EXOSC4

Summary

EXOSC4 (exosome component 4, HGNC:18189) is a protein-coding gene on chromosome 8q24.3, encoding Exosome complex component RRP41 (Q9NPD3). Non-catalytic component of the RNA exosome complex which has 3’->5’ exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. It is a common-essential gene (DepMap: required in 99.4% of cancer cell lines).

Enables mRNA 3’-UTR AU-rich region binding activity. Involved in several processes, including DNA deamination; maturation of 5.8S rRNA; and nuclear-transcribed mRNA catabolic process. Acts upstream of or within defense response to virus. Located in cytosol; euchromatin; and nuclear lumen. Part of exosome (RNase complex).

Source: NCBI Gene 54512 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Limited, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 35 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.4% of screened cell lines (common-essential)
• MANE Select transcript: NM_019037

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18189
Approved symbol	EXOSC4
Name	exosome component 4
Location	8q24.3
Locus type	gene with protein product
Status	Approved
Aliases	hRrp41p, FLJ20591, Rrp41p, RRP41, RRP41A, Ski6p, SKI6, p12A
Ensembl gene	ENSG00000178896
Ensembl biotype	protein_coding
OMIM	606491
Entrez	54512

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000316052, ENST00000525936, ENST00000527954, ENST00000905027, ENST00000917254, ENST00000917255, ENST00000917256

RefSeq mRNA: 1 — MANE Select: NM_019037 NM_019037

CCDS: CCDS6414

Canonical transcript exons

ENST00000316052 — 3 exons

Exon	Start	End
ENSE00001254956	144079943	144080149
ENSE00001292034	144078672	144078899
ENSE00001300596	144080242	144080648

Expression profiles

Bgee: expression breadth ubiquitous, 203 present calls, max score 96.62.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.4050 / max 216.1845, expressed in 1813 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
91467	17.6132	1807
91466	4.2481	1539
91468	0.5054	287
91465	0.0383	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	96.62	gold quality
right testis	UBERON:0004534	96.54	gold quality
testis	UBERON:0000473	93.65	gold quality
mucosa of transverse colon	UBERON:0004991	91.76	gold quality
apex of heart	UBERON:0002098	91.18	gold quality
right adrenal gland	UBERON:0001233	90.21	gold quality
left adrenal gland	UBERON:0001234	89.81	gold quality
right adrenal gland cortex	UBERON:0035827	89.75	gold quality
left adrenal gland cortex	UBERON:0035825	89.63	gold quality
right lobe of liver	UBERON:0001114	88.53	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.34	gold quality
adrenal cortex	UBERON:0001235	88.24	gold quality
body of stomach	UBERON:0001161	88.17	gold quality
anterior cingulate cortex	UBERON:0009835	87.60	gold quality
prefrontal cortex	UBERON:0000451	87.47	gold quality
cingulate cortex	UBERON:0003027	87.45	gold quality
esophagus mucosa	UBERON:0002469	87.23	gold quality
stromal cell of endometrium	CL:0002255	87.01	gold quality
nucleus accumbens	UBERON:0001882	86.97	gold quality
adrenal gland	UBERON:0002369	86.97	gold quality
right atrium auricular region	UBERON:0006631	86.88	gold quality
lower esophagus mucosa	UBERON:0035834	86.83	gold quality
left coronary artery	UBERON:0001626	86.44	gold quality
adenohypophysis	UBERON:0002196	86.38	gold quality
right frontal lobe	UBERON:0002810	86.31	gold quality
esophagus	UBERON:0001043	86.24	gold quality
caudate nucleus	UBERON:0001873	86.17	gold quality
lower esophagus muscularis layer	UBERON:0035833	85.95	gold quality
lower esophagus	UBERON:0013473	85.94	gold quality
left uterine tube	UBERON:0001303	85.90	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

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.4% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 5)

• Protein-protein interactions between human exosome components support the assembly of RNase PH-type subunits into a six-membered PNPase-like ring. (PMID:12419256)
• Knock-down of hRrp41p or hRrp4p but not PM/Scl-100 or PM/Scl-75 leads to codepletion of other subunits. (PMID:17545563)
• Findings show that EXOSC4 is highly expressed in colorectal cancer (CRC) tumors and cell lines and demonstrate its oncogenic role in development and progression of CRC. (PMID:30155936)
• RNA Exosome Component EXOSC4 Amplified in Multiple Cancer Types Is Required for the Cancer Cell Survival. (PMID:35008922)
• RUNX3 exerts tumor-suppressive role through inhibiting EXOSC4 expression. (PMID:38913281)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	exosc4	ENSDARG00000103432
mus_musculus	Exosc4	ENSMUSG00000034259
rattus_norvegicus	Exosc4	ENSRNOG00000012348
drosophila_melanogaster	Ski6	FBGN0032487
caenorhabditis_elegans		WBGENE00007201

Paralogs (2): EXOSC5 (ENSG00000077348), EXOSC6 (ENSG00000223496)

Protein

Protein identifiers

Exosome complex component RRP41 — Q9NPD3 (reviewed: Q9NPD3)

Alternative names: Exosome component 4, Ribosomal RNA-processing protein 41, p12A

All UniProt accessions (3): E9PI41, E9PPI9, Q9NPD3

UniProt curated annotations — full annotation on UniProt →

Function. Non-catalytic component of the RNA exosome complex which has 3’->5’ exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events. In the nucleus, the RNA exosome complex is involved in proper maturation of stable RNA species such as rRNA, snRNA and snoRNA, in the elimination of RNA processing by-products and non-coding ‘pervasive’ transcripts, such as antisense RNA species and promoter-upstream transcripts (PROMPTs), and of mRNAs with processing defects, thereby limiting or excluding their export to the cytoplasm. The RNA exosome may be involved in Ig class switch recombination (CSR) and/or Ig variable region somatic hypermutation (SHM) by targeting AICDA deamination activity to transcribed dsDNA substrates. In the cytoplasm, the RNA exosome complex is involved in general mRNA turnover and specifically degrades inherently unstable mRNAs containing AU-rich elements (AREs) within their 3’ untranslated regions, and in RNA surveillance pathways, preventing translation of aberrant mRNAs. It seems to be involved in degradation of histone mRNA. The catalytic inactive RNA exosome core complex of 9 subunits (Exo-9) is proposed to play a pivotal role in the binding and presentation of RNA for ribonucleolysis, and to serve as a scaffold for the association with catalytic subunits and accessory proteins or complexes. EXOSC4 binds to ARE-containing RNAs.

Subunit / interactions. Component of the RNA exosome core complex (Exo-9), composed of EXOSC1, EXOSC2, EXOSC3, EXOSC4, EXOSC5, EXOSC6, EXOSC7, EXOSC8 and EXOSC9; within the complex interacts with EXOSC2, EXOSC7 and EXOSC9. The catalytically inactive RNA exosome core complex (Exo-9) associates with the catalytic subunit EXOSC10/RRP6. Exo-9 may associate with DIS3 to form the nucleolar exosome complex, or DIS3L to form the cytoplasmic exosome complex. Exo-9 is formed by a hexameric base ring consisting of the heterodimers EXOSC4-EXOSC9, EXOSC5-EXOSC8 and EXOSC6-EXOSC7, and a cap ring consisting of EXOSC1, EXOSC2 and EXOSC3. The RNA exosome complex associates with cofactors C1D/RRP47, MPHOSPH6/MPP6 and MTREX/MTR4. Interacts with DDX60. Interacts with DIS3; the interaction is direct.

Subcellular location. Cytoplasm. Nucleus. Nucleolus. Nucleoplasm.

Similarity. Belongs to the RNase PH family.

RefSeq proteins (1): NP_061910* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001247	ExoRNase_PH_dom1	Domain
IPR015847	ExoRNase_PH_dom2	Domain
IPR020568	Ribosomal_Su5_D2-typ_SF	Homologous_superfamily
IPR027408	PNPase/RNase_PH_dom_sf	Homologous_superfamily
IPR036345	ExoRNase_PH_dom2_sf	Homologous_superfamily
IPR050080	RNase_PH	Family

Pfam: PF01138, PF03725

UniProt features (24 total): strand 13, helix 5, turn 3, initiator methionine 1, chain 1, modified residue 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
9G8M	ELECTRON MICROSCOPY	3.3
2NN6	X-RAY DIFFRACTION	3.35
9G8O	ELECTRON MICROSCOPY	3.4
6D6Q	ELECTRON MICROSCOPY	3.45
6D6R	ELECTRON MICROSCOPY	3.45
9G8N	ELECTRON MICROSCOPY	3.7
6H25	ELECTRON MICROSCOPY	3.8
9G8P	ELECTRON MICROSCOPY	7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NPD3-F1	90.34	0.71

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 (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-380994	ATF4 activates genes in response to endoplasmic reticulum stress
R-HSA-429958	mRNA decay by 3’ to 5’ exoribonuclease
R-HSA-450385	Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA
R-HSA-450513	Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA
R-HSA-450604	KSRP (KHSRP) binds and destabilizes mRNA
R-HSA-6791226	Major pathway of rRNA processing in the nucleolus and cytosol
R-HSA-9930044	Nuclear RNA decay

MSigDB gene sets: 185 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, ELVIDGE_HYPOXIA_DN, GOBP_RIBOSOME_BIOGENESIS, MULLIGHAN_NPM1_SIGNATURE_3_UP, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, GOMF_RNA_NUCLEASE_ACTIVITY, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOMF_NUCLEASE_ACTIVITY, MODULE_151, GOBP_SNO_S_RNA_METABOLIC_PROCESS, MATTIOLI_MGUS_VS_PCL, GOBP_GROWTH, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MODULE_503, GOBP_DNA_MODIFICATION

GO Biological Process (13): maturation of 5.8S rRNA (GO:0000460), nuclear-transcribed mRNA catabolic process (GO:0000956), rRNA processing (GO:0006364), RNA processing (GO:0006396), RNA catabolic process (GO:0006401), rRNA catabolic process (GO:0016075), positive regulation of cell growth (GO:0030307), U4 snRNA 3’-end processing (GO:0034475), DNA deamination (GO:0045006), defense response to virus (GO:0051607), nuclear mRNA surveillance (GO:0071028), histone mRNA catabolic process (GO:0071044), poly(A)-dependent snoRNA 3’-end processing (GO:0071051)

GO Molecular Function (4): 3’-5’-RNA exonuclease activity (GO:0000175), RNA binding (GO:0003723), mRNA 3’-UTR AU-rich region binding (GO:0035925), protein binding (GO:0005515)

GO Cellular Component (11): nuclear exosome (RNase complex) (GO:0000176), cytoplasmic exosome (RNase complex) (GO:0000177), exosome (RNase complex) (GO:0000178), euchromatin (GO:0000791), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), nucleolar exosome (RNase complex) (GO:0101019), exoribonuclease complex (GO:1905354)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Regulation of mRNA stability by proteins that bind AU-rich elements	3
PERK regulates gene expression	1
Deadenylation-dependent mRNA decay	1
rRNA processing in the nucleus and cytosol	1
Metabolism of RNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nuclear lumen	3
cellular anatomical structure	3
rRNA metabolic process	2
nuclear-transcribed mRNA catabolic process	2
exosome (RNase complex)	2
cytoplasm	2
intracellular anatomical structure	2
rRNA processing	1
mRNA catabolic process	1
RNA processing	1
ribosome biogenesis	1
gene expression	1
RNA biosynthetic process	1
primary metabolic process	1
RNA metabolic process	1
nucleic acid catabolic process	1
RNA catabolic process	1
regulation of cell growth	1
cell growth	1
positive regulation of growth	1
positive regulation of cellular process	1
snRNA 3’-end processing	1
DNA modification	1
defense response	1
response to virus	1
nuclear RNA surveillance	1
histone mRNA metabolic process	1
sno(s)RNA 3’-end processing	1
3’-5’ exonuclease activity	1
RNA exonuclease activity, producing 5’-phosphomonoesters	1
nucleic acid binding	1
mRNA 3’-UTR binding	1
binding	1
nucleus	1
nuclear protein-containing complex	1
exoribonuclease complex	1
chromatin	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
nuclear exosome (RNase complex)	1

Protein interactions and networks

STRING

2893 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EXOSC4	EXOSC7	Q15024	999
EXOSC4	EXOSC9	Q06265	999
EXOSC4	EXOSC8	Q96B26	999
EXOSC4	EXOSC3	Q9NQT5	999
EXOSC4	EXOSC1	Q9Y3B2	999
EXOSC4	EXOSC5	Q9NQT4	991
EXOSC4	EXOSC6	Q5RKV6	991
EXOSC4	EXOSC2	Q13868	982
EXOSC4	EXOSC10	Q01780	974
EXOSC4	DIS3	Q9Y2L1	910
EXOSC4	SKIC2	Q15477	853
EXOSC4	DIS3L	Q8TF46	814
EXOSC4	MTREX	P42285	743
EXOSC4	C1D	Q13901	728
EXOSC4	XRN1	Q8IZH2	716

IntAct

131 interactions, top by confidence:

A	B	Type	Score
EXOSC4	EXOSC2	psi-mi:“MI:0915”(physical association)	0.910
EXOSC2	EXOSC4	psi-mi:“MI:0915”(physical association)	0.910
EXOSC4	EXOSC7	psi-mi:“MI:0915”(physical association)	0.900
EXOSC4	EXOSC9	psi-mi:“MI:0915”(physical association)	0.900
EXOSC7	EXOSC4	psi-mi:“MI:0915”(physical association)	0.900
EXOSC1	EXOSC2	psi-mi:“MI:0914”(association)	0.850
EXOSC4	EXOSC10	psi-mi:“MI:0914”(association)	0.840
EXOSC2	EXOSC10	psi-mi:“MI:0914”(association)	0.840
EXOSC1	EXOSC10	psi-mi:“MI:0915”(physical association)	0.810
EXOSC1	EXOSC10	psi-mi:“MI:0914”(association)	0.810
EXOSC3	EXOSC10	psi-mi:“MI:0914”(association)	0.790
DIS3	EXOSC10	psi-mi:“MI:0914”(association)	0.740
RBM7	MTREX	psi-mi:“MI:0914”(association)	0.730
DIS3L	EXOSC2	psi-mi:“MI:0914”(association)	0.690
MPHOSPH6	MTREX	psi-mi:“MI:0914”(association)	0.690
C1D	ZFC3H1	psi-mi:“MI:0914”(association)	0.640
EXOSC3	MTREX	psi-mi:“MI:0914”(association)	0.640
ESR1	TRIM24	psi-mi:“MI:0914”(association)	0.640
EXOSC9	EXOSC10	psi-mi:“MI:0914”(association)	0.640
EXOSC5	ZFC3H1	psi-mi:“MI:0914”(association)	0.640
DIS3	EXOSC2	psi-mi:“MI:0914”(association)	0.620
DIS3L	EXOSC9	psi-mi:“MI:0914”(association)	0.600
POLE2	EXOSC4	psi-mi:“MI:0915”(physical association)	0.560
LNX1	EXOSC4	psi-mi:“MI:0915”(physical association)	0.560
SDCBP	EXOSC4	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (338): EXOSC4 (Affinity Capture-MS), EXOSC4 (Affinity Capture-MS), EXOSC4 (Affinity Capture-MS), EXOSC4 (Affinity Capture-MS), EXOSC4 (Affinity Capture-MS), EXOSC4 (Affinity Capture-MS), EXOSC10 (Co-fractionation), EXOSC2 (Co-fractionation), EXOSC3 (Co-fractionation), EXOSC4 (Co-fractionation), EXOSC4 (Co-fractionation), EXOSC4 (Co-fractionation), EXOSC4 (Co-fractionation), EXOSC4 (Co-fractionation), EXOSC4 (Co-fractionation)

ESM2 similar proteins: A2RVK7, A2X0Q3, A6QLJ3, O00442, O23617, O81147, O81852, P0CT46, P31754, P37142, P48605, P49080, P49368, P80318, Q01415, Q06265, Q14181, Q2HJ88, Q2KHU3, Q3SWZ4, Q3T0K2, Q4QR75, Q4R3J0, Q4R963, Q5NVF9, Q5R6J8, Q5R7P3, Q5RCW2, Q5RGJ5, Q5XJQ5, Q69LE7, Q6P502, Q6STH5, Q6YXZ7, Q7YRA3, Q84T68, Q8C3X4, Q8GZQ3, Q8K1R3, Q8N442

Diamond homologs: A0RXU1, A1AHH4, A1KID0, A1RST0, A1TY30, A2BKC0, A2RVK7, A3MUP1, A4QGQ6, A4WM67, A4Y0L7, A5G3S1, A5IMM8, A5N2V9, A5U240, A5WB10, A6VLF1, A7ZTJ4, A8WQQ5, A9A5C9, B0KQ94, B1J4L4, B1LBY0, B1LK80, B1Y978, B1YI57, B2TJ05, B2TTV7, B2UZ31, B5YEU4, B5YWE1, B6I3M0, B6YSI2, B7IE23, B7UM50, B8E0G7, B8ZR59, B9DWL2, B9K8Y9, C1A1V2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
EXOSC4	“form complex”	Exosome_Complex	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 84 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
mRNA decay by 3’ to 5’ exoribonuclease	9	95.9×	7e-15
Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA	8	75.8×	2e-12
Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA	8	75.8×	2e-12
KSRP (KHSRP) binds and destabilizes mRNA	8	75.8×	2e-12
Nuclear RNA decay	16	73.7×	1e-24
ATF4 activates genes in response to endoplasmic reticulum stress	9	54.8×	2e-12
rRNA processing in the nucleus and cytosol	7	16.8×	8e-06
Major pathway of rRNA processing in the nucleolus and cytosol	18	16.6×	2e-15

GO biological processes:

GO term	Partners	Fold	FDR
rRNA catabolic process	6	76.2×	6e-09
RNA catabolic process	12	70.1×	4e-17
nuclear-transcribed mRNA catabolic process	5	49.1×	2e-06
RNA processing	12	33.7×	3e-13
mRNA catabolic process	5	31.8×	2e-05
rRNA processing	13	23.6×	1e-12
ribosomal small subunit biogenesis	5	14.6×	7e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	31
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

472 predictions. Top by Δscore:

Variant	Effect	Δscore
8:144079937:TTCCA:T	acceptor_loss	1.0000
8:144079938:TCCAG:T	acceptor_loss	1.0000
8:144079940:CAGA:C	acceptor_loss	1.0000
8:144079941:A:AG	acceptor_gain	1.0000
8:144079941:A:T	acceptor_loss	1.0000
8:144079942:G:GG	acceptor_gain	1.0000
8:144079942:G:T	acceptor_loss	1.0000
8:144080147:CAGGT:C	donor_loss	1.0000
8:144080148:AGG:A	donor_loss	1.0000
8:144080149:GGTG:G	donor_loss	1.0000
8:144080240:AGG:A	acceptor_loss	1.0000
8:144080241:G:A	acceptor_loss	1.0000
8:144078871:C:T	donor_gain	0.9900
8:144078904:G:GG	donor_gain	0.9900
8:144079942:GATCC:G	acceptor_gain	0.9900
8:144080146:GCAG:G	donor_gain	0.9900
8:144080151:T:G	donor_loss	0.9900
8:144080240:A:AG	acceptor_gain	0.9900
8:144080240:AG:A	acceptor_gain	0.9900
8:144080240:AGGT:A	acceptor_gain	0.9900
8:144080241:G:GC	acceptor_gain	0.9900
8:144080241:GG:G	acceptor_gain	0.9900
8:144080241:GGT:G	acceptor_gain	0.9900
8:144080241:GGTG:G	acceptor_gain	0.9900
8:144080241:GGTGC:G	acceptor_gain	0.9900
8:144078881:G:GA	donor_gain	0.9800
8:144078882:GTC:G	donor_gain	0.9800
8:144078883:TCT:T	donor_gain	0.9800
8:144078895:ACGAG:A	donor_loss	0.9800
8:144078896:CGAGG:C	donor_loss	0.9800

AlphaMissense

1548 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:144080012:T:C	F81L	0.999
8:144080014:C:A	F81L	0.999
8:144080014:C:G	F81L	0.999
8:144078883:T:A	V52D	0.998
8:144078795:C:A	R23S	0.997
8:144078838:G:A	G37D	0.997
8:144078844:C:A	A39D	0.997
8:144078888:G:C	G54R	0.997
8:144078889:G:A	G54D	0.997
8:144080297:C:A	A145E	0.997
8:144080308:G:C	A149P	0.997
8:144078843:G:C	A39P	0.996
8:144078869:G:C	K47N	0.996
8:144078869:G:T	K47N	0.996
8:144078877:C:A	A50D	0.996
8:144079991:T:C	C74R	0.996
8:144080126:T:C	S119P	0.996
8:144080285:C:A	A141E	0.996
8:144080288:C:A	A142D	0.996
8:144078840:T:C	S38P	0.995
8:144078858:G:C	G44R	0.995
8:144080133:T:A	I121N	0.995
8:144080139:T:A	I123N	0.995
8:144080291:C:A	T143K	0.995
8:144078837:G:C	G37R	0.994
8:144078838:G:T	G37V	0.994
8:144078859:G:T	G44V	0.994
8:144080012:T:A	F81I	0.994
8:144080013:T:C	F81S	0.994
8:144080013:T:G	F81C	0.994

dbSNP variants (sampled 300 via entrez): RS1000400568 (8:144067164 G>A), RS1000490332 (8:144071319 C>G,T), RS1000609741 (8:144071527 G>A), RS1000765258 (8:144076507 G>A), RS1001007560 (8:144065654 G>A), RS1001165456 (8:144073595 G>A), RS1001510912 (8:144063089 C>T), RS1001561867 (8:144062892 C>A,G,T), RS1002488125 (8:144077597 C>T), RS1002820853 (8:144074814 T>G), RS1002844426 (8:144077817 T>C), RS1002935614 (8:144075001 T>A,C), RS1002996225 (8:144079832 C>T), RS1003158290 (8:144080110 A>C), RS1003171747 (8:144063988 G>A)

Disease associations

OMIM: gene MIM:606491 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Limited	Autosomal recessive

Mondo (1): complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST008103_86	Bipolar disorder	1.000000e-06
GCST008115_8	Bipolar I disorder	2.000000e-08
GCST009798_65	Asthma	1.000000e-08
GCST012353_35	Serum metabolite concentrations in chronic kidney disease	2.000000e-22

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009963	bipolar I disorder

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725126 (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
5.90	Kd	1268	nM	CHEMBL5653589
5.90	ED50	1268	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 8 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	2148352: Binding affinity to human EXOSC4 incubated for 45 mins by Kinobead based pull down assay	kd	1.2684	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, decreases expression	2
Hydrogen Peroxide	affects expression, affects cotreatment, decreases expression	2
Valproic Acid	affects expression, increases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
deoxynivalenol	increases expression	1
cobaltous chloride	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	increases abundance, decreases expression	1
deguelin	decreases expression	1
K 7174	decreases expression	1
fenpyroximate	decreases expression	1
thifluzamide	decreases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	decreases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Vorinostat	decreases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases expression	1
Cadmium	increases expression	1
Cannabidiol	increases expression	1
Clozapine	increases expression	1
Diazinon	increases methylation	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Homocysteine	affects cotreatment, affects expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651394	Binding	Binding affinity to human EXOSC4 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)

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

Trial	Phase	Status	Title
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder