CSTF2

Summary

CSTF2 (cleavage stimulation factor subunit 2, HGNC:2484) is a protein-coding gene on chromosome Xq22.1, encoding Cleavage stimulation factor subunit 2 (P33240). One of the multiple factors required for polyadenylation and 3’-end cleavage of mammalian pre-mRNAs.

This gene encodes a nuclear protein with an RRM (RNA recognition motif) domain. The protein is a member of the cleavage stimulation factor (CSTF) complex that is involved in the 3’ end cleavage and polyadenylation of pre-mRNAs. Specifically, this protein binds GU-rich elements within the 3’-untranslated region of mRNAs.

Source: NCBI Gene 1478 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual developmental disorder, X-linked 113 (Limited, GenCC)
• Clinical variants (ClinVar): 123 total — 3 pathogenic
• Regional missense constraint (gnomAD): 2 of 3 regions constrained (≈38% of expected missense variation)
• GTEx eGene: eQTL in 9 tissues, sQTL in 0 (q < 0.05)
• Phenotypes (HPO): 5
• MANE Select transcript: NM_001325
• Interaction hub: 1,971 STRING partners (top 8% of genes corpus-wide)
• Notable: 123 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2484
Approved symbol	CSTF2
Name	cleavage stimulation factor subunit 2
Location	Xq22.1
Locus type	gene with protein product
Status	Approved
Aliases	CstF-64
Ensembl gene	ENSG00000101811
Ensembl biotype	protein_coding
OMIM	300907
Entrez	1478

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 15 protein_coding, 8 nonsense_mediated_decay

MANE Select: ENST00000372972

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 5: 2

ENST00000372972, ENST00000413437, ENST00000415585, ENST00000475126, ENST00000866722, ENST00000866723, ENST00000866724, ENST00000924424, ENST00000924425, ENST00000924426, ENST00000948100, ENST00000948101, ENST00001000298, ENST00001000299, ENST00001028495, ENST00001073908, ENST00001073909, ENST00001073910, ENST00001073911, ENST00001108577, ENST00001108578, ENST00001127947, ENST00001134211

RefSeq mRNA: 3 — MANE Select: NM_001325 NM_001306206, NM_001306209, NM_001325

CCDS: CCDS14473, CCDS78498

Canonical transcript exons

ENST00000372972 — 14 exons

Exon	Start	End
ENSE00000673632	100822251	100822420
ENSE00000673635	100823292	100823428
ENSE00000673638	100823886	100824005
ENSE00000673657	100833180	100833472
ENSE00001797690	100820391	100820474
ENSE00001943170	100840714	100841520
ENSE00003482279	100837339	100837449
ENSE00003559745	100821527	100821605
ENSE00003604446	100831515	100831656
ENSE00003641637	100838239	100838364
ENSE00003646086	100828040	100828102
ENSE00003664785	100832734	100832909
ENSE00003693529	100826634	100826757
ENSE00003788551	100824120	100824257

Expression profiles

Bgee: expression breadth ubiquitous, 248 present calls, max score 95.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.3231 / max 224.4737, expressed in 1802 samples.

Highest expression (Bgee): oocyte, secondary oocyte, oral cavity, primordial germ cell in gonad, palpebral conjunctiva.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CSTF2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 9 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

9 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Esophagus Mucosa	eqtl	1.2e-22	-0.20	X:100826925:G:A
Bladder	eqtl	1.8e-04	+1.68	X:100002797:T:C
Skin Sun Exposed Lower leg	eqtl	2.2e-03	+0.20	X:100713893:T:C
Thyroid	eqtl	2.4e-03	+0.36	X:101062373:A:T
Heart Atrial Appendage	eqtl	4.7e-03	-0.12	X:100763472:G:C
Pituitary	eqtl	8.7e-03	+1.97	X:101348375:T:C
Cells Cultured fibroblasts	eqtl	1.9e-02	+0.21	X:100280622:T:C
Testis	eqtl	2.8e-02	-0.35	X:99909869:A:G
Colon Sigmoid	eqtl	4.6e-02	+0.10	X:100843366:TAAG:T

FANTOM5 promoters

1 alternative TSS:

Promoter ID	TPM avg	Samples expressed
196938	19.3231	1802

Top tissues by expression

showing 100 of 277 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	95.95	gold quality
secondary oocyte	CL:0000655	94.96	gold quality
oral cavity	UBERON:0000167	86.67	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.30	gold quality
palpebral conjunctiva	UBERON:0001812	85.83	gold quality
pharyngeal mucosa	UBERON:0000355	85.73	gold quality
esophagus squamous epithelium	UBERON:0006920	85.63	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.62	gold quality
epithelium of esophagus	UBERON:0001976	85.45	gold quality
esophagus mucosa	UBERON:0002469	85.44	gold quality
ganglionic eminence	UBERON:0004023	84.38	gold quality
buccal mucosa cell	CL:0002336	84.37	silver quality
epithelium of nasopharynx	UBERON:0001951	84.21	gold quality
ventricular zone	UBERON:0003053	84.20	gold quality
squamous epithelium	UBERON:0006914	84.17	gold quality
mucosa of transverse colon	UBERON:0004991	83.39	gold quality
rectum	UBERON:0001052	83.25	gold quality
cervix squamous epithelium	UBERON:0006922	83.15	gold quality
lower esophagus mucosa	UBERON:0035834	82.63	gold quality
tonsil	UBERON:0002372	82.37	gold quality
embryo	UBERON:0000922	82.24	gold quality
olfactory bulb	UBERON:0002264	82.04	gold quality
colonic mucosa	UBERON:0000317	81.84	gold quality
stromal cell of endometrium	CL:0002255	81.66	gold quality
mucosa of sigmoid colon	UBERON:0004993	81.56	gold quality
gingival epithelium	UBERON:0001949	81.30	silver quality
male germ cell	CL:0000015	80.97	silver quality
type B pancreatic cell	CL:0000169	80.91	gold quality
gingiva	UBERON:0001828	80.87	gold quality
sperm	CL:0000019	80.66	silver quality
islet of Langerhans	UBERON:0000006	80.59	gold quality
cortical plate	UBERON:0005343	80.58	gold quality
esophagus	UBERON:0001043	80.52	gold quality
diaphragm	UBERON:0001103	80.32	gold quality
parotid gland	UBERON:0001831	80.21	silver quality
lymph node	UBERON:0000029	80.10	gold quality
nasal cavity epithelium	UBERON:0005384	79.96	gold quality
smooth muscle tissue	UBERON:0001135	79.95	gold quality
tongue squamous epithelium	UBERON:0006919	79.76	silver quality
granulocyte	CL:0000094	79.67	gold quality
cerebellar hemisphere	UBERON:0002245	79.62	gold quality
cerebellar cortex	UBERON:0002129	79.54	gold quality
right hemisphere of cerebellum	UBERON:0014890	79.36	gold quality
prefrontal cortex	UBERON:0000451	79.31	gold quality
vermiform appendix	UBERON:0001154	79.07	gold quality
testis	UBERON:0000473	79.02	gold quality
right testis	UBERON:0004534	79.00	gold quality
transverse colon	UBERON:0001157	78.92	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	78.86	gold quality
left testis	UBERON:0004533	78.81	gold quality
nasal cavity mucosa	UBERON:0001826	78.73	gold quality
cerebellum	UBERON:0002037	78.73	gold quality
corpus epididymis	UBERON:0004359	78.70	gold quality
amniotic fluid	UBERON:0000173	78.54	gold quality
caecum	UBERON:0001153	78.54	gold quality
leukocyte	CL:0000738	78.51	gold quality
substantia nigra pars reticulata	UBERON:0001966	78.46	gold quality
monocyte	CL:0000576	78.40	gold quality
mononuclear cell	CL:0000842	78.28	gold quality
lateral globus pallidus	UBERON:0002476	77.98	silver quality
epithelium of bronchus	UBERON:0002031	77.92	gold quality
large intestine	UBERON:0000059	77.77	gold quality
endometrium	UBERON:0001295	77.74	gold quality
bronchus	UBERON:0002185	77.69	gold quality
colon	UBERON:0001155	77.68	gold quality
middle temporal gyrus	UBERON:0002771	77.66	silver quality
intestine	UBERON:0000160	77.65	gold quality
gall bladder	UBERON:0002110	77.53	gold quality
right adrenal gland cortex	UBERON:0035827	77.52	gold quality
small intestine Peyer’s patch	UBERON:0003454	77.50	gold quality
right adrenal gland	UBERON:0001233	77.48	gold quality
small intestine	UBERON:0002108	77.30	gold quality
mouth mucosa	UBERON:0003729	77.22	gold quality
left adrenal gland	UBERON:0001234	77.18	gold quality
lateral nuclear group of thalamus	UBERON:0002736	77.16	silver quality
bronchial epithelial cell	CL:0002328	77.11	gold quality
vagina	UBERON:0000996	77.09	gold quality
saliva-secreting gland	UBERON:0001044	76.99	gold quality
adrenal gland	UBERON:0002369	76.93	gold quality
ectocervix	UBERON:0012249	76.67	gold quality
minor salivary gland	UBERON:0001830	76.66	gold quality
frontal cortex	UBERON:0001870	76.59	gold quality
substantia nigra pars compacta	UBERON:0001965	76.59	gold quality
skin of leg	UBERON:0001511	76.57	gold quality
duodenum	UBERON:0002114	76.57	gold quality
left adrenal gland cortex	UBERON:0035825	76.54	gold quality
bone marrow	UBERON:0002371	76.52	gold quality
adrenal cortex	UBERON:0001235	76.47	gold quality
neocortex	UBERON:0001950	76.46	gold quality
right frontal lobe	UBERON:0002810	76.41	gold quality
uterus	UBERON:0000995	76.38	gold quality
Brodmann (1909) area 9	UBERON:0013540	76.33	gold quality
uterine cervix	UBERON:0000002	76.12	gold quality
urinary bladder	UBERON:0001255	76.07	gold quality
sigmoid colon	UBERON:0001159	76.04	gold quality
Brodmann (1909) area 23	UBERON:0013554	76.02	silver quality
cervix epithelium	UBERON:0004801	75.82	silver quality
nucleus accumbens	UBERON:0001882	75.81	gold quality
female reproductive system	UBERON:0000474	75.78	gold quality
skin of abdomen	UBERON:0001416	75.78	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.89

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Frontal cortex	tissue	32.3
Caudate putamen	tissue	31.5
Tonsil	tissue	18.4	high
Cerebral cortex	tissue	16.6	medium
Midbrain	tissue	16.6
Somatosensory cortex	tissue	16.6
Occipital cortex	tissue	16.5
Thalamus	tissue	16.4
Esophagus	tissue	16.3	medium
Pons	tissue	15.9
Hippocampal formation	tissue	15.8
Putamen	tissue	15.7
Septum	tissue	15.7
Hypothalamus	tissue	15.6
Medulla oblongata	tissue	15.3
Motor cortex	tissue	15.0
Spinal cord	tissue	15.0
Substantia nigra	tissue	14.9
Superior colliculi	tissue	14.8
Ventral forebrain	tissue	14.6
Prefrontal cortex	tissue	14.3
Entorhinal cortex	tissue	14.2
Periaqueductal gray	tissue	14.1
Cerebellum	tissue	13.7	high
Retrosplenial and cingulate cortex	tissue	13.7
Retrosplenial cortex	tissue	13.6
Temporal cortex	tissue	13.6
Basal ganglia	tissue	13.4	medium
Corpus callosum	tissue	13.4
Olfactory bulb	tissue	13.2
Amygdala	tissue	12.5
Insular cortex	tissue	12.3
Rectum	tissue	12.1	high
Nucleus accumbens	tissue	11.8
Postcentral gyrus	tissue	11.5
Testis	tissue	11.4	high
Hippocampus	tissue	11.3	medium
Lymph node	tissue	11.2	medium
Thymus	tissue	11.2
Colon	tissue	10.9	medium
Choroid plexus	tissue	10.5
Locus coeruleus	tissue	10.1
Urinary bladder	tissue	9.3	high
Bone marrow	tissue	8.7	low
Parathyroid gland	tissue	8.3	medium
Appendix	tissue	8.0	high
Seminal vesicle	tissue	7.7	medium
Fallopian tube	tissue	7.6	medium
Skin 1	tissue	7.5	medium
Duodenum	tissue	7.5	medium
Small intestine	tissue	7.4	medium
Epididymis	tissue	7.3	medium
Kidney	tissue	7.3	medium
Retina	tissue	7.1
Vagina	tissue	7.1	medium
Salivary gland	tissue	6.9	high
Endometrium 1	tissue	6.9	medium
Breast	tissue	6.8	medium
Smooth muscle	tissue	6.8	medium
Prostate	tissue	6.8	medium

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Dorsal hippocampus (15.8), Ventral spinal cord (15.0), Subiculum (14.4), Dorsal spinal cord (14.3), Ventral hippocampus (14.3).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting CSTF2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 41 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-7156-5P	99.64	68.81	1369
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-3616-5P	99.55	67.02	989
HSA-MIR-573	99.55	67.44	955
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-16-2-3P	99.29	70.60	1954
HSA-MIR-195-3P	99.29	70.61	1954
HSA-MIR-6739-3P	99.22	68.84	1843
HSA-MIR-10524-5P	99.05	66.08	963
HSA-MIR-421	98.90	67.04	1883
HSA-MIR-5006-5P	98.79	66.92	1246

Functional genomics

Regional missense constraint (gnomAD)

ENST00000372972 splits into 3 regions with different missense tolerance; 2 are missense-constrained (≈38% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
X:100,820,417–100,824,129	45 / 147.5	0.31	yes (p 3.2e-17)
X:100,824,130–100,837,415	200 / 294.0	0.68	no
X:100,837,416–100,838,358	8 / 35.5	0.23	yes (p 3.9e-06)

Literature-anchored findings (GeneRIF, showing 21)

• dynamics of the CstF-64 RNA-binding domain, both free and bound to two GU-rich RNA sequences that represent polyadenylation regulatory elements, by NMR Spectroscopy (PMID:15769465)
• CstF64 (cstf2) and not other CstF subunits induced by lipopolysaccharide (LPS) in murine macrophages and changes polyA site use (PMID:16207706)
• The inactivity of the RSV poly(A) site was at least in part due to poor CstF binding since tethering CstF to the RSV substrate activated polyadenylation. (PMID:18272196)
• The Hinge domain is necessary for CstF-64 interaction with CstF-77 and consequent nuclear localization. (PMID:19887456)
• nuclear accumulation of CstF-64 depends on binding to CstF-77 not symplekin; interaction between CstF-64/CstF-64Tau and CstF-77 are important for maintenance of nuclear levels of CstF complex components and intracellular localization, stability, function (PMID:21119002)
• CSTF2 is likely to play an important role in lung carcinogenesis and be a prognostic biomarker in the clinic. (PMID:21813631)
• CstF64 binds to thousands of dormant intronic PASs that are suppressed, at least in part, by U1 small nuclear ribonucleoproteins (PMID:23112178)
• CstF64 and CstF64tau modulate one another’s expression and play overlapping as well as distinct roles in regulating global alternative polyadenylation profiles. (PMID:24149845)
• CstF64 is central to the function of a heat-labile factor, composed of cleavage/polyadenylation specificity factor, symplekin, and cleavage stimulation factor 64 and appears to be at least partly responsible for its cell cycle regulation. (PMID:25266659)
• CstF64, an essential polyadenylation factor, is a master regulator of 3’-UTR shortening across multiple tumour types. (PMID:25409906)
• CstF-64 is dispensable for the expression/3’-end processing of Star-PAP target mRNAs.CstF-64 and 3’-UTR cis-element determine Star-PAP specificity for target mRNA selection by excluding poly A polymerase. (PMID:26496945)
• hnRNP H binds to two specific G-runs in exon 5a of ACHE and activates the distal alternative 3 splice site (ss) between exons 5a and 5b. Furthermore, hnRNP H competes for binding of CstF64 to the overlapping binding sites in exon 5a, and suppresses the selection of a cryptic polyadenylation site, which additionally ensures transcription of the distal 3 ss required for the generation of AChET isoform. (PMID:28180311)
• The findings demonstrate that constitutive Tip110 expression in human cord blood CD34(+) cells is regulated, at least in part, through its interaction with CstF64, recruitment of CstF64 to, and selective usage of two polyadenylation sites within its 3’UTR. (PMID:29583087)
• CSTF2 exerts critical roles in activation of RAC1 by promoting 3’UTR shortening of RAC1 mRNAs through two transcription elongation factors, AFF1 and AFF4, in urothelial carcinoma of the bladder pathogenesis (PMID:30143523)
• Reverse genetics and nuclear magnetic resonance studies of recombinant CstF-64 (RRM-Hinge) and CstF-77 (monkeytail-carboxy-terminal domain) indicate that the last 30 amino acids of CstF-77 increases the stability of the RRM, thus altering the affinity of the complex for RNA. These results provide new insights into the mechanism by which CstF regulates the location of the RNA cleavage site during Cleavage/polyadenylation. (PMID:30257008)
• A missense mutation in the CSTF2 gene that impairs the function of the RNA recognition motif and causes defects in 3’ end processing is associated with intellectual disability in humans. (PMID:32816001)
• CstF64-Induced Shortening of the BID 3’UTR Promotes Esophageal Squamous Cell Carcinoma Progression by Disrupting ceRNA Cross-talk with ZFP36L2. (PMID:34607841)
• Cleavage stimulation factor 2 promotes malignant progression of liver hepatocellular carcinoma by activating phosphatidylinositol 3’-kinase/protein kinase B/mammalian target of rapamycin pathway. (PMID:35412944)
• Alternative polyadenylation writer CSTF2 forms a positive loop with FGF2 to promote tubular epithelial-mesenchymal transition and renal fibrosis. (PMID:36113752)
• CSTF2 mediated mRNA N[6]-methyladenosine modification drives pancreatic ductal adenocarcinoma m[6]A subtypes. (PMID:37816727)
• Describes the induction of CSTF2 in the growth phase of cells. (PMID:9736695)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cstf2	ENSDARG00000090788
mus_musculus	Cstf2	ENSMUSG00000031256
rattus_norvegicus	Cstf2	ENSRNOG00000048025
drosophila_melanogaster	CstF64	FBGN0027841
caenorhabditis_elegans		WBGENE00000774
caenorhabditis_elegans	R06C1.4	WBGENE00011059

Paralogs (5): U2AF2 (ENSG00000063244), RBMX2 (ENSG00000134597), ZCRB1 (ENSG00000139168), UHMK1 (ENSG00000152332), CSTF2T (ENSG00000177613)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1343054) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 4 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal mesoderm development	1
abnormal endoderm development	1
abnormal pluripotent precursor cell morphology	1
absent blastocoele	1

Additional cross-species homologs

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

Organism	UniProt	Identity	Method
Drosophila persimilis	B4GLK8	100.0%	Diamond
Drosophila sechellia	B4IBA4	100.0%	Diamond
Drosophila simulans	B4QV17	100.0%	Diamond
Gorilla gorilla gorilla	P60047	100.0%	Diamond
Hylobates lar	P60048	100.0%	Diamond
Pan troglodytes	P60049	100.0%	Diamond
Pongo pygmaeus	P60050	100.0%	Diamond
Drosophila pseudoobscura pseudoobscura	Q293V6	100.0%	Diamond
Bos taurus	Q3ZCE8	100.0%	Diamond
Macaca fascicularis	Q4R979	100.0%	Diamond
Pongo abelii	Q5NVC8	100.0%	Diamond
Macaca mulatta	Q7JGR2	99.7%	Diamond
Oryza sativa Indica Group	B8BCZ8	99.5%	Diamond
Oryza sativa Japonica Group	Q6K271	99.5%	Diamond
Sus scrofa	Q06AT9	98.9%	Diamond
Xenopus tropicalis	Q28BZ1	98.9%	Diamond
Xenopus laevis	Q6PH90	98.9%	Diamond
Drosophila grimshawi	B4JUT1	98.7%	Diamond
Drosophila mojavensis	B4KCD5	98.7%	Diamond
Drosophila virilis	B4LZ88	98.7%	Diamond
Drosophila ananassae	B3LYP1	98.1%	Diamond
Drosophila erecta	B3P0D7	98.1%	Diamond
Drosophila yakuba	B4PL68	98.1%	Diamond
Drosophila willistoni	B4NB54	96.8%	Diamond
Caenorhabditis briggsae	A8Y1R8	96.7%	Diamond
Nicotiana plumbaginifolia	P49314	96.6%	Diamond
Nicotiana sylvestris	Q08937	96.6%	Diamond
Salmo salar	C0H859	96.1%	Diamond
Taeniopygia guttata	B5G279	95.8%	Diamond
Gallus gallus	Q5ZKR5	95.8%	Diamond
Culex quinquefasciatus	B0W939	94.4%	Diamond
Aedes aegypti	Q177H0	94.4%	Diamond
Siniperca chuatsi	A2SW84	92.1%	Diamond
Anopheles gambiae	Q7QCB6	91.7%	Diamond
Triticum aestivum	Q2QKB4	90.8%	Diamond
Zea mays	P10979	89.8%	Diamond

Genomic neighbors (locus context)

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

Symbol	Type	Entrez
NOX1	protein-coding	27035
XKRX	protein-coding	402415
SRPX2	protein-coding	27286
SYTL4	protein-coding	94121
ARL13A	protein-coding	392509
TRMT2B	protein-coding	79979
TSPAN6	protein-coding	7105

Protein

Protein identifiers

Cleavage stimulation factor subunit 2 — P33240 (reviewed: P33240)

Alternative names: CF-1 64 kDa subunit, Cleavage stimulation factor 64 kDa subunit

All UniProt accessions (4): A0A0A0MT56, E7EWR4, E9PID8, P33240

UniProt curated annotations — full annotation on UniProt →

Function. One of the multiple factors required for polyadenylation and 3’-end cleavage of mammalian pre-mRNAs. This subunit is directly involved in the binding to pre-mRNAs.

Subunit / interactions. The CSTF complex is composed of CSTF1 (50 kDa subunit), CSTF2 (64 kDa subunit) and CSTF3 (77 kDa subunit). CSTF2 directly interacts with CSTF3, SYMPK and RPO2TC1. Interacts with HSF1 in heat-stressed cells. Interacts with CPSF2, CPSF3 and FIP1L1. Interacts with DDX1.

Subcellular location. Nucleus.

Disease relevance. Intellectual developmental disorder, X-linked 113 (XLID113) [MIM:301116] A disorder characterized by mild intellectual disability, and developmental delay mainly affecting verbal and non-verbal communication skills. Motor development is normal. The disease is caused by variants affecting the gene represented in this entry.

Induction. Up-regulated during the G0 to S phase transition.

Isoforms (2)

UniProt ID	Names	Canonical?
P33240-1	1	yes
P33240-2	2

RefSeq proteins (3): NP_001293135, NP_001293138, NP_001316* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000504	RRM_dom	Domain
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR025742	CSTF2_hinge	Domain
IPR026896	CSTF_C	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily
IPR038192	CSTF_C_sf	Homologous_superfamily

Pfam: PF00076, PF14304, PF14327

UniProt features (48 total): repeat 12, helix 9, strand 7, region of interest 6, modified residue 6, compositionally biased region 2, chain 1, domain 1, cross-link 1, splice variant 1, sequence variant 1, turn 1

Structure

Experimental structures (PDB)

4 structures by resolution:

PDB	Title	Method	Resolution (Å)
1P1T	NMR Structure of the N-terminal RRM domain of Cleavage stimulation factor 64 KDa subunit	SOLUTION NMR
2J8P	NMR structure of C-terminal domain of human CstF-64	SOLUTION NMR
6Q2I	Solution state NMR structures of the RNA recognition motif (RRM) domain of human CstF-64	SOLUTION NMR
6TZE	Human CstF-64 RRM mutant - D50A	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P33240-F1	60.94	0.12

Human Protein Atlas

Protein class: Predicted intracellular proteins, Plasma proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm; nuclear bodies

Antibody reliability (HPA): IH supported · IF enhanced

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 (7)

Type	Positions
Phosphoserine	14, 518, 524
Omega-n-methylarginine	308, 468, 475
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in sumo2)	189

Function

Pathways and Gene Ontology

Reactome pathways

6 curated (TAS) of 12; 1 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

12 pathways:

ID	Pathway	Evidence
R-HSA-9918481	Dengue Virus-Host Interactions ⚕	curated
R-HSA-77595	Processing of Intronless Pre-mRNAs	curated
R-HSA-73856	RNA Polymerase II Transcription Termination	curated
R-HSA-72187	mRNA 3’-end processing	curated
R-HSA-9770562	mRNA Polyadenylation	curated
R-HSA-6784531	tRNA processing in the nucleus	curated
R-HSA-74160	Gene expression (Transcription)	—
R-HSA-8953854	Metabolism of RNA	—
R-HSA-72203	Processing of Capped Intron-Containing Pre-mRNA	—
R-HSA-75067	Processing of Capped Intronless Pre-mRNA	—
R-HSA-73857	RNA Polymerase II Transcription	—
R-HSA-72306	tRNA processing	—

MSigDB gene sets: 187 (showing top): GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, GOBP_RESPONSE_TO_NERVE_GROWTH_FACTOR, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, GOBP_REGULATION_OF_MRNA_3_END_PROCESSING, REACTOME_MRNA_3_END_PROCESSING, REACTOME_PROCESSING_OF_CAPPED_INTRON_CONTAINING_PRE_MRNA, GOBP_MRNA_3_END_PROCESSING, GARY_CD5_TARGETS_DN, WANG_CISPLATIN_RESPONSE_AND_XPC_DN, GOBP_RESPONSE_TO_GROWTH_FACTOR, GOBP_HISTONE_MRNA_METABOLIC_PROCESS, ZHAN_EARLY_DIFFERENTIATION_GENES_DN

GO Biological Process (5): mRNA 3’-end processing (GO:0031124), regulation of mRNA 3’-end processing (GO:0031440), nuclear histone mRNA catabolic process (GO:0071045), cellular response to nerve growth factor stimulus (GO:1990090), mRNA processing (GO:0006397)

GO Molecular Function (4): RNA binding (GO:0003723), mRNA binding (GO:0003729), nucleic acid binding (GO:0003676), protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), mRNA cleavage and polyadenylation specificity factor complex (GO:0005847), nuclear body (GO:0016604), cleavage body (GO:0071920)

Reactome top-level categories

8 top-level categories:

Category	Pathways
Metabolism of RNA	3
tRNA processing	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
Gene expression (Transcription)	1

GO top-level categories

19 GO namespaces:

Category	Terms
binding	2
mRNA processing	1
RNA 3’-end processing	1
mRNA 3’-end processing	1
regulation of mRNA processing	1
histone mRNA catabolic process	1
cellular response to growth factor stimulus	1
response to nerve growth factor	1
RNA processing	1
mRNA metabolic process	1
nucleic acid binding	1
RNA binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
mRNA cleavage factor complex	1
nucleoplasm	1
intracellular membraneless organelle	1
nuclear body	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 8 of 14 annotations. The rest are phylogenetic / computational / electronic (IEA).

8 experimentally-supported GO terms:

GO term	NS	Evidence
mRNA 3’-end processing	BP	mutant phenotype
regulation of mRNA 3’-end processing	BP	direct assay
cleavage body	CC	direct assay
mRNA cleavage and polyadenylation specificity factor complex	CC	direct assay
nuclear body	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	mutant phenotype
RNA binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,971 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CSTF2	CSTF3	Q12996	982
CSTF2	CSTF1	Q05048	967
CSTF2	LMOD1	P29536	892
CSTF2	CPSF3	Q9UKF6	845
CSTF2	CPSF2	Q9P2I0	841
CSTF2	PCF11	O94913	839
CSTF2	CPSF1	Q10570	837
CSTF2	SYMPK	Q92797	826
CSTF2	WDR33	Q9C0J8	817
CSTF2	NUDT21	O43809	808
CSTF2	CPSF4	O95639	797
CSTF2	CPSF7	Q8N684	765
CSTF2	CPSF6	Q16630	755
CSTF2	LSM11	P83369	688
CSTF2	PAPOLG	Q9BWT3	685

IntAct

Human interaction partners of CSTF2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 53 partners by confidence:

Partner	Interaction type	MIscore	Records
UBQLN1	physical association	0.780	10
HGS	physical association	0.720	6
TFG	physical association	0.720	6
BARD1	physical association	0.700	4
CDC73	association	0.580	4
SPAG8	physical association	0.560	6
UBQLN2	physical association	0.560	5
ABHD11	physical association	0.560	3
AKAP8L	physical association	0.560	3
ANKRD10	physical association	0.560	3
ATP23	physical association	0.560	3
CEACAM6	physical association	0.560	3
CNOT2	physical association	0.560	3
CTBP2	physical association	0.560	3
FAM168B	physical association	0.560	3
HDHD3	physical association	0.560	3
INCA1	physical association	0.560	3
METTL15	physical association	0.560	3
METTL27	physical association	0.560	3
POU6F2	physical association	0.560	3
PRDM6	physical association	0.560	3
RFX6	physical association	0.560	3
SAXO4	physical association	0.560	3
SS18L1	physical association	0.560	3
STH	physical association	0.560	3
TLE3	physical association	0.560	3
TLE5	physical association	0.560	3
TSC1	physical association	0.560	3
UFSP1	physical association	0.560	3
USP54	physical association	0.560	3

BioGRID (244 interactions; top human partners by supporting records): CSTF2T (Co-fractionation; 8 records), SYMPK (Affinity Capture-MS; 6 records), BARD1 (Affinity Capture-Western; 5 records), CSTF3 (Co-fractionation; 5 records), BRCA1 (Co-purification; 4 records), CDC73 (Affinity Capture-MS; 3 records), CPSF2 (Co-fractionation; 3 records), CPSF3 (Affinity Capture-MS; 3 records), SUB1 (Two-hybrid; 3 records), UBQLN1 (Two-hybrid; 3 records), BRD4 (Affinity Capture-MS; 2 records), CPEB1 (Affinity Capture-MS; 2 records), CPSF1 (Co-fractionation; 2 records), CPSF4 (Affinity Capture-MS; 2 records), CPSF6 (Affinity Capture-MS; 2 records)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
CSTF2	“form complex”	“CSTF complex”	binding

Protein complexes (CORUM) (4)

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

4 complexes by size:

Complex	Subunits	Members
Polyadenylation complex (CSTF1, CSTF2, CSTF3, SYMPK CPSF1, CPSF2, CPSF3)	7	CSTF2, CSTF3, SYMPK, CPSF1, CPSF2, CPSF3, CSTF1
BARD1-BRCA1-CSTF complex	5	CSTF3, BARD1, BRCA1, CSTF1, CSTF2
Cleavage stimulation factor	3	CSTF1, CSTF2, CSTF3
BARD1-BRCA1-CSTF64 complex	3	BRCA1, CSTF2, BARD1

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 53 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	5	92.1×	3e-07
RNA Polymerase II Transcription Termination	5	35.4×	2e-05
mRNA 3’-end processing	5	31.8×	3e-05
mRNA Polyadenylation	6	17.0×	5e-05
Dengue Virus-Host Interactions	5	7.4×	3e-03

Disease & clinical

Genetic variants

Variant evidence for CSTF2: 123 ClinVar records (3 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	39
Likely benign	4
Benign	2

Top pathogenic / likely-pathogenic (3)

Showing all 3 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
1526828	GRCh37/hg19 Xq21.32-22.1(chrX:92879337-100099708)x1	Pathogenic	criteria provided, single submitter	1
2423943	NC_000023.10:g.(?99551275)(100099087_?)del	Pathogenic	criteria provided, single submitter	1
2692386	NM_001325.3(CSTF2):c.149A>C (p.Asp50Ala)	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore CSTF2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 32 predictions of 1,085):

Position(s)	Effect	Δscore	Sites
X:100821525–100821526	acceptor_loss	1.0000	2
X:100821606–100821607	donor_loss	1.0000	5
X:100822249–100822250	acceptor_loss	1.0000	4
X:100822421–100822422	donor_loss	1.0000	5
X:100823411	donor_gain	1.0000
X:100823884–100823885	acceptor_loss	1.0000	6
X:100824006–100824007	donor_loss	1.0000	5
X:100826758–100826759	donor_loss	1.0000	2
X:100827651	donor_gain	1.0000
X:100827677	donor_gain	1.0000

AlphaMissense

1,720 missense substitutions predicted likely pathogenic (of 3,736 scored), across 372 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M147	9	0.996	1.000
M140	9	0.990	1.000
M144	9	0.989	1.000
M179	9	0.988	1.000
M74	9	0.985	1.000
M542	9	0.957	0.999
M161	9	0.917	0.999
D50	8	1.000	1.000
F61	8	1.000	1.000
F19	8	0.999	1.000
N22	8	0.999	1.000
F36	8	0.999	1.000
D90	8	0.999	1.000
N76	8	0.997	1.000
F45	8	0.996	1.000
S72	8	0.996	1.000
D66	8	0.995	0.999
N165	8	0.989	1.000
D534	8	0.978	0.998
D183	8	0.976	0.997

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

6 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	4.03e-06
Kidney Chromophobe (TCGA)	unfavorable	9.46e-06
Lung Adenocarcinoma (validation)	unfavorable	2.61e-05
Liver Hepatocellular Carcinoma (validation)	unfavorable	8.68e-05
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	9.71e-05
Glioblastoma Multiforme (validation)	favorable	0.000289

Disease associations

OMIM: gene MIM:300907 | disease phenotypes: MIM:300088, MIM:301116

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
intellectual developmental disorder, X-linked 113	Limited	X-linked

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (4 panels, 0 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

4 panels:

Panel	Rating
Hypotonic infant	amber
Intellectual disability	amber
Leukodystrophy, childhood onset	amber
Paediatric disorders	amber

Mondo (2): developmental and epileptic encephalopathy, 9 (MONDO:0010246), intellectual developmental disorder, X-linked 113 (MONDO:0958200)

Orphanet (2): Female restricted epilepsy with intellectual disability (Orphanet:101039), X-linked intellectual disability-epilepsy syndrome (Orphanet:2076)

HPO phenotypes

5 phenotypes (HPO-id order):

HPO	Term
HP:0000750	Delayed speech and language development
HP:0001256	Mild intellectual disability
HP:0001270	Motor delay
HP:0001419	X-linked recessive inheritance
HP:0011463	Childhood onset

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
C564715	Epilepsy, Female-Restricted, with Mental Retardation *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression, increases methylation	3
sodium arsenite	increases expression, affects cotreatment, increases abundance	2
Arsenic	increases methylation, affects cotreatment, increases abundance, increases expression	2
Quercetin	decreases expression	2
Cyclosporine	decreases expression	2
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
coumarin	increases phosphorylation	1
K 7174	decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	increases methylation, affects methylation	1
Benztropine	decreases expression	1
Caffeine	affects phosphorylation	1
Carbamazepine	affects expression	1
Clozapine	decreases expression	1
Coumestrol	increases expression	1
Diclofenac	affects expression	1
Doxorubicin	affects expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Plant Extracts	affects cotreatment, increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1PI	Abcam HeLa CSTF2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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