SPEN

Summary

SPEN (spen family transcriptional repressor, HGNC:17575) is a protein-coding gene on chromosome 1p36.21-p36.13, encoding Msx2-interacting protein (Q96T58). May serve as a nuclear matrix platform that organizes and integrates transcriptional responses. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a hormone inducible transcriptional repressor. Repression of transcription by this gene product can occur through interactions with other repressors, by the recruitment of proteins involved in histone deacetylation, or through sequestration of transcriptional activators. The product of this gene contains a carboxy-terminal domain that permits binding to other corepressor proteins. This domain also permits interaction with members of the NuRD complex, a nucleosome remodeling protein complex that contains deacetylase activity. In addition, this repressor contains several RNA recognition motifs that confer binding to a steroid receptor RNA coactivator; this binding can modulate the activity of both liganded and nonliganded steroid receptors.

Source: NCBI Gene 23013 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Radio-Tartaglia syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 976 total — 64 pathogenic, 36 likely-pathogenic
• Phenotypes (HPO): 155
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 11 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_015001

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17575
Approved symbol	SPEN
Name	spen family transcriptional repressor
Location	1p36.21-p36.13
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0929, MINT, SHARP, RBM15C
Ensembl gene	ENSG00000065526
Ensembl biotype	protein_coding
OMIM	613484
Entrez	23013

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000375759, ENST00000438066, ENST00000442985, ENST00000471538, ENST00000487496, ENST00000673875, ENST00000704274

RefSeq mRNA: 1 — MANE Select: NM_015001 NM_015001

CCDS: CCDS164

Canonical transcript exons

ENST00000375759 — 15 exons

Exon	Start	End
ENSE00000751295	15937163	15937645
ENSE00000827972	15909321	15909481
ENSE00000827978	15928091	15936266
ENSE00000827979	15937812	15938006
ENSE00000827980	15938718	15938876
ENSE00000955468	15876202	15876678
ENSE00001065383	15872816	15873136
ENSE00001468270	15939296	15940456
ENSE00001468313	15847707	15848150
ENSE00001597480	15922249	15922349
ENSE00001633894	15918926	15919051
ENSE00001734774	15916128	15916279
ENSE00001771430	15920870	15920983
ENSE00001776313	15919404	15919517
ENSE00003787681	15911101	15911301

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 97.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.5786 / max 715.0289, expressed in 1822 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
930	25.6263	1813
925	4.8175	1223
928	2.7260	1263
929	0.7561	461
924	0.3941	187
927	0.2586	115

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	97.56	gold quality
ganglionic eminence	UBERON:0004023	95.97	gold quality
cortical plate	UBERON:0005343	94.86	gold quality
cranial nerve II	UBERON:0000941	94.75	gold quality
popliteal artery	UBERON:0002250	94.71	gold quality
tibial artery	UBERON:0007610	94.70	gold quality
aorta	UBERON:0000947	94.24	gold quality
parotid gland	UBERON:0001831	94.00	gold quality
descending thoracic aorta	UBERON:0002345	93.91	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.76	gold quality
calcaneal tendon	UBERON:0003701	93.68	gold quality
ascending aorta	UBERON:0001496	93.63	gold quality
thoracic aorta	UBERON:0001515	93.63	gold quality
left ovary	UBERON:0002119	93.63	gold quality
mucosa of stomach	UBERON:0001199	93.62	gold quality
sperm	CL:0000019	93.60	gold quality
cerebellar hemisphere	UBERON:0002245	93.51	gold quality
right ovary	UBERON:0002118	93.50	gold quality
cerebellar cortex	UBERON:0002129	93.50	gold quality
cerebellar vermis	UBERON:0004720	93.47	gold quality
cerebellum	UBERON:0002037	93.30	gold quality
corpus callosum	UBERON:0002336	93.27	gold quality
right lobe of thyroid gland	UBERON:0001119	93.19	gold quality
right lung	UBERON:0002167	93.12	gold quality
apex of heart	UBERON:0002098	93.08	gold quality
lower esophagus mucosa	UBERON:0035834	92.97	gold quality
male germ cell	CL:0000015	92.95	gold quality
left coronary artery	UBERON:0001626	92.82	gold quality
medial globus pallidus	UBERON:0002477	92.82	gold quality
ovary	UBERON:0000992	92.81	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
DMPK	Activation
NCOR2	Unknown

Upstream regulators (CollecTRI, top): HIVEP1, NCOR2, RUNX1, TCF3

miRNA regulators (miRDB)

165 targeting SPEN, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-656-3P	100.00	72.15	2788
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-8485	100.00	77.57	4731
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
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-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-4745-5P	99.98	65.95	1028
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-19A-3P	99.98	75.33	2762

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 17)

• SHARP is a novel component of the HDAC corepressor complex, recruited by RBP-Jkappa to repress transcription of target genes in the absence of activated Notch. (PMID:12374742)
• the conserved function of the SPOC domain of SHARP is to mediate interaction with SMRT/NCoR corepressors, and that Spen proteins play an essential role in the repression complex (PMID:12897056)
• both the androgen receptor interacting domains of the coactivator SRC1 and of the corepressor SMRT compete for interaction with the androgen receptor N-terminus (PMID:15062576)
• Pak1-SHARP interaction plays an essential role in enhancing the corepressor functions of SHARP, thereby modulating Notch signaling in human cancer cells. (PMID:15824732)
• Msx2-interacting protein(MINT), human interacts with the UbcH8. (PMID:16583136)
• SHARP gene and protein expression is elevated in human colon and ovarian endometrioid adenocarcinomas carrying gene defects leading to beta-catenin dysregulation. (PMID:17234755)
• In functional assays, corepressor ETO, but not AML1/ETO, augments SHARP-mediated repression in an histone deacetylase-dependent manner. (PMID:18332109)
• MINT3 and MINT17 were informative for patient grouping to predict local recurrence in rectal cancer patients (PMID:20460484)
• These results demonstrate a role for the inactivation of SHARP transcription in DM1 biology. (PMID:21637295)
• Phosphorylation of the CK2 site on SMRT significantly increased affinity for SHARP. (PMID:24268649)
• A structural study of the RNA binding properties of the RNA recognition motifs of SHARP. (PMID:24748666)
• SPEN mutations were associated with diffuse large B-cell lymphoma with hepatitis C virus infection. (PMID:25381127)
• SPEN is a novel tumor-suppressor gene that may be clinically useful as a predictive biomarker of tamoxifen response in ERalpha-positive breast cancers. (PMID:26297734)
• our data demonstrate a role for SPEN in the regulation of primary cilia formation and cell migration in breast cancer cells, which may collectively explain why its expression is associated with time to metastasis in cohorts of patients with ERalpha-negative breast cancers. (PMID:28877752)
• SPEN induces miR-4652-3p to target HIPK2 in nasopharyngeal carcinoma. (PMID:32641685)
• SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females. (PMID:33596411)
• Dissection of protein and RNA regions required for SPEN binding to XIST A-repeat RNA. (PMID:38164599)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	spen	ENSDARG00000074245
danio_rerio	SPEN	ENSDARG00000074332
mus_musculus	Spen	ENSMUSG00000040761
rattus_norvegicus	Spen	ENSRNOG00000033556
drosophila_melanogaster	spen	FBGN0016977

Paralogs (7): SFPQ (ENSG00000116560), PSPC1 (ENSG00000121390), NONO (ENSG00000147140), RAVER1 (ENSG00000161847), RAVER2 (ENSG00000162437), RBM15 (ENSG00000162775), RBM15B (ENSG00000259956)

Protein

Protein identifiers

Msx2-interacting protein — Q96T58 (reviewed: Q96T58)

Alternative names: SMART/HDAC1-associated repressor protein, SPEN homolog

All UniProt accessions (5): Q96T58, A0A669KB49, A0A994J7B7, F6WRY4, H0Y5U7

UniProt curated annotations — full annotation on UniProt →

Function. May serve as a nuclear matrix platform that organizes and integrates transcriptional responses. In osteoblasts, supports transcription activation: synergizes with RUNX2 to enhance FGFR2-mediated activation of the osteocalcin FGF-responsive element (OCFRE). Has also been shown to be an essential corepressor protein, which probably regulates different key pathways such as the Notch pathway. Negative regulator of the Notch pathway via its interaction with RBPSUH, which prevents the association between NOTCH1 and RBPSUH, and therefore suppresses the transactivation activity of Notch signaling. Blocks the differentiation of precursor B-cells into marginal zone B-cells. Probably represses transcription via the recruitment of large complexes containing histone deacetylase proteins. May bind both to DNA and RNA.

Subunit / interactions. Interacts with MSX2 and HIPK3. Interacts with NCOR2, HDAC1, HDAC2, RBBP4, MBD3 and MTA1L1. Interacts with RBPSUH; this interaction may prevent the interaction between RBPSUH and NOTCH1. Interacts with the nuclear receptors RAR and PPARD. Interacts with RAR in absence of ligand. Binds to the steroid receptor RNA coactivator SRA. (Microbial infection) Interacts with Epstein-Barr virus BSFL2/BMLF1.

Subcellular location. Nucleus.

Tissue specificity. Expressed at high level in brain, testis, spleen and thymus. Expressed at intermediate level in kidney, liver, mammary gland and skin.

Disease relevance. Radio-Tartaglia syndrome (RATARS) [MIM:619312] An autosomal dominant neurodevelopmental disorder characterized by global developmental delay, hypotonia, mild motor difficulties, impaired intellectual development, speech delay, craniofacial dysmorphism, and variable behavioral abnormalities. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The RID domain mediates the interaction with nuclear receptors. The SPOC domain, which mediates the interaction with NCOR2, is essential for the repressive activity.

Induction. By 17-beta-estradiol.

Similarity. Belongs to the RRM Spen family.

RefSeq proteins (1): NP_055816* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000504	RRM_dom	Domain
IPR010912	SPOC_met	Domain
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR012921	SPOC_C	Domain
IPR016194	SPOC-like_C_dom_sf	Homologous_superfamily
IPR034172	SHARP_RRM1	Domain
IPR034173	SHARP_RRM2	Domain
IPR034174	SHARP_RRM3	Domain
IPR034175	SHARP_RRM4	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily
IPR049093	MINT_RID	Domain
IPR049094	MINT_RAM7	Domain
IPR049095	MINT_MID	Domain

Pfam: PF00076, PF07744, PF20808, PF20809, PF20810

UniProt features (199 total): modified residue 55, compositionally biased region 43, region of interest 22, strand 22, sequence variant 18, helix 18, coiled-coil region 7, domain 6, turn 5, chain 1, sequence conflict 1, DNA-binding region 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
7Z1K	X-RAY DIFFRACTION	1.55
1OW1	X-RAY DIFFRACTION	1.8
4P6Q	X-RAY DIFFRACTION	2
2RT5	SOLUTION NMR

Predicted structure (AlphaFold)

No AlphaFold model available for Q96T58 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

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 (55): 1261, 1268, 1278, 1283, 1287, 1333, 1380, 1382, 1439, 1441, 1619, 1633, 1826, 1897, 1918, 1947, 2101, 2120, 2126, 2159 …

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-9013422	RHOBTB1 GTPase cycle
R-HSA-162582	Signal Transduction
R-HSA-194315	Signaling by Rho GTPases
R-HSA-9012999	RHO GTPase cycle
R-HSA-9706574	RHOBTB GTPase Cycle
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 530 (showing top): AHRARNT_01, TGGTGCT_MIR29A_MIR29B_MIR29C, YAGI_AML_WITH_INV_16_TRANSLOCATION, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, MITSIADES_RESPONSE_TO_APLIDIN_DN, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GGGTGGRR_PAX4_03, GOBP_POSITIVE_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, RODRIGUES_NTN1_TARGETS_DN, NFKB_Q6, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, CATTTCA_MIR203

GO Biological Process (8): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of transcription by RNA polymerase II (GO:0006357), Notch signaling pathway (GO:0007219), regulatory ncRNA-mediated heterochromatin formation (GO:0031048), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of neurogenesis (GO:0050769), random inactivation of X chromosome (GO:0060816), negative regulation of macromolecule biosynthetic process (GO:0010558)

GO Molecular Function (7): DNA binding (GO:0003677), transcription corepressor activity (GO:0003714), RNA binding (GO:0003723), mRNA binding (GO:0003729), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), nucleic acid binding (GO:0003676), protein binding (GO:0005515)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription repressor complex (GO:0017053), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
RHOBTB GTPase Cycle	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Signaling by Rho GTPases	1
RHO GTPase cycle	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transcription by RNA polymerase II	2
negative regulation of DNA-templated transcription	2
regulation of DNA-templated transcription	2
nucleic acid binding	2
binding	2
regulation of transcription by RNA polymerase II	1
cell surface receptor signaling pathway	1
regulatory ncRNA-mediated gene silencing	1
heterochromatin formation	1
DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
positive regulation of cell development	1
neurogenesis	1
regulation of neurogenesis	1
positive regulation of nervous system development	1
dosage compensation by inactivation of X chromosome	1
macromolecule biosynthetic process	1
negative regulation of biosynthetic process	1
regulation of macromolecule biosynthetic process	1
negative regulation of macromolecule metabolic process	1
transcription coregulator activity	1
RNA binding	1
DNA-binding transcription factor binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
transcription regulator complex	1
extracellular vesicle	1

Protein interactions and networks

STRING

1536 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPEN	NCOR2	Q9Y618	931
SPEN	MSX2	P35548	887
SPEN	NCOR1	O75376	845
SPEN	RBPJ	Q06330	834
SPEN	NOTCH1	P46531	775
SPEN	CIZ1	Q9ULV3	668
SPEN	HDAC1	Q13547	640
SPEN	CTBP1	Q13363	622
SPEN	MAML2	Q8IZL2	615
SPEN	MAML3	Q96JK9	615
SPEN	MAML1	Q92585	612
SPEN	HNRNPK	P61978	607
SPEN	WTAP	Q15007	605
SPEN	TBL1XR1	Q9BZK7	573
SPEN	CIRSR	Q86X95	560

IntAct

129 interactions, top by confidence:

A	B	Type	Score
RBPJ	NOTCH1	psi-mi:“MI:0914”(association)	0.910
MED23	MED19	psi-mi:“MI:2364”(proximity)	0.770
HSPA8	GAK	psi-mi:“MI:0914”(association)	0.760
CCNC	MED14	psi-mi:“MI:0914”(association)	0.740
RBPJ	SPEN	psi-mi:“MI:0407”(direct interaction)	0.690
CAMKV	AP3B1	psi-mi:“MI:0914”(association)	0.640
SPEN	NCOR2	psi-mi:“MI:0407”(direct interaction)	0.620
SPEN	CRK	psi-mi:“MI:0915”(physical association)	0.610
CRK	SPEN	psi-mi:“MI:0407”(direct interaction)	0.610
PIP4K2A	AP3B1	psi-mi:“MI:0914”(association)	0.530
TRIML2	SRGAP2	psi-mi:“MI:0914”(association)	0.530
FHL2	CNOT1	psi-mi:“MI:0914”(association)	0.530
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
ZC3H18	AQR	psi-mi:“MI:0914”(association)	0.530
BAG4	DNAJC13	psi-mi:“MI:0914”(association)	0.530
DAXX	TNRC18	psi-mi:“MI:0914”(association)	0.530
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
ITCH	SPEN	psi-mi:“MI:0407”(direct interaction)	0.440
SPEN	GRB2	psi-mi:“MI:0915”(physical association)	0.400
SPEN	NCK1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (203): SPEN (Affinity Capture-MS), SPEN (Affinity Capture-MS), SPEN (Affinity Capture-MS), SPEN (Affinity Capture-MS), SPEN (Affinity Capture-MS), SPEN (Affinity Capture-MS), SPEN (Affinity Capture-MS), SPEN (Proximity Label-MS), SPEN (Affinity Capture-MS), SPEN (Biochemical Activity), SPEN (Biochemical Activity), SPEN (Proximity Label-MS), SPEN (Affinity Capture-MS), SPEN (Affinity Capture-MS), SPEN (Affinity Capture-MS)

ESM2 similar proteins: A1YFA7, A2T806, B0BN49, E1BB52, E9Q5K9, F1Q8W0, F4I2J8, F4JCU0, O60828, O74418, P0C196, P0CO16, P0CO17, P30651, P97868, Q10B98, Q14004, Q2HJC9, Q3KPW4, Q4IL82, Q4KLN7, Q4P4G8, Q4PB36, Q4PGL2, Q4V8I5, Q502P0, Q5AQ12, Q5F4A9, Q5RAA7, Q5U317, Q5XJD3, Q62504, Q66PJ3, Q6AXY7, Q6C1V6, Q6CEK8, Q6PCT5, Q6UN15, Q7Z6E9, Q80SY5

Diamond homologs: A0A0D1DZT6, A2RVS6, A5A6M3, D4AE41, F4JHI7, G3V6S8, O22315, O22703, O35326, O75494, O81127, O93235, P19682, P26686, P28644, P30352, P33240, P38159, P60824, P60825, P60826, P78814, P84103, P84104, P84586, P92964, Q01130, Q02427, Q04836, Q06AT9, Q07955, Q08170, Q09167, Q0VCY7, Q10021, Q13242, Q13243, Q13247, Q14011, Q16629

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
NCOR2	up-regulates	SPEN	binding
RBBP8	down-regulates	SPEN	binding
MSX2	up-regulates	SPEN	binding
PAK1	“down-regulates activity”	SPEN	phosphorylation
SPEN	down-regulates	RBPJ	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 145 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
Downstream signal transduction	6	23.8×	1e-05
RHOU GTPase cycle	6	17.4×	6e-05
mRNA 3’-end processing	8	16.4×	2e-06
Signaling by FGFR1 in disease	5	15.2×	7e-04
mRNA Splicing	13	14.9×	4e-10
RNA Polymerase II Transcription Termination	6	13.7×	2e-04
Processing of Capped Intron-Containing Pre-mRNA	16	13.7×	8e-12
mRNA Polyadenylation	14	12.8×	4e-10

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of mRNA splicing, via spliceosome	6	35.9×	3e-06
regulation of alternative mRNA splicing, via spliceosome	6	11.4×	2e-03
mRNA splicing, via spliceosome	15	10.7×	1e-08
RNA polymerase II preinitiation complex assembly	5	10.6×	7e-03
somatic stem cell population maintenance	5	9.7×	9e-03
mRNA processing	14	8.6×	3e-07
response to endoplasmic reticulum stress	6	7.8×	8e-03
RNA splicing	10	6.9×	4e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 11 cancer types — AML, BRCA, CCRCC, CESC, CLLSLL, DLBCLNOS, LUAD, MLYM, NPC, PRAD, SACA.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	64
Likely pathogenic	36
Uncertain significance	582
Likely benign	200
Benign	37

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1223225	NM_015001.3(SPEN):c.6364G>T (p.Glu2122Ter)	Pathogenic
1301851	NM_015001.3(SPEN):c.7144C>T (p.Gln2382Ter)	Pathogenic
1301995	NM_015001.3(SPEN):c.4345G>T (p.Glu1449Ter)	Pathogenic
1329951	NM_015001.3(SPEN):c.2104C>T (p.Arg702Ter)	Pathogenic
1342038	NM_015001.3(SPEN):c.4408C>T (p.Arg1470Ter)	Pathogenic
1700179	NM_015001.3(SPEN):c.6006dup (p.Glu2003Ter)	Pathogenic
1707514	NM_015001.3(SPEN):c.4943_4944insTA (p.Glu1648fs)	Pathogenic
1708238	NM_015001.3(SPEN):c.4828C>T (p.Gln1610Ter)	Pathogenic
1709827	NM_015001.3(SPEN):c.7464dup (p.Ile2489fs)	Pathogenic
1801743	NM_015001.3(SPEN):c.5197G>A (p.Ala1733Thr)	Pathogenic
1805886	NM_015001.3(SPEN):c.922C>T (p.Arg308Ter)	Pathogenic
2223587	NM_015001.3(SPEN):c.8732del (p.Lys2911fs)	Pathogenic
2391426	NM_015001.3(SPEN):c.373C>T (p.Arg125Ter)	Pathogenic
2430170	NM_015001.3(SPEN):c.6925dup (p.Ser2309fs)	Pathogenic
2473706	NM_015001.3(SPEN):c.3721C>T (p.Arg1241Ter)	Pathogenic
2573924	NM_015001.3(SPEN):c.6307del (p.Arg2103fs)	Pathogenic
2637757	NM_015001.3(SPEN):c.9008C>A (p.Ser3003Ter)	Pathogenic
2691008	NM_015001.3(SPEN):c.6164del (p.Pro2055fs)	Pathogenic
3026939	NM_015001.3(SPEN):c.3541C>T (p.Gln1181Ter)	Pathogenic
3067573	NM_015001.3(SPEN):c.8819_8820del (p.Pro2940fs)	Pathogenic
3168943	NM_015001.3(SPEN):c.6061del (p.Gln2020_Ile2021insTer)	Pathogenic
3337659	NM_015001.3(SPEN):c.8406_8407del (p.Ala2804fs)	Pathogenic
3358998	NM_015001.3(SPEN):c.3682_3686del (p.Lys1228fs)	Pathogenic
3358999	NM_015001.3(SPEN):c.9031C>T (p.Arg3011Ter)	Pathogenic
3363187	NM_015001.3(SPEN):c.10026+1G>T	Pathogenic
3366955	NM_015001.3(SPEN):c.7115_7116del (p.Gly2372fs)	Pathogenic
3448407	NM_015001.3(SPEN):c.5021_5022del (p.Val1674fs)	Pathogenic
3800617	NM_015001.3(SPEN):c.10525_10528del (p.Trp3509fs)	Pathogenic
4056835	NM_015001.3(SPEN):c.4441_4444del (p.Glu1481fs)	Pathogenic
4070284	NM_015001.3(SPEN):c.598C>T (p.Arg200Ter)	Pathogenic

SpliceAI

2819 predictions. Top by Δscore:

Variant	Effect	Δscore
1:15872812:CCAG:C	acceptor_loss	1.0000
1:15872813:CAGA:C	acceptor_loss	1.0000
1:15872814:A:AG	acceptor_gain	1.0000
1:15872815:G:GA	acceptor_gain	1.0000
1:15872815:G:GT	acceptor_loss	1.0000
1:15872815:GA:G	acceptor_gain	1.0000
1:15872815:GAT:G	acceptor_gain	1.0000
1:15872815:GATAT:G	acceptor_gain	1.0000
1:15876675:ACAGG:A	donor_loss	1.0000
1:15876678:GGT:G	donor_loss	1.0000
1:15876679:GTA:G	donor_loss	1.0000
1:15876680:T:A	donor_loss	1.0000
1:15900593:G:GT	donor_gain	1.0000
1:15909315:TTGCA:T	acceptor_loss	1.0000
1:15909316:T:A	acceptor_gain	1.0000
1:15909316:TGCA:T	acceptor_loss	1.0000
1:15909318:CAG:C	acceptor_loss	1.0000
1:15909319:A:AC	acceptor_loss	1.0000
1:15909319:A:AG	acceptor_gain	1.0000
1:15909320:G:GT	acceptor_gain	1.0000
1:15909320:GC:G	acceptor_gain	1.0000
1:15909320:GCA:G	acceptor_gain	1.0000
1:15909320:GCAG:G	acceptor_loss	1.0000
1:15909320:GCAGT:G	acceptor_gain	1.0000
1:15909478:ACAG:A	donor_loss	1.0000
1:15909479:CAGGT:C	donor_loss	1.0000
1:15909480:AGGTA:A	donor_loss	1.0000
1:15909481:GGT:G	donor_loss	1.0000
1:15911090:T:TA	acceptor_gain	1.0000
1:15911091:G:A	acceptor_gain	1.0000

AlphaMissense

23861 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:15848074:C:T	R3W	1.000
1:15848077:G:A	E4K	1.000
1:15848078:A:T	E4V	1.000
1:15848081:C:T	T5I	1.000
1:15848083:A:T	R6W	1.000
1:15848084:G:C	R6T	1.000
1:15848084:G:T	R6M	1.000
1:15848085:G:C	R6S	1.000
1:15848085:G:T	R6S	1.000
1:15848086:C:G	H7D	1.000
1:15848090:T:A	L8H	1.000
1:15848090:T:C	L8P	1.000
1:15848090:T:G	L8R	1.000
1:15848092:T:A	W9R	1.000
1:15848092:T:C	W9R	1.000
1:15848093:G:C	W9S	1.000
1:15848094:G:C	W9C	1.000
1:15848094:G:T	W9C	1.000
1:15848096:T:A	V10E	1.000
1:15848098:G:C	G11R	1.000
1:15848098:G:T	G11C	1.000
1:15848099:G:A	G11D	1.000
1:15848099:G:T	G11V	1.000
1:15848103:C:A	N12K	1.000
1:15848103:C:G	N12K	1.000
1:15848105:T:C	L13S	1.000
1:15848132:T:A	I22N	1.000
1:15848132:T:G	I22S	1.000
1:15848143:T:C	F26L	1.000
1:15848144:T:C	F26S	1.000

dbSNP variants (sampled 300 via entrez): RS1000068840 (1:15859570 C>T), RS1000071623 (1:15921063 C>T), RS1000075906 (1:15865278 C>G), RS1000099383 (1:15925589 A>G), RS1000113303 (1:15857960 T>A), RS1000126969 (1:15907680 C>T), RS1000169117 (1:15853254 A>G), RS1000176212 (1:15904690 T>G), RS1000185360 (1:15869634 A>C,G), RS1000225267 (1:15895246 A>G), RS1000283303 (1:15901487 A>C), RS1000310700 (1:15907388 A>G), RS1000320835 (1:15939894 C>A,T), RS1000335350 (1:15889668 G>C,T), RS1000392062 (1:15863268 A>C,G)

Disease associations

OMIM: gene MIM:613484 | disease phenotypes: MIM:619312

GenCC curated gene-disease

Disease	Classification	Inheritance
Radio-Tartaglia syndrome	Definitive	Autosomal dominant
complex neurodevelopmental disorder	No Known Disease Relationship	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Radio-Tartaglia syndrome	Definitive	AD

Mondo (5): Radio-Tartaglia syndrome (MONDO:0859143), myoepithelial tumor (MONDO:0002380), breast ductal adenocarcinoma (MONDO:0005590), autism spectrum disorder (MONDO:0005258), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (2): Neurodevelopmental delay-congenital heart defects-intellectual disability syndrome (Orphanet:662234), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

155 total (30 of 155 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000055	Abnormal female external genitalia morphology
HP:0000077	Abnormality of the kidney
HP:0000107	Renal cyst
HP:0000126	Hydronephrosis
HP:0000135	Hypogonadism
HP:0000154	Wide mouth
HP:0000160	Narrow mouth
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000270	Delayed cranial suture closure
HP:0000276	Long face
HP:0000278	Retrognathia
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000294	Low anterior hairline
HP:0000300	Oval face
HP:0000307	Pointed chin
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000341	Narrow forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST006288_595	Heel bone mineral density	2.000000e-14
GCST006288_702	Heel bone mineral density	3.000000e-07
GCST006288_97	Heel bone mineral density	5.000000e-09
GCST006956_22	Erectile dysfunction	3.000000e-06
GCST010083_93	Hemoglobin levels	3.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0004509	hemoglobin measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390
D009208	Myoepithelioma	C04.557.435.585

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724626 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.16	IC50	70	nM	MOLIBRESIB

PubChem BioAssay actives

1 with measured affinity, of 6 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	2178643: Inhibition of SPEN (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.0700	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Formaldehyde	decreases expression, increases expression	3
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	3
sodium arsenite	increases abundance, increases expression, decreases expression	2
Arsenic	affects methylation, decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
6,7-dimethoxy-2-(pyrrolidin-1-yl)-N-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	decreases sumoylation	1
dicrotophos	increases expression	1
testosterone enanthate	increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
arsenite	affects binding, decreases reaction	1
coumarin	affects phosphorylation	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases expression	1
beta-methylcholine	affects expression	1
cyclic 3’,5’-uridine monophosphate	affects binding	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
enzalutamide	affects expression	1
bisphenol S	decreases methylation	1
picoxystrobin	decreases expression	1
Temozolomide	affects response to substance	1
Vorinostat	decreases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Caffeine	affects phosphorylation	1
Carmustine	affects response to substance	1
Cisplatin	decreases expression	1
Doxorubicin	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
CHEMBL5697373	Binding	Inhibition of SPEN (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

Cellosaurus cell lines

9 cell lines: 5 induced pluripotent stem cell, 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1372	LC-1F	Cancer cell line	Male
CVCL_3008	LC-1/sq	Cancer cell line	Male
CVCL_5480	LC-1/sq-SF	Cancer cell line	Male
CVCL_RK73	SU042-1	Induced pluripotent stem cell	Female
CVCL_RK74	SU042-2	Induced pluripotent stem cell	Female
CVCL_RK75	SU042-3	Induced pluripotent stem cell	Female
CVCL_RK76	SU042-4	Induced pluripotent stem cell	Female
CVCL_RK77	SU042-5	Induced pluripotent stem cell	Female
CVCL_ZE82	BMA19	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	PHASE3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD