CWC22

Summary

CWC22 (CWC22 spliceosome associated protein, HGNC:29322) is a protein-coding gene on chromosome 2q31.3, encoding Pre-mRNA-splicing factor CWC22 homolog (Q9HCG8). Required for pre-mRNA splicing as component of the spliceosome. It is a common-essential gene (DepMap: required in 99.7% of cancer cell lines).

Enables RNA binding activity. Involved in mRNA splicing, via spliceosome. Located in nuclear speck. Part of U2-type catalytic step 1 spliceosome; U2-type catalytic step 2 spliceosome; and U2-type precatalytic spliceosome.

Source: NCBI Gene 57703 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 153 total
• GTEx eGene: eQTL in 23 tissues, sQTL in 2 (q < 0.05)
• ChEMBL bioactivity: 1 clinical-phase molecule tested; no curated mechanism-of-action drug
• Cancer dependency (DepMap): dependent in 99.7% of screened cell lines (common-essential)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.88 (unconstrained)
• MANE Select transcript: NM_020943
• Notable: 153 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29322
Approved symbol	CWC22
Name	CWC22 spliceosome associated protein
Location	2q31.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1604, EIF4GL, fSAPb, NCM
Ensembl gene	ENSG00000163510
Ensembl biotype	protein_coding
OMIM	615186
Entrez	57703

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 12 protein_coding, 6 nonsense_mediated_decay

MANE Select: ENST00000410053

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

ENST00000410053, ENST00000404136, ENST00000910802, ENST00000910803, ENST00000918074, ENST00000962033, ENST00000991800, ENST00000991802, ENST00000991803, ENST00001018788, ENST00001018789, ENST00001018790, ENST00001089234, ENST00001108107, ENST00001108108, ENST00001108109, ENST00001114122, ENST00001138810

RefSeq mRNA: 5 — MANE Select: NM_020943 NM_001376029, NM_001376030, NM_001376032, NM_001376033, NM_020943

CCDS: CCDS46465

Canonical transcript exons

ENST00000410053 — 20 exons

Exon	Start	End
ENSE00001075491	179964547	179964628
ENSE00001075494	179970501	179970563
ENSE00001075498	179986695	179986805
ENSE00001075504	179965878	179965982
ENSE00001075505	179944876	179945715
ENSE00001075506	179954957	179955034
ENSE00001075507	179993315	179993454
ENSE00001075509	179959022	179959082
ENSE00001075511	179952471	179952598
ENSE00001075514	179950512	179950732
ENSE00001075517	179970941	179971076
ENSE00001075520	179950825	179950926
ENSE00001075522	179970650	179970856
ENSE00001075525	179981752	179981997
ENSE00001075529	179954205	179954357
ENSE00001075532	179988577	179988644
ENSE00001075534	179973193	179973246
ENSE00001558768	180006867	180007297
ENSE00001577932	179973634	179973802
ENSE00001578434	179978190	179978318

Expression profiles

Bgee: expression breadth ubiquitous, 251 present calls, max score 95.40.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.0498 / max 1277.4717, expressed in 1789 samples.

Highest expression (Bgee): epithelial cell of pancreas, calcaneal tendon, tendon, layer of synovial tissue, tendon of biceps brachii.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CWC22 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 23 tissues and its splicing (sQTL) in 2 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 25 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	eqtl	5.5e-51	+0.25	2:180004430:C:T
Thyroid	eqtl	2.1e-13	+0.37	2:179984363:A:T
Testis	eqtl	2.3e-13	+0.27	2:179984363:A:T
Pancreas	eqtl	1.1e-12	+0.57	2:179916817:C:T
Nerve Tibial	eqtl	4.0e-08	+0.27	2:179916817:C:T
Spleen	eqtl	4.1e-07	+0.41	2:179918444:G:A
Esophagus Mucosa	eqtl	1.5e-06	+0.22	2:179984363:A:T
Stomach	eqtl	2.2e-06	+0.34	2:179919676:A:G
Adipose Visceral Omentum	eqtl	5.4e-06	+0.23	2:180007524:A:T
Skin Not Sun Exposed Suprapubic	eqtl	5.9e-05	+0.20	2:179918444:G:A
Artery Tibial	eqtl	6.8e-05	+0.14	2:180007524:A:T
Colon Transverse	eqtl	8.0e-05	+0.70	2:179979343:C:T
Prostate	eqtl	2.2e-04	+0.33	2:179984363:A:T
Skin Sun Exposed Lower leg	eqtl	3.3e-04	+0.17	2:179984363:A:T
Esophagus Muscularis	eqtl	7.7e-04	+0.20	2:180007524:A:T
Pituitary	eqtl	8.4e-04	+0.37	2:179984363:A:T
Brain Cerebellar Hemisphere	eqtl	2.6e-03	+0.32	2:179984363:A:T
Adrenal Gland	eqtl	4.2e-03	+0.36	2:179918444:G:A
Brain Hypothalamus	eqtl	9.2e-03	-0.33	2:179510847:C:T
Brain Hippocampus	eqtl	1.0e-02	+0.36	2:179918444:G:A

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
32708	19.7068	1780
32709	2.3430	1113

Top tissues by expression

showing 100 of 252 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
epithelial cell of pancreas	CL:0000083	95.40	gold quality
calcaneal tendon	UBERON:0003701	92.78	gold quality
tendon	UBERON:0000043	91.80	gold quality
layer of synovial tissue	UBERON:0007616	91.49	gold quality
tendon of biceps brachii	UBERON:0008188	89.87	gold quality
amniotic fluid	UBERON:0000173	88.28	gold quality
synovial joint	UBERON:0002217	88.17	gold quality
epithelium of nasopharynx	UBERON:0001951	87.99	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.96	gold quality
ventricular zone	UBERON:0003053	87.86	gold quality
superficial temporal artery	UBERON:0001614	87.79	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	87.19	gold quality
parietal pleura	UBERON:0002400	86.72	gold quality
oral cavity	UBERON:0000167	86.70	gold quality
smooth muscle tissue	UBERON:0001135	86.29	gold quality
endometrium	UBERON:0001295	86.21	gold quality
visceral pleura	UBERON:0002401	86.10	gold quality
biceps brachii	UBERON:0001507	86.02	gold quality
islet of Langerhans	UBERON:0000006	85.85	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.57	gold quality
leukocyte	CL:0000738	85.57	gold quality
monocyte	CL:0000576	85.55	gold quality
kidney epithelium	UBERON:0004819	85.55	silver quality
lymph node	UBERON:0000029	85.39	gold quality
gingival epithelium	UBERON:0001949	85.39	gold quality
seminal vesicle	UBERON:0000998	85.35	gold quality
upper arm skin	UBERON:0004263	85.24	silver quality
gingiva	UBERON:0001828	85.20	gold quality
popliteal artery	UBERON:0002250	85.16	gold quality
tibial artery	UBERON:0007610	85.15	gold quality
deltoid	UBERON:0001476	84.75	gold quality
ganglionic eminence	UBERON:0004023	84.70	gold quality
mucosa of paranasal sinus	UBERON:0005030	84.69	gold quality
secondary oocyte	CL:0000655	84.66	gold quality
sural nerve	UBERON:0015488	84.65	gold quality
upper leg skin	UBERON:0004262	84.63	gold quality
placenta	UBERON:0001987	84.56	gold quality
uterus	UBERON:0000995	84.48	gold quality
descending thoracic aorta	UBERON:0002345	84.29	gold quality
aorta	UBERON:0000947	84.23	gold quality
gastrocnemius	UBERON:0001388	84.17	gold quality
skin of hip	UBERON:0001554	84.11	gold quality
left ovary	UBERON:0002119	83.94	gold quality
cortical plate	UBERON:0005343	83.93	gold quality
vermiform appendix	UBERON:0001154	83.91	gold quality
rectum	UBERON:0001052	83.90	gold quality
ovary	UBERON:0000992	83.89	gold quality
tonsil	UBERON:0002372	83.89	gold quality
female reproductive system	UBERON:0000474	83.70	gold quality
gall bladder	UBERON:0002110	83.69	gold quality
urinary bladder	UBERON:0001255	83.66	gold quality
muscle of leg	UBERON:0001383	83.66	gold quality
tibia	UBERON:0000979	83.61	gold quality
body of uterus	UBERON:0009853	83.54	gold quality
myocardium	UBERON:0002349	83.47	silver quality
mucosa of sigmoid colon	UBERON:0004993	83.35	gold quality
endocervix	UBERON:0000458	83.34	gold quality
thymus	UBERON:0002370	83.30	gold quality
right ovary	UBERON:0002118	83.26	gold quality
muscle tissue	UBERON:0002385	83.24	gold quality
subcutaneous adipose tissue	UBERON:0002190	83.18	gold quality
left uterine tube	UBERON:0001303	83.05	gold quality
thoracic aorta	UBERON:0001515	83.04	gold quality
skeletal muscle tissue	UBERON:0001134	82.98	gold quality
pigmented layer of retina	UBERON:0001782	82.98	gold quality
adrenal tissue	UBERON:0018303	82.92	gold quality
ascending aorta	UBERON:0001496	82.91	gold quality
parotid gland	UBERON:0001831	82.88	gold quality
pericardium	UBERON:0002407	82.88	gold quality
colonic mucosa	UBERON:0000317	82.87	gold quality
jejunum	UBERON:0002115	82.85	gold quality
left coronary artery	UBERON:0001626	82.83	gold quality
adipose tissue	UBERON:0001013	82.76	gold quality
ectocervix	UBERON:0012249	82.72	gold quality
coronary artery	UBERON:0001621	82.66	gold quality
myometrium	UBERON:0001296	82.64	gold quality
muscle layer of sigmoid colon	UBERON:0035805	82.61	gold quality
mucosa of stomach	UBERON:0001199	82.58	gold quality
palpebral conjunctiva	UBERON:0001812	82.57	gold quality
peritoneum	UBERON:0002358	82.55	gold quality
omental fat pad	UBERON:0010414	82.55	gold quality
tibialis anterior	UBERON:0001385	82.54	silver quality
fallopian tube	UBERON:0003889	82.50	gold quality
quadriceps femoris	UBERON:0001377	82.48	silver quality
ileal mucosa	UBERON:0000331	82.47	gold quality
caecum	UBERON:0001153	82.45	gold quality
bone marrow	UBERON:0002371	82.41	gold quality
right coronary artery	UBERON:0001625	82.34	gold quality
uterine cervix	UBERON:0000002	82.31	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	82.28	gold quality
pancreatic ductal cell	CL:0002079	82.23	silver quality
adipose tissue of abdominal region	UBERON:0007808	82.19	gold quality
lower esophagus	UBERON:0013473	82.16	gold quality
lower esophagus muscularis layer	UBERON:0035833	82.16	gold quality
vastus lateralis	UBERON:0001379	82.14	silver quality
cauda epididymis	UBERON:0004360	82.14	gold quality
jejunal mucosa	UBERON:0000399	82.10	gold quality
pancreas	UBERON:0001264	82.08	gold quality
vagina	UBERON:0000996	81.99	gold quality
cartilage tissue	UBERON:0002418	81.99	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-7303	no	68.52
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Cerebellum	tissue	29.3	high
Thymus	tissue	20.3
Olfactory bulb	tissue	19.3
Hippocampal formation	tissue	18.5
Putamen	tissue	18.4
Cerebral cortex	tissue	18.2	high
Midbrain	tissue	18.2
Occipital cortex	tissue	18.2
Spinal cord	tissue	17.9
Corpus callosum	tissue	17.9
Superior colliculi	tissue	17.8
Postcentral gyrus	tissue	17.8
Septum	tissue	17.7
Pons	tissue	17.6
Somatosensory cortex	tissue	17.6
Lymph node	tissue	17.3	medium
Nucleus accumbens	tissue	17.1
Medulla oblongata	tissue	17.1
Thalamus	tissue	17.0
Tonsil	tissue	17.0	high
Retrosplenial and cingulate cortex	tissue	16.8
Prefrontal cortex	tissue	16.6
Substantia nigra	tissue	16.6
Ventral forebrain	tissue	16.6
Retrosplenial cortex	tissue	16.5
Entorhinal cortex	tissue	16.4
Motor cortex	tissue	16.3
Periaqueductal gray	tissue	16.3
Choroid plexus	tissue	16.2
Hypothalamus	tissue	16.1
Basal ganglia	tissue	16.0	high
Endometrium 1	tissue	15.8	high
Hippocampus	tissue	15.8	high
Temporal cortex	tissue	15.8
Liver	tissue	15.7	high
Ovary	tissue	15.6	medium
Amygdala	tissue	15.2
Bone marrow	tissue	15.1	high
Thyroid gland	tissue	15.0	high
Insular cortex	tissue	14.4
Breast	tissue	14.0	high
Spleen	tissue	13.9	medium
Tongue	tissue	13.6
Placenta	tissue	13.6	high
Cervix	tissue	13.2	high
Urinary bladder	tissue	13.1	high
Smooth muscle	tissue	13.0	high
Locus coeruleus	tissue	12.8
Parathyroid gland	tissue	12.7	medium
Kidney	tissue	12.5	high
Appendix	tissue	12.4	high
Caudate putamen	tissue	12.2
Adipose tissue	tissue	11.9	medium
Esophagus	tissue	11.7	high
Prostate	tissue	11.7	high
Retina	tissue	11.5
Gallbladder	tissue	11.3	high
Fallopian tube	tissue	11.3	high
Rectum	tissue	11.1	high
Vagina	tissue	10.9	high

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Cerebellar cortex (29.4), Flocculonodular lobe (27.0), Vermis (26.8), Angular gyrus (white matter) (19.4), Corpus callosum, genu (white matter) (19.3).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting CWC22 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 48 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
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-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4775	99.98	75.00	6394
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-3671	99.90	73.04	3897

Functional genomics

gnomAD constraint: pLI 1.94e-07, LOEUF 0.875, missense Z 0.968 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000410053 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
2:179,945,132–179,950,709	306 / 296.8	1.03	no
2:179,950,710–179,954,976	115 / 169.8	0.68	no
2:179,954,977–179,993,341	559 / 602.3	0.93	no
DepMap (CRISPR cell-line fitness): dependent in 99.7% of screened cell lines, common-essential.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): MFE-280 (-3.023), RERF-GC-1B (-3.0), NCI-H226 (-2.932), Calu-6 (-2.876), SLR 20 (-2.7), HCC1187 (-2.578), AU565 (-2.461), SK-BR-3 (-2.394), COR-L311 (-2.388), NCI-H747 (-2.376), MCF-7 (-2.371), VCaP (-2.365), 42-MG-BA (-2.339), EFO-21 (-2.284), CCF-STTG1 (-2.276).

Literature-anchored findings (GeneRIF, showing 6)

• CWC22 connects pre-mRNA splicing and exon junction complex assembly. (PMID:22959432)
• CWC22 escorts the helicase eIF4AIII to spliceosomes and promotes exon junction complex assembly (PMID:22961380)
• The essential splicing factor CWC22 has acquired functions in exon junction complex assembly and nonsense-mediated decay during evolution from single-celled to complex eukaryotes. (PMID:23236153)
• The binding mode of CWC22 to eIF4AIII reveals a facet of how MIF4G domains use their versatile structural frameworks to activate or inhibit DEAD-box proteins. (PMID:24218557)
• Structural and functional insights into CWC27/CWC22 heterodimer linking the exon junction complex to spliceosomes. (PMID:32329775)
• Gene expression network analysis of lymph node involvement in colon cancer identifies AHSA2, CDK10, and CWC22 as possible prognostic markers. (PMID:32345988)

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
danio_rerio	cwc22	ENSDARG00000014008
mus_musculus	Cwc22	ENSMUSG00000027014
mus_musculus	Cwc22rt6	ENSMUSG00000079247
mus_musculus	Cwc22rt1	ENSMUSG00000094125
mus_musculus	Cwc22rt2	ENSMUSG00000094336
mus_musculus	Cwc22rt7	ENSMUSG00000095824
mus_musculus	Cwc22rt5	ENSMUSG00000096337
mus_musculus	Cwc22rt4	ENSMUSG00000096484
mus_musculus	Cwc22rt3	ENSMUSG00000096729
rattus_norvegicus	Cwc22	ENSRNOG00000012651
rattus_norvegicus	LOC134479416	ENSRNOG00000071808
rattus_norvegicus		ENSRNOG00000082394
rattus_norvegicus	LOC134479417	ENSRNOG00000085537
drosophila_melanogaster	ncm	FBGN0086707
caenorhabditis_elegans		WBGENE00002957

Paralogs (1): NOM1 (ENSG00000146909)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2136773) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 11 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal liver morphology	1
abnormal spleen morphology	1
hemorrhage	1
spina bifida	1
increased circulating aspartate transaminase level	1
urinary bladder obstruction	1
increased bone mineral content	1
preweaning lethality, complete penetrance	1
cystolithiasis	1
embryonic lethality prior to organogenesis	1
prenatal lethality prior to heart atrial septation	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
Musca domestica	P0DP80	99.8%	Diamond
Cryptococcus deneoformans JEC21	P0CM96	99.7%	Diamond
Cryptococcus deneoformans B-3501A	P0CM97	99.7%	Diamond
Pongo abelii	Q5RA93	96.0%	Diamond
Aspergillus fumigatus Af293	Q4WKB9	92.1%	Diamond
Aspergillus nidulans FGSC A4	Q5BGP1	92.1%	Diamond
Xenopus laevis	Q52KN9	88.6%	Diamond
Gallus gallus	Q5ZKA3	88.6%	Diamond
Caenorhabditis briggsae	A8WT19	87.9%	Diamond
Neurospora crassa OR74A	Q7RX84	77.5%	Diamond
Pyricularia oryzae 70-15	Q52B63	75.7%	Diamond
Schizosaccharomyces pombe 972h-	Q9P6R9	65.5%	Diamond
Mycosarcoma maydis	Q4PCY0	65.0%	Diamond
Yarrowia lipolytica CLIB122	Q6C8C5	52.4%	Diamond
Debaryomyces hansenii CBS767	Q6BU84	50.8%	Diamond
Candida albicans SC5314	Q59XY0	50.7%	Diamond
Saccharomyces cerevisiae S288C	P53333	34.5%	Diamond
Eremothecium gossypii ATCC 10895	Q751P4	33.9%	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
ZNF385B	protein-coding	151126
EPCART	ncRNA	105373767
MIR1258	ncRNA	100302172
SESTD1	protein-coding	91404

Protein

Protein identifiers

Pre-mRNA-splicing factor CWC22 homolog — Q9HCG8 (reviewed: Q9HCG8)

Alternative names: Nucampholin homolog, fSAPb

All UniProt accessions (2): Q9HCG8, B7WP74

UniProt curated annotations — full annotation on UniProt →

Function. Required for pre-mRNA splicing as component of the spliceosome. As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs. Promotes exon-junction complex (EJC) assembly. Hinders EIF4A3 from non-specifically binding RNA and escorts it to the splicing machinery to promote EJC assembly on mature mRNAs. Through its role in EJC assembly, required for nonsense-mediated mRNA decay.

Subunit / interactions. Component of the pre-catalytic spliceosome B and the catalytic spliceosome C complexes. Component of the minor spliceosome, which splices U12-type introns. Interacts with EIF4A3 and PRPF19 in an RNA-independent manner. Direct interaction with EIF4A3 is mediated by the MIF4G domain. Full interaction with EIF4A3 occurs only when EIF4A3 is not part of the EJC and prevents EIF4A3 binding to RNA.

Subcellular location. Nucleus. Nucleus speckle.

Similarity. Belongs to the CWC22 family.

RefSeq proteins (5): NP_001362958, NP_001362959, NP_001362961, NP_001362962, NP_065994* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003890	MIF4G-like_typ-3	Domain
IPR003891	Initiation_fac_eIF4g_MI	Domain
IPR016024	ARM-type_fold	Homologous_superfamily
IPR050781	CWC22_splicing_factor	Family

Pfam: PF02847, PF02854

UniProt features (79 total): helix 30, compositionally biased region 11, sequence conflict 7, strand 7, modified residue 5, mutagenesis site 5, turn 5, sequence variant 3, region of interest 3, domain 2, chain 1

Structure

Experimental structures (PDB)

29 structures by resolution:

PDB	Title	Method	Resolution (Å)
4C9B	Crystal structure of eIF4AIII-CWC22 complex	X-RAY DIFFRACTION	2
8C6J	Human spliceosomal PM5 C* complex	ELECTRON MICROSCOPY	2.8
7DVQ	Cryo-EM Structure of the Activated Human Minor Spliceosome (minor Bact Complex)	ELECTRON MICROSCOPY	2.89
9XTT	Human minor spliceosome branching-completed C complex (after step-I)	ELECTRON MICROSCOPY	2.92
6ICZ	Cryo-EM structure of a human post-catalytic spliceosome (P complex) at 3.0 angstrom	ELECTRON MICROSCOPY	3
8I0R	The cryo-EM structure of human Bact-I complex	ELECTRON MICROSCOPY	3
8I0T	The cryo-EM structure of human Bact-III complex	ELECTRON MICROSCOPY	3
8I0V	The cryo-EM structure of human post-Bact complex	ELECTRON MICROSCOPY	3
9XU3	Human minor spliceosome exon-ligation-ready C* complex (prior to step-II)	ELECTRON MICROSCOPY	3
7QTT	Structural organization of a late activated human spliceosome (Baqr, core region)	ELECTRON MICROSCOPY	3.1
6YVH	CWC22-CWC27-EIF4A3 Complex	X-RAY DIFFRACTION	3.19
6QDV	Human post-catalytic P complex spliceosome	ELECTRON MICROSCOPY	3.3
8I0U	The cryo-EM structure of human Bact-IV complex	ELECTRON MICROSCOPY	3.3
9FMD	Integrative model of the human post-catalytic spliceosome (P-complex)	ELECTRON MICROSCOPY	3.3
6ZYM	Human C Complex Spliceosome - High-resolution CORE	ELECTRON MICROSCOPY	3.4
8I0W	The cryo-EM structure of human C complex	ELECTRON MICROSCOPY	3.4
5XJC	Cryo-EM structure of the human spliceosome just prior to exon ligation at 3.6 angstrom	ELECTRON MICROSCOPY	3.6
7W59	The cryo-EM structure of human pre-C*-I complex	ELECTRON MICROSCOPY	3.6
7W5A	The cryo-EM structure of human pre-C*-II complex	ELECTRON MICROSCOPY	3.6
5YZG	The Cryo-EM Structure of Human Catalytic Step I Spliceosome (C complex) at 4.1 angstrom …	ELECTRON MICROSCOPY	4.1
8I0S	The cryo-EM structure of human Bact-II complex	ELECTRON MICROSCOPY	4.2
7W5B	The cryo-EM structure of human C* complex	ELECTRON MICROSCOPY	4.3
6FF7	human Bact spliceosome core structure	ELECTRON MICROSCOPY	4.5
5Z58	Cryo-EM structure of a human activated spliceosome (early Bact) at 4.9 angstrom.	ELECTRON MICROSCOPY	4.9
7A5P	Human C Complex Spliceosome - Medium-resolution PERIPHERY	ELECTRON MICROSCOPY	5
5Z56	cryo-EM structure of a human activated spliceosome (mature Bact) at 5.1 angstrom.	ELECTRON MICROSCOPY	5.1
5MQF	Cryo-EM structure of a human spliceosome activated for step 2 of splicing (C* complex)	ELECTRON MICROSCOPY	5.9
8CH6	Structure of a late-stage activated spliceosome (BAqr) arrested with a dominant-negative …	ELECTRON MICROSCOPY	5.9
5Z57	Cryo-EM structure of the human activated spliceosome (late Bact) at 6.5 angstrom	ELECTRON MICROSCOPY	6.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HCG8-F1	65.00	0.32

Human Protein Atlas

Protein class: Predicted intracellular proteins, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nuclear speckles; cytosol

Antibody reliability (HPA): IH approved · IF supported

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)

Type	Positions
Phosphoserine	39, 61, 107, 786, 829

Mutagenesis-validated functional residues (5)

Position	Phenotype
168	no effect on eif4a3 incorporation into ejcs.
171–174	loss of eif4a3-binding.
171–172	loss of eif4a3-binding.
331	decreased eif4a3-binding; when associated with a-334.
334	decreased eif4a3-binding; when associated with a-331.

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 5; 1 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

5 pathways:

ID	Pathway	Evidence
R-HSA-9918481	Dengue Virus-Host Interactions ⚕	curated
R-HSA-72163	mRNA Splicing - Major Pathway	curated
R-HSA-8953854	Metabolism of RNA	—
R-HSA-72203	Processing of Capped Intron-Containing Pre-mRNA	—
R-HSA-72172	mRNA Splicing	—

MSigDB gene sets: 127 (showing top): RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, REACTOME_PROCESSING_OF_CAPPED_INTRON_CONTAINING_PRE_MRNA, GOBP_RNA_SPLICING, REACTOME_MRNA_SPLICING, WANG_TARGETS_OF_MLL_CBP_FUSION_DN, GOBP_REGULATION_OF_MRNA_SPLICING_VIA_SPLICEOSOME, GOBP_REGULATION_OF_RNA_SPLICING, REACTOME_METABOLISM_OF_RNA, GOCC_U2_TYPE_SPLICEOSOMAL_COMPLEX, GOCC_NUCLEAR_SPECK, GOCC_PRECATALYTIC_SPLICEOSOME, GOCC_NUCLEAR_BODY, GOCC_RIBONUCLEOPROTEIN_GRANULE, GOCC_CATALYTIC_STEP_2_SPLICEOSOME, GOCC_SPLICEOSOMAL_COMPLEX

GO Biological Process (4): mRNA splicing, via spliceosome (GO:0000398), regulation of mRNA splicing, via spliceosome (GO:0048024), mRNA processing (GO:0006397), RNA splicing (GO:0008380)

GO Molecular Function (2): RNA binding (GO:0003723), protein binding (GO:0005515)

GO Cellular Component (8): nucleus (GO:0005634), nucleoplasm (GO:0005654), spliceosomal complex (GO:0005681), nuclear speck (GO:0016607), U2-type precatalytic spliceosome (GO:0071005), U2-type catalytic step 1 spliceosome (GO:0071006), U2-type catalytic step 2 spliceosome (GO:0071007), catalytic step 2 spliceosome (GO:0071013)

Reactome top-level categories

4 top-level categories:

Category	Pathways
mRNA Splicing	1
Dengue Virus Infection	1
Processing of Capped Intron-Containing Pre-mRNA	1
Metabolism of RNA	1

GO top-level categories

27 GO namespaces:

Category	Terms
U2-type spliceosomal complex	3
U2 snRNP	3
RNA processing	2
U6 snRNP	2
RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	1
mRNA processing	1
mRNA splicing, via spliceosome	1
regulation of RNA splicing	1
regulation of mRNA processing	1
mRNA metabolic process	1
nucleic acid binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
nuclear protein-containing complex	1
ribonucleoprotein complex	1
nuclear ribonucleoprotein granule	1
U1 snRNP	1
U4/U6 x U5 tri-snRNP complex	1
precatalytic spliceosome	1
catalytic step 1 spliceosome	1
catalytic step 2 spliceosome	1
Prp19 complex	1
spliceosomal complex	1
U5 snRNP	1
catalytic complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 9 of 14 annotations. The rest are phylogenetic / computational / electronic (IEA).

9 experimentally-supported GO terms:

GO term	NS	Evidence
mRNA splicing, via spliceosome	BP	direct assay
U2-type catalytic step 1 spliceosome	CC	direct assay
U2-type catalytic step 2 spliceosome	CC	direct assay
U2-type precatalytic spliceosome	CC	direct assay
catalytic step 2 spliceosome	CC	direct assay
nuclear speck	CC	direct assay
nucleus	CC	direct assay
spliceosomal complex	CC	direct assay
RNA binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,565 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CWC22	CWC25	Q9NXE8	747
CWC22	YJU2	Q9BW85	730
CWC22	SLU7	O95391	694
CWC22	CWC27	Q6UX04	693
CWC22	XAB2	Q9HCS7	653
CWC22	DHX8	Q14562	650
CWC22	CDC5L	Q99459	647
CWC22	MAGOHB	Q96A72	645
CWC22	MAGOH	P50606	645
CWC22	PRPF18	Q99633	635
CWC22	BUD13	Q9BRD0	630
CWC22	RNF113A	O15541	628
CWC22	EIF4A3	P38919	628
CWC22	DHX38	Q92620	619
CWC22	EFTUD2	Q15029	607

IntAct

Human interaction partners of CWC22 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

8 partners by confidence:

Partner	Interaction type	MIscore	Records
EIF4A3	direct interaction	0.860	5
KLHL2	physical association	0.560	3
PTPN21	physical association	0.560	3
FAM32A	physical association	0.510	2
FRG1	physical association	0.510	2
CFTR	physical association	0.370	1
EXOSC8	physical association	0.000	1
YWHAB	physical association	0.000	1

BioGRID (170 interactions; top human partners by supporting records): EIF4A3 (Affinity Capture-Western; 11 records), FAM32A (Two-hybrid; 4 records), CAMKV (Affinity Capture-MS; 3 records), CTDSP2 (Affinity Capture-MS; 3 records), DENND2D (Affinity Capture-MS; 3 records), DOK4 (Affinity Capture-MS; 3 records), EDA (Affinity Capture-MS; 3 records), FAM9A (Affinity Capture-MS; 3 records), FMR1NB (Affinity Capture-MS; 3 records), FRG1 (Two-hybrid; 3 records), GPR183 (Affinity Capture-MS; 3 records), PTGER3 (Affinity Capture-MS; 3 records), VTI1B (Affinity Capture-MS; 3 records), C11orf57 (Affinity Capture-MS; 2 records), EPB41L2 (Affinity Capture-MS; 2 records)

Protein complexes (CORUM) (2)

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

2 complexes by size:

Complex	Subunits	Members
C complex spliceosome	80	RBM8A, ZCCHC8, EFTUD2, HNRNPK, PNN, SRSF1, CDC40, DHX35, HNRNPA2B1, HNRNPC, SF3B3, SYNCRIP, U2AF1, PLRG1, RBM22, SNRNP40, SNRPB2, EIF4A3, FRG1, GPATCH1, HNRNPA3, PPIL1, SF3B1, DHX38, HNRNPR, LSM2, LSM3, SNRPE, DDX23, HNRNPU, MTREX, SLU7, AQR, CWC15, CWC22, DDX41, PABPC1, SF3B2, SNRPD1, SNRPD2, DHX8, CWC27, HNRNPA1, HNRNPH1, MAGOH, SF3A1, PPIE, PPIL3, PRP4K, PRPF6, RALY, SNRPA1, SYF2, TFIP11, CACTIN, CRNKL1, DDX5, SF3A3, SNRNP200, SNRPD3, SNRPF, SRRM1, ALYREF, PPWD1, PRPF19, RBMX, SF3A2, SRRM2, WDR83, XAB2, CDC5L, HNRNPF, SART1, SNRPG, ESS2, ISY1, SNRPB, SNW1, HNRNPM, PRPF8
Spliceosome, C complex	39	MAGOH, PPWD1, RBM8A, SNRPF, SNRPG, SYF2, PPIE, SNRPB2, SNRPA1, BCAS2, BUD31, CWC25, SNRPD2, SNRPD3, CASC3, EIF4A3, PRPF19, SNRPD1, SNRPE, YJU2, SRRM2, XAB2, CWC22, RBM22, SNRNP200, AQR, CWC15, EFTUD2, ISY1, PPIG, CDC40, CDC5L, DHX38, PLRG1, PPIL1, PRPF8, SNRPB, SNW1, CRNKL1

Disease & clinical

Genetic variants

Variant evidence for CWC22: 153 ClinVar records (0 pathogenic / likely pathogenic); 6 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	122
Likely benign	8
Benign	4

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 40 predictions of 1,290):

Position(s)	Effect	Δscore	Sites
2:179945722	acceptor_gain	1.0000
2:179950927–179950928	acceptor_loss	1.0000	6
2:179952469–179952470	donor_loss	1.0000	5
2:179952474	donor_gain	1.0000
2:179954203–179954204	donor_loss	1.0000	5
2:179954358–179954359	acceptor_loss	1.0000	6
2:179954361	acceptor_gain	1.0000
2:179964545–179964546	donor_loss	1.0000	5
2:179964629–179964630	acceptor_loss	1.0000	6
2:179965876–179965877	donor_loss	1.0000	4

AlphaMissense

2,505 missense substitutions predicted likely pathogenic (of 6,045 scored), across 478 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
M492	9	0.997	1.000
M335	9	0.965	0.997
M479	9	0.874	0.986
H474	8	0.999	1.000
N171	8	0.998	1.000
D446	8	0.998	0.999
D495	8	0.998	0.999
N629	8	0.998	1.000
H537	8	0.997	1.000
N189	8	0.995	1.000
F626	8	0.995	1.000
S466	8	0.992	1.000
F211	8	0.991	1.000
F385	8	0.989	1.000
F340	8	0.987	0.999
N546	8	0.986	1.000
D388	8	0.985	0.997
F582	8	0.985	0.999
H368	8	0.984	0.998
H324	8	0.983	0.998

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	6.3e-06
Kidney Renal Clear Cell Carcinoma (validation)	favorable	0.000344
Kidney Chromophobe (TCGA)	unfavorable	0.00098

Disease associations

OMIM: gene MIM:615186 | disease phenotypes:

GWAS associations

6 associations:

Study	Trait	p-value
GCST004904_17	Body mass index	2e-13
GCST010988_474	Adult body size	3e-13
GCST004904_208	Body mass index	5e-8
GCST007201_315	Schizophrenia	1e-6
GCST010396_150	Gut microbiota (bacterial taxa, hurdle binary method)	1e-6
GCST009391_844	Metabolite levels	5e-6

EFO canonical traits (from GWAS)

3 canonical traits:

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0010400	triacylglycerol 46:0 measurement
EFO:0007874	gut microbiome measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724778 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,601 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

1 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,601

PharmGKB: 1 entry (CPIC guideline: no)

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
7.82	Kd	15	nM	MOLIBRESIB
7.70	IC50	20	nM	MOLIBRESIB

PubChem BioAssay actives

2 with measured affinity, of 7 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
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2179153: Binding affinity against CWC22 (unknown origin) assessed as apparent dissociation constant incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	kd	0.0150	uM

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects expression, decreases methylation, affects cotreatment	7
sodium arsenite	affects methylation, decreases expression, increases abundance, increases expression	4
trichostatin A	affects cotreatment, decreases expression	3
perfluorooctane sulfonic acid	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	decreases sumoylation	1
dicrotophos	decreases expression	1
arsenite	decreases reaction, affects binding	1
zinc chromate	increases abundance, increases expression	1
coumarin	affects phosphorylation	1
chromium hexavalent ion	increases expression, increases abundance	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
ICG 001	decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Arsenic	increases abundance, increases expression	1
Benzo(a)pyrene	decreases methylation	1
Cisplatin	affects cotreatment, decreases expression	1
Copper	increases expression	1
Formaldehyde	decreases expression	1
Ribonucleotides	affects binding	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Cyclosporine	increases expression	1
Asbestos, Crocidolite	increases 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
CHEMBL5697219	Binding	Inhibition of CWC22 (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)

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

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for CWC22 across ~30M SureChEMBL compounds — explore on Sugi Predict.