor_loss	1.0000
20:33848642:CAT:C	donor_gain	1.0000
20:33848643:AT:A	donor_gain	1.0000
20:33848643:ATGT:A	donor_loss	1.0000
20:33848644:TGTA:T	donor_loss	1.0000
20:33848645:G:GG	donor_gain	1.0000
20:33848645:G:T	donor_loss	1.0000
20:33848646:T:G	donor_loss	1.0000
20:33850944:A:AG	acceptor_gain	1.0000
20:33850944:ATTT:A	acceptor_gain	1.0000
20:33851064:GAGGT:G	donor_loss	1.0000
20:33851065:AGGT:A	donor_loss	1.0000
20:33851066:GGT:G	donor_loss	1.0000
20:33851067:GTGA:G	donor_loss	1.0000
20:33851068:T:A	donor_loss	1.0000
20:33852072:A:AG	acceptor_gain	1.0000

AlphaMissense

1480 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:33811554:T:C	L29P	1.000
20:33811587:A:C	Q40P	1.000
20:33811596:T:C	L43P	1.000
20:33811629:C:A	A54D	1.000
20:33848470:C:A	A65D	1.000
20:33848478:G:C	A68P	1.000
20:33848482:T:C	L69P	1.000
20:33848488:G:C	R71P	1.000
20:33848512:T:C	L79P	1.000
20:33848551:A:C	Q92P	1.000
20:33848554:G:C	R93P	1.000
20:33848559:G:C	A95P	1.000
20:33848563:T:C	L96P	1.000
20:33848571:G:C	A99P	1.000
20:33848611:C:A	A112D	1.000
20:33848613:G:C	A113P	1.000
20:33848619:G:C	A115P	1.000
20:33851019:T:C	S146P	1.000
20:33851025:G:C	A148P	1.000
20:33811541:G:C	A25P	0.999
20:33811557:G:C	R30P	0.999
20:33811575:T:C	L36S	0.999
20:33811585:A:C	K39N	0.999
20:33811585:A:T	K39N	0.999
20:33811620:T:C	L51P	0.999
20:33811628:G:C	A54P	0.999
20:33811641:G:A	G58D	0.999
20:33848473:T:C	L66P	0.999
20:33848482:T:A	L69Q	0.999
20:33848490:A:G	K72E	0.999

dbSNP variants (sampled 300 via entrez): RS1000089208 (20:33836663 C>A), RS1000147865 (20:33819308 C>G), RS1000153482 (20:33846080 T>C), RS1000207432 (20:33847731 C>T), RS1000291516 (20:33844487 C>T), RS1000292447 (20:33836132 CTT>C), RS1000455003 (20:33854832 C>A,G), RS1000554888 (20:33823997 G>A), RS1000640877 (20:33837383 A>G), RS1000719319 (20:33810766 C>T), RS1000791379 (20:33837815 T>C), RS1000824159 (20:33847742 G>C), RS1000878644 (20:33850836 G>A), RS1000922771 (20:33809542 T>C), RS1001088042 (20:33848130 C>A)

Disease associations

OMIM: gene MIM:610897 | disease phenotypes: MIM:605387

GenCC curated gene-disease

Disease	Classification	Inheritance
cataract 31 multiple types	Strong	Autosomal dominant
early-onset posterior subcapsular cataract	Supportive	Autosomal dominant
early-onset posterior polar cataract	Supportive	Autosomal dominant

Mondo (3): cataract 31 multiple types (MONDO:0011547), early-onset posterior subcapsular cataract (MONDO:0018610), early-onset posterior polar cataract (MONDO:0020378)

Orphanet (1): Early onset non-syndromic cataract (Orphanet:91492)

HPO phenotypes

4 total (4 of 4 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0007787	Posterior subcapsular cataract
HP:0010923	Anterior subcapsular cataract
HP:0100018	Nuclear cataract

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001840_1	Stearic acid (18:0) levels	3.000000e-07
GCST003771_21	Loneliness	3.000000e-07
GCST006948_53	Feeling nervous	2.000000e-08
GCST008363_12	Offspring birth weight	3.000000e-09
GCST010002_65	Refractive error	5.000000e-19

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007865	loneliness measurement
EFO:0009597	feeling nervous measurement
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C535343	Cataract, posterior polar, 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066344 (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
5.58	Kd	2613	nM	CHEMBL5653589
5.48	ED50	3285	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	2148070: Binding affinity to human CHMP4B incubated for 45 mins by Kinobead based pull down assay	kd	2.6131	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	3
bisphenol A	affects cotreatment, decreases methylation, decreases expression	2
Tobacco Smoke Pollution	increases expression, affects expression	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
nobiletin	decreases expression, decreases reaction	1
sodium arsenate	decreases reaction, decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
perfluorooctanoic acid	increases expression	1
perfluorooctane sulfonic acid	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
nutlin 3	affects cotreatment, increases secretion	1
abrine	increases expression	1
LDN 193189	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Sunitinib	decreases expression	1
Zoledronic Acid	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Vorinostat	decreases expression	1
Arsenic	decreases expression	1
Dactinomycin	affects cotreatment, increases secretion	1
Dexamethasone	affects cotreatment, decreases expression	1
Furaldehyde	affects cotreatment, affects localization, decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Smoke	decreases expression	1
Sodium Chloride	affects localization, decreases expression, increases expression, affects cotreatment	1
Tretinoin	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	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
CHEMBL5651112	Binding	Binding affinity to human CHMP4B 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)

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