CPSF3

Summary

CPSF3 (cleavage and polyadenylation specific factor 3, HGNC:2326) is a protein-coding gene on chromosome 2p25.1, encoding Cleavage and polyadenylation specificity factor subunit 3 (Q9UKF6). Component of the cleavage and polyadenylation specificity factor (CPSF) complex that plays a key role in pre-mRNA 3’-end formation, recognizing the AAUAAA signal sequence and interacting with poly(A) polymerase and other factors to bring about cleavage and poly(A) addition. It is a common-essential gene (DepMap: required in 99.3% of cancer cell lines).

This gene encodes a member of the metallo-beta-lactamase family. The encoded protein is a 73kDa subunit of the cleavage and polyadenylation specificity factor and functions as an endonuclease that recognizes the pre-mRNA 3’-cleavage site AAUAAA prior to polyadenylation. It also cleaves after the pre-mRNA sequence ACCCA during histone 3’-end pre-mRNA processing.

Source: NCBI Gene 51692 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures (Moderate, GenCC)
• Clinical variants (ClinVar): 91 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 29
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.3% of screened cell lines (common-essential)
• MANE Select transcript: NM_016207

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2326
Approved symbol	CPSF3
Name	cleavage and polyadenylation specific factor 3
Location	2p25.1
Locus type	gene with protein product
Status	Approved
Aliases	CPSF-73, CPSF73, YSH1
Ensembl gene	ENSG00000119203
Ensembl biotype	protein_coding
OMIM	606029
Entrez	51692

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 9 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000238112, ENST00000460593, ENST00000475482, ENST00000489403, ENST00000489629, ENST00000882813, ENST00000882814, ENST00000921418, ENST00000921419, ENST00000921420, ENST00000947880

RefSeq mRNA: 5 — MANE Select: NM_016207 NM_001321833, NM_001321834, NM_001321835, NM_001321836, NM_016207

CCDS: CCDS1664, CCDS82417

Canonical transcript exons

ENST00000238112 — 18 exons

Exon	Start	End
ENSE00000804640	9441818	9441976
ENSE00000804641	9440491	9440666
ENSE00000804643	9436211	9436361
ENSE00000804644	9433871	9433960
ENSE00001001216	9467707	9467776
ENSE00001001219	9430752	9430880
ENSE00001001221	9452913	9453021
ENSE00001001222	9455659	9455757
ENSE00001001223	9429923	9430020
ENSE00001001224	9456933	9457027
ENSE00001830696	9423654	9423823
ENSE00001853797	9472916	9473101
ENSE00003572906	9459531	9459618
ENSE00003624665	9428765	9428828
ENSE00003639913	9443515	9443661
ENSE00003646250	9448198	9448350
ENSE00003650049	9471343	9471439
ENSE00003787979	9432511	9432688

Expression profiles

Bgee: expression breadth ubiquitous, 256 present calls, max score 94.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.0206 / max 494.4929, expressed in 1813 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
18759	26.6231	1808
18758	7.3713	1714
18760	0.0110	3
18762	0.0094	4
18761	0.0058	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	94.76	gold quality
embryo	UBERON:0000922	94.75	gold quality
ventricular zone	UBERON:0003053	94.70	gold quality
left testis	UBERON:0004533	93.62	gold quality
right testis	UBERON:0004534	93.50	gold quality
testis	UBERON:0000473	93.30	gold quality
endothelial cell	CL:0000115	93.04	gold quality
tendon of biceps brachii	UBERON:0008188	92.28	gold quality
adrenal tissue	UBERON:0018303	92.02	gold quality
sperm	CL:0000019	91.61	gold quality
monocyte	CL:0000576	91.52	gold quality
stromal cell of endometrium	CL:0002255	91.44	gold quality
leukocyte	CL:0000738	91.34	gold quality
islet of Langerhans	UBERON:0000006	91.19	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.62	gold quality
tendon	UBERON:0000043	90.29	gold quality
cortical plate	UBERON:0005343	90.03	gold quality
epithelial cell of pancreas	CL:0000083	89.82	gold quality
calcaneal tendon	UBERON:0003701	89.80	gold quality
trabecular bone tissue	UBERON:0002483	89.76	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.57	gold quality
medial globus pallidus	UBERON:0002477	89.57	gold quality
bone marrow	UBERON:0002371	89.20	gold quality
rectum	UBERON:0001052	89.18	gold quality
right adrenal gland cortex	UBERON:0035827	89.18	gold quality
right adrenal gland	UBERON:0001233	89.16	gold quality
gingival epithelium	UBERON:0001949	88.95	gold quality
smooth muscle tissue	UBERON:0001135	88.91	gold quality
vermiform appendix	UBERON:0001154	88.83	gold quality
visceral pleura	UBERON:0002401	88.81	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.34
E-GEOD-124858	no	456.82
E-CURD-112	no	4.01

Regulation

Is transcription factor: no

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.3% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 18)

• up-regulated by HIV-1 TAT protein; this could represent a novel mechanism by which HIV increases mRNA processing, causing an increase in both cell and viral gene expression. (PMID:15194760)
• crystal structures of human CPSF-73 at 2.1 A resolution, complexed with zinc ions and a sulphate that might mimic the phosphate group of the substrate; CPSF-73 is the pre-mRNA 3’-end-processing endonuclease (PMID:17128255)
• this study identifies CPSF-73 as an important regulatory protein that represses the basal transcriptional activity of the HIV-1 LTR promoter (PMID:17669424)
• Conserved residues in CPSF-73 and CPSF2 are required for assembly of the endonuclease activity that cleaves histone pre-mRNAs. (PMID:18688255)
• CSR1 appears to induce cell death through a novel mechanism by hijacking a critical RNA processing enzyme CPSF3. (PMID:18806823)
• Degradation of the downstream cleavage product (DCP) does not depend on the Xrn2 5’ exonuclease, suggesting that CPSF-73 degrades the DCP both in vitro and in vivo. (PMID:18955505)
• The tumor suppressor Cdc73 functionally associates with CPSF and CstF 3’ mRNA processing factors. (PMID:19136632)
• The data support a model where Star-PAP binds to the pre-mRNA, recruits the CPSF complex to the 3’-end of pre-mRNA and then defines cleavage by CPSF 73 and subsequent polyadenylation of its target mRNAs. (PMID:21102410)
• the molecular mechanism that recruits the CPSF73 endonuclease to histone pre-mRNAs (PMID:23071092)
• CASC9 is a promising prognostic predictor for patients with CRC and the CASC9-CPSF3-TGFbeta2 axis is a potential therapeutic target for CRC treatment. (PMID:31186036)
• CPSF3 represents a synthetic lethal node in a subset of acute myeloid leukemia and Ewing’s sarcoma cancer cell lines (PMID:31819276)
• Cleavage and polyadenylation-specific factor 3 induces cell cycle arrest via PI3K/Akt/GSK-3beta signaling pathways and predicts a negative prognosis in hepatocellular carcinoma. (PMID:33666519)
• A real-time fluorescence assay for CPSF73, the nuclease for pre-mRNA 3’-end processing. (PMID:34230059)
• Population-level deficit of homozygosity unveils CPSF3 as an intellectual disability syndrome gene. (PMID:35121750)
• An examination of the metal ion content in the active sites of human endonucleases CPSF73 and INTS11. (PMID:36822327)
• Therapeutic targeting of CPSF3-dependent transcriptional termination in ovarian cancer. (PMID:37992178)
• CPSF3 inhibition blocks pancreatic cancer cell proliferation through disruption of core histone mRNA processing. (PMID:38191171)
• CPSF3 regulates alternative polyadenylation of CNIH2 to promote esophageal squamous cell carcinoma progression. (PMID:38718887)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cpsf3	ENSDARG00000027649
mus_musculus	Cpsf3	ENSMUSG00000054309
rattus_norvegicus	Cpsf3	ENSRNOG00000052418
drosophila_melanogaster	Cpsf73	FBGN0261065
caenorhabditis_elegans		WBGENE00013460

Paralogs (3): INTS9 (ENSG00000104299), INTS11 (ENSG00000127054), CPSF2 (ENSG00000165934)

Protein

Protein identifiers

Cleavage and polyadenylation specificity factor subunit 3 — Q9UKF6 (reviewed: Q9UKF6)

Alternative names: Cleavage and polyadenylation specificity factor 73 kDa subunit, mRNA 3’-end-processing endonuclease CPSF-73

All UniProt accessions (3): Q9UKF6, C9JZH6, G5E9W3

UniProt curated annotations — full annotation on UniProt →

Function. Component of the cleavage and polyadenylation specificity factor (CPSF) complex that plays a key role in pre-mRNA 3’-end formation, recognizing the AAUAAA signal sequence and interacting with poly(A) polymerase and other factors to bring about cleavage and poly(A) addition. Has endonuclease activity, and functions as an mRNA 3’-end-processing endonuclease. Also involved in the histone 3’-end pre-mRNA processing. U7 snRNP-dependent protein that induces both the 3’-endoribonucleolytic cleavage of histone pre-mRNAs and acts as a 5’ to 3’ exonuclease for degrading the subsequent downstream cleavage product (DCP) of mature histone mRNAs. Cleavage occurs after the 5’-ACCCA-3’ sequence in the histone pre-mRNA leaving a 3’hydroxyl group on the upstream fragment containing the stem loop (SL) and 5’ phosphate on the downstream cleavage product (DCP) starting with CU nucleotides. The U7-dependent 5’ to 3’ exonuclease activity is processive and degrades the DCP RNA substrate even after complete removal of the U7-binding site. Binds to the downstream cleavage product (DCP) of histone pre-mRNAs and the cleaved DCP RNA substrate in a U7 snRNP dependent manner. Required for entering/progressing through S-phase of the cell cycle. Required for the selective processing of microRNAs (miRNAs) during embryonic stem cell differentiation via its interaction with ISY1. Required for the biogenesis of all miRNAs from the pri-miR-17-92 primary transcript except miR-92a. Only required for the biogenesis of miR-290 and miR-96 from the pri-miR-290-295 and pri-miR-96-183 primary transcripts, respectively.

Subunit / interactions. Component of the cleavage and polyadenylation specificity factor (CPSF) complex, composed of CPSF1, CPSF2, CPSF3, CPSF4 and FIP1L1. Interacts with CPSF2, CSTF2 and SYMPK. Interacts with TUT1; the interaction is direct and mediates the recruitment of the CPSF complex on the 3’UTR of pre-mRNAs. Interacts with WDR33. Interacts with ZC3H3.

Subcellular location. Nucleus.

Post-translational modifications. Sumoylated on Lys-462, Lys-465 and Lys-545, preferentially by SUMO3.

Disease relevance. Neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures (NEDMHS) [MIM:619876] An autosomal recessive disorder characterized by global developmental delay and impaired intellectual development apparent from infancy. Affected individuals have hypotonia, poor or absent motor skills, feeding difficulties with poor overall growth, microcephaly, mild dysmorphic features, and early-onset seizures. Additional variable features include nystagmus, cortical blindness, and spasticity. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 2 Zn(2+) ions per subunit.

Similarity. Belongs to the metallo-beta-lactamase superfamily. RNA-metabolizing metallo-beta-lactamase-like family. CPSF3 subfamily.

RefSeq proteins (5): NP_001308762, NP_001308763, NP_001308764, NP_001308765, NP_057291* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001279	Metallo-B-lactamas	Domain
IPR011108	RMMBL	Domain
IPR021718	CPSF73-100_C	Domain
IPR022712	Beta_Casp	Domain
IPR036866	RibonucZ/Hydroxyglut_hydro	Homologous_superfamily
IPR050698	MBL	Family

Pfam: PF00753, PF07521, PF10996, PF11718

UniProt features (85 total): strand 28, helix 21, mutagenesis site 9, binding site 8, turn 6, sequence variant 4, modified residue 3, cross-link 3, initiator methionine 1, chain 1, active site 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
8T1Q	X-RAY DIFFRACTION	1.7
2I7T	X-RAY DIFFRACTION	2.1
2I7V	X-RAY DIFFRACTION	2.1
8T1R	X-RAY DIFFRACTION	2.2
6M8Q	X-RAY DIFFRACTION	2.49
9NH5	ELECTRON MICROSCOPY	2.82
9NH6	ELECTRON MICROSCOPY	2.82
9NGO	ELECTRON MICROSCOPY	3.01
6V4X	ELECTRON MICROSCOPY	3.2
9NB1	ELECTRON MICROSCOPY	3.85

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UKF6-F1	90.41	0.65

Functional residue map

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

Catalytic / active sites (1): 396 (proton donor)

Ligand- & substrate-binding residues (8): 418; 71; 73; 75; 76; 158; 179; 179

Post-translational modifications (6): 2, 659, 681, 462, 465, 545

Mutagenesis-validated functional residues (9):

Position	Phenotype
73	inhibits histone 3’-end processing.
75–76	loss of histone 3’-end processing.
75	inhibits histone 3’-end processing.
76	inhibits histone 3’-end processing.
334	does not inhibit histone 3’-end processing.
396	inhibits histone 3’-end processing.
462	reduced sumoylation; when associated with r-465 and r-545.
465	reduced sumoylation; when associated with r-462 and r-545.
545	reduced sumoylation; when associated with r-462 and r-465.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-159231	Transport of Mature mRNA Derived from an Intronless Transcript
R-HSA-72187	mRNA 3’-end processing
R-HSA-73856	RNA Polymerase II Transcription Termination
R-HSA-77595	Processing of Intronless Pre-mRNAs
R-HSA-9770562	mRNA Polyadenylation
R-HSA-9918481	Dengue Virus-Host Interactions
R-HSA-72203	Processing of Capped Intron-Containing Pre-mRNA

MSigDB gene sets: 223 (showing top): RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, chr2p25, GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOMF_NUCLEASE_ACTIVITY, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_POSITIVE_REGULATION_OF_MITOTIC_CELL_CYCLE, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_G1_S_TRANSITION_OF_MITOTIC_CELL_CYCLE, GOMF_RNA_ENDONUCLEASE_ACTIVITY, REACTOME_MRNA_3_END_PROCESSING, REACTOME_PROCESSING_OF_CAPPED_INTRON_CONTAINING_PRE_MRNA, GOBP_REGULATION_OF_CELL_CYCLE

GO Biological Process (6): mRNA 3’-end processing by stem-loop binding and cleavage (GO:0006398), mRNA 3’-end processing (GO:0031124), co-transcriptional mRNA 3’-end processing, cleavage and polyadenylation pathway (GO:0180010), positive regulation of G1/S transition of mitotic cell cycle (GO:1900087), RNA processing (GO:0006396), mRNA processing (GO:0006397)

GO Molecular Function (8): RNA binding (GO:0003723), RNA endonuclease activity (GO:0004521), 5’-3’ RNA exonuclease activity (GO:0004534), metal ion binding (GO:0046872), nuclease activity (GO:0004518), endonuclease activity (GO:0004519), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (4): nucleoplasm (GO:0005654), mRNA cleavage and polyadenylation specificity factor complex (GO:0005847), ribonucleoprotein complex (GO:1990904), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Transport of Mature mRNAs Derived from Intronless Transcripts	1
Processing of Capped Intron-Containing Pre-mRNA	1
RNA Polymerase II Transcription	1
Processing of Capped Intronless Pre-mRNA	1
mRNA 3’-end processing	1
Dengue Virus Infection	1
Metabolism of RNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mRNA 3’-end processing	2
histone mRNA metabolic process	1
mRNA processing	1
RNA 3’-end processing	1
co-transcriptional RNA 3’-end processing, cleavage and polyadenylation pathway	1
G1/S transition of mitotic cell cycle	1
positive regulation of mitotic cell cycle phase transition	1
positive regulation of cell cycle G1/S phase transition	1
regulation of G1/S transition of mitotic cell cycle	1
gene expression	1
RNA biosynthetic process	1
primary metabolic process	1
RNA processing	1
mRNA metabolic process	1
nucleic acid binding	1
endonuclease activity	1
RNA nuclease activity	1
5’-3’ exonuclease activity	1
RNA exonuclease activity, producing 5’-phosphomonoesters	1
cation binding	1
catalytic activity, acting on a nucleic acid	1
nuclease activity	1
binding	1
catalytic activity	1
nuclear lumen	1
cellular anatomical structure	1
mRNA cleavage factor complex	1
protein-containing complex	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2928 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CPSF3	CPSF1	Q10570	998
CPSF3	CPSF4	O95639	997
CPSF3	SYMPK	Q92797	997
CPSF3	WDR33	Q9C0J8	997
CPSF3	CPSF2	Q9P2I0	993
CPSF3	FIP1L1	Q6UN15	979
CPSF3	CSTF2	P33240	974
CPSF3	SCARA3	Q6AZY7	966
CPSF3	CSTF3	Q12996	944
CPSF3	DCLRE1A	Q6PJP8	940
CPSF3	PCF11	O94913	939
CPSF3	LSM11	P83369	911
CPSF3	SSU72	Q9NP77	885
CPSF3	CSTF1	Q05048	875
CPSF3	PAPOLG	Q9BWT3	854

IntAct

94 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:2364”(proximity)	0.900
CPSF2	SYMPK	psi-mi:“MI:0915”(physical association)	0.850
SYMPK	CPSF2	psi-mi:“MI:0914”(association)	0.850
CPSF2	SYMPK	psi-mi:“MI:0914”(association)	0.850
LMO1	ZBTB43	psi-mi:“MI:0914”(association)	0.830
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CPSF3	CPSF4	psi-mi:“MI:0914”(association)	0.640
CDC73	CSTF2	psi-mi:“MI:0914”(association)	0.580
TUT1	PIP5K1A	psi-mi:“MI:0914”(association)	0.560
HTT	CPSF3	psi-mi:“MI:0915”(physical association)	0.560
CPSF1	CPSF4	psi-mi:“MI:0915”(physical association)	0.560
SYMPK	CPSF4	psi-mi:“MI:0914”(association)	0.530
KSR2	POLR3A	psi-mi:“MI:0914”(association)	0.530
TUT1	CSTF2	psi-mi:“MI:0914”(association)	0.530
UBE3D	STIP1	psi-mi:“MI:0914”(association)	0.530
NCBP3	SAP18	psi-mi:“MI:0914”(association)	0.530
WDR33	CPSF4	psi-mi:“MI:0914”(association)	0.530
CPSF4L	CCNH	psi-mi:“MI:0914”(association)	0.530
CPSF3	CSTF2	psi-mi:“MI:0914”(association)	0.530
CDC73	CPSF4	psi-mi:“MI:0914”(association)	0.500
CPSF2	CSTF2	psi-mi:“MI:0914”(association)	0.500
CPSF6	DDX39A	psi-mi:“MI:0914”(association)	0.480

BioGRID (218): CPSF3 (Affinity Capture-RNA), CPSF3 (Affinity Capture-MS), CPSF3 (Two-hybrid), CPSF2 (Co-fractionation), CPSF3 (Co-fractionation), CPSF3 (Co-fractionation), CPSF3 (Co-fractionation), CPSF3 (Co-fractionation), DDX23 (Co-fractionation), WDR33 (Co-fractionation), CPSF3 (Affinity Capture-MS), FIP1L1 (Co-fractionation), FIP1L1 (Affinity Capture-MS), CPSF3 (Affinity Capture-Western), CPSF3 (Proximity Label-MS)

ESM2 similar proteins: A0A1L8F5J9, A0JN27, F1LTR1, F1NBL0, O15294, P35438, P35439, P56558, P61201, P61202, P61203, P61599, P61600, P63138, P79101, P81436, Q03555, Q05586, Q13888, Q15303, Q27HV0, Q2PFM2, Q2TBV5, Q4L208, Q58ED9, Q5R1P0, Q5SP67, Q5ZJ75, Q61527, Q62956, Q6IQT4, Q6IR75, Q6P1K8, Q6P632, Q7ZXR3, Q8BUV3, Q8C6G8, Q8CGY8, Q8R4D1, Q91854

Diamond homologs: A0QVT2, B7VIP5, B9XZG7, C4K7Z9, M4MR97, O31760, O50112, P0CM88, P0CM89, P47385, P54122, P54123, P56185, P75497, P79101, P9WGZ8, P9WGZ9, Q2FHG3, Q2FHZ1, Q2FZ19, Q2FZG9, Q2YX35, Q2YXP1, Q45493, Q49WL3, Q49X63, Q4L5A3, Q4L5X8, Q5HGF6, Q5HGZ5, Q5HPR6, Q5HQ80, Q5JH24, Q6G9T8, Q6GAC5, Q6GHG0, Q6GHZ6, Q72JJ7, Q74ZC0, Q7A115

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
CPSF3	“form complex”	“CPSF complex”	binding
CPSF3	up-regulates	mRNA_polyadenylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 92 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
Processing of Intronless Pre-mRNAs	9	72.4×	1e-13
RNA Polymerase II Transcription Termination	12	37.1×	3e-14
mRNA 3’-end processing	13	36.0×	4e-15
Transport of Mature mRNA Derived from an Intronless Transcript	7	26.8×	3e-07
mRNA Polyadenylation	18	22.3×	2e-17
Processing of Capped Intron-Containing Pre-mRNA	11	12.7×	5e-08
Dengue Virus-Host Interactions	19	12.2×	5e-14
mRNA Splicing	7	10.8×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of mRNA splicing, via spliceosome	5	46.7×	7e-06
mRNA 3’-end processing	6	41.1×	1e-06
regulation of alternative mRNA splicing, via spliceosome	6	17.9×	9e-05
mRNA processing	14	13.4×	1e-09
mRNA splicing, via spliceosome	11	12.3×	4e-07
RNA splicing	7	7.5×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	50
Likely benign	9
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1686866	NM_016207.4(CPSF3):c.1403G>A (p.Gly468Glu)	Pathogenic
3899256	NM_016207.4(CPSF3):c.761-1G>T	Likely pathogenic

SpliceAI

2802 predictions. Top by Δscore:

Variant	Effect	Δscore
2:9423655:G:GT	donor_gain	1.0000
2:9423845:G:T	donor_gain	1.0000
2:9428752:T:TA	acceptor_gain	1.0000
2:9428756:T:G	acceptor_gain	1.0000
2:9428760:TACA:T	acceptor_loss	1.0000
2:9428762:CAGT:C	acceptor_loss	1.0000
2:9428763:A:AG	acceptor_gain	1.0000
2:9428763:AGT:A	acceptor_gain	1.0000
2:9428763:AGTG:A	acceptor_gain	1.0000
2:9428764:G:GA	acceptor_gain	1.0000
2:9428764:GT:G	acceptor_gain	1.0000
2:9428764:GTG:G	acceptor_gain	1.0000
2:9428764:GTGG:G	acceptor_gain	1.0000
2:9428764:GTGGA:G	acceptor_gain	1.0000
2:9428815:G:GT	donor_gain	1.0000
2:9428825:AATGG:A	donor_loss	1.0000
2:9428826:ATGG:A	donor_loss	1.0000
2:9428827:TGGT:T	donor_loss	1.0000
2:9428829:G:GG	donor_gain	1.0000
2:9428829:GT:G	donor_loss	1.0000
2:9428830:T:A	donor_loss	1.0000
2:9429917:TTTCA:T	acceptor_loss	1.0000
2:9429918:TTCAG:T	acceptor_loss	1.0000
2:9429921:A:AG	acceptor_gain	1.0000
2:9429921:AGCTC:A	acceptor_gain	1.0000
2:9429922:G:GA	acceptor_gain	1.0000
2:9429922:GC:G	acceptor_gain	1.0000
2:9429922:GCT:G	acceptor_gain	1.0000
2:9429922:GCTC:G	acceptor_gain	1.0000
2:9429922:GCTCG:G	acceptor_gain	1.0000

AlphaMissense

4561 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:9428766:G:A	G18R	1.000
2:9428766:G:C	G18R	1.000
2:9428767:G:A	G18E	1.000
2:9428772:G:T	G20W	1.000
2:9428773:G:A	G20E	1.000
2:9428784:G:A	G24R	1.000
2:9428784:G:C	G24R	1.000
2:9428785:G:A	G24E	1.000
2:9428785:G:T	G24V	1.000
2:9428788:G:C	R25T	1.000
2:9428788:G:T	R25I	1.000
2:9428789:A:C	R25S	1.000
2:9428789:A:T	R25S	1.000
2:9428794:G:A	C27Y	1.000
2:9428795:T:G	C27W	1.000
2:9429924:T:C	L39P	1.000
2:9429926:G:C	D40H	1.000
2:9429932:G:A	G42R	1.000
2:9429932:G:C	G42R	1.000
2:9429932:G:T	G42W	1.000
2:9429933:G:A	G42E	1.000
2:9429933:G:T	G42V	1.000
2:9429938:C:G	H44D	1.000
2:9429939:A:G	H44R	1.000
2:9429966:T:C	L53P	1.000
2:9429969:C:A	P54H	1.000
2:9429969:C:G	P54R	1.000
2:9430005:T:C	L66P	1.000
2:9430008:T:C	L67P	1.000
2:9430016:A:C	S70R	1.000

dbSNP variants (sampled 300 via entrez): RS1000032243 (2:9429088 C>A), RS1000075612 (2:9423385 G>A,T), RS1000140703 (2:9466366 A>C,G), RS1000151459 (2:9469174 G>A,T), RS1000281044 (2:9436425 G>A,C,T), RS1000305242 (2:9472393 T>C), RS1000558547 (2:9453452 G>C), RS1000567529 (2:9423399 T>C), RS1000791481 (2:9447706 T>G), RS1000841644 (2:9464129 C>T), RS1000864601 (2:9442014 C>G,T), RS1000894420 (2:9434688 A>C,G), RS1000936440 (2:9441602 G>A,C,T), RS1000952119 (2:9464508 G>C), RS1001012105 (2:9443651 C>T)

Disease associations

OMIM: gene MIM:606029 | disease phenotypes: MIM:618862, MIM:619876

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures	Moderate	Autosomal recessive

Mondo (2): neurodevelopmental disorder with hypotonia, microcephaly, and seizures (MONDO:0030025), neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures (MONDO:0859250)

Orphanet (0):

HPO phenotypes

29 total (29 of 29 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000158	Macroglossia
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000276	Long face
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001320	Cerebellar vermis hypoplasia
HP:0001508	Failure to thrive
HP:0001558	Decreased fetal movement
HP:0002020	Gastroesophageal reflux
HP:0002059	Cerebral atrophy
HP:0002181	Cerebral edema
HP:0002719	Recurrent infections
HP:0003593	Infantile onset
HP:0007178	Motor polyneuropathy
HP:0007371	Corpus callosum atrophy
HP:0011461	Fetal onset
HP:0011968	Feeding difficulties
HP:0100021	Cerebral palsy
HP:0100704	Cerebral visual impairment

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724779 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	2
sodium arsenite	affects cotreatment, decreases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Tretinoin	affects cotreatment, decreases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	decreases expression	1
arsenite	increases reaction, affects binding	1
tetrabromobisphenol A	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
pentabrominated diphenyl ether 100	increases expression	1
jinfukang	decreases expression	1
NSC 689534	decreases expression, affects binding	1
Acetaminophen	decreases expression	1
Air Pollutants, Occupational	decreases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Benztropine	affects cotreatment, decreases expression	1
Cadmium	increases expression, increases abundance	1
Caffeine	increases phosphorylation	1
Copper	affects binding, decreases expression	1
Coumestrol	increases expression	1
Cuprizone	affects cotreatment, decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697611	Binding	Inhibition of CPSF3 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Clinical trials (associated diseases)

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