SF3B4

Summary

SF3B4 (splicing factor 3b subunit 4, HGNC:10771) is a protein-coding gene on chromosome 1q21.2, encoding Splicing factor 3B subunit 4 (Q15427). Component of the 17S U2 SnRNP complex of the spliceosome, a large ribonucleoprotein complex that removes introns from transcribed pre-mRNAs. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines) and haploinsufficient (ClinGen: sufficient evidence).

This gene encodes one of four subunits of the splicing factor 3B. The protein encoded by this gene cross-links to a region in the pre-mRNA immediately upstream of the branchpoint sequence in pre-mRNA in the prespliceosomal complex A. It also may be involved in the assembly of the B, C and E spliceosomal complexes. In addition to RNA-binding activity, this protein interacts directly and highly specifically with subunit 2 of the splicing factor 3B. This protein contains two N-terminal RNA-recognition motifs (RRMs), consistent with the observation that it binds directly to pre-mRNA.

Source: NCBI Gene 10262 — RefSeq curated summary.

At a glance

• Gene–disease (curated): SF3B4-related acrofacial dysostosis (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 25
• Clinical variants (ClinVar): 153 total — 38 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 110
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_005850

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10771
Approved symbol	SF3B4
Name	splicing factor 3b subunit 4
Location	1q21.2
Locus type	gene with protein product
Status	Approved
Aliases	SAP49, SF3b49, Hsh49
Ensembl gene	ENSG00000143368
Ensembl biotype	protein_coding
OMIM	605593
Entrez	10262

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000271628, ENST00000457312, ENST00000940764, ENST00000940765

RefSeq mRNA: 1 — MANE Select: NM_005850 NM_005850

CCDS: CCDS72900

Canonical transcript exons

ENST00000271628 — 6 exons

Exon	Start	End
ENSE00000959613	149926376	149926918
ENSE00001043702	149925836	149926042
ENSE00001043720	149923841	149924014
ENSE00001321984	149923317	149923729
ENSE00001360125	149927726	149927803
ENSE00003580666	149927166	149927294

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 97.59.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 83.5235 / max 443.1959, expressed in 1825 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14270	82.0351	1825
14271	0.8662	393
14272	0.6222	302

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	97.59	gold quality
transverse colon	UBERON:0001157	96.64	gold quality
granulocyte	CL:0000094	96.15	gold quality
endometrium epithelium	UBERON:0004811	96.11	gold quality
left uterine tube	UBERON:0001303	95.75	gold quality
left testis	UBERON:0004533	95.67	gold quality
right testis	UBERON:0004534	95.67	gold quality
popliteal artery	UBERON:0002250	95.55	gold quality
tibial artery	UBERON:0007610	95.55	gold quality
monocyte	CL:0000576	95.48	gold quality
leukocyte	CL:0000738	95.37	gold quality
right coronary artery	UBERON:0001625	95.32	gold quality
mononuclear cell	CL:0000842	95.30	gold quality
aorta	UBERON:0000947	95.24	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.07	gold quality
descending thoracic aorta	UBERON:0002345	95.04	gold quality
thoracic aorta	UBERON:0001515	95.01	gold quality
right ovary	UBERON:0002118	94.99	gold quality
ascending aorta	UBERON:0001496	94.91	gold quality
skin of leg	UBERON:0001511	94.87	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.82	gold quality
oocyte	CL:0000023	94.81	gold quality
body of uterus	UBERON:0009853	94.70	gold quality
mucosa of stomach	UBERON:0001199	94.68	gold quality
right uterine tube	UBERON:0001302	94.68	gold quality
ectocervix	UBERON:0012249	94.61	gold quality
skin of abdomen	UBERON:0001416	94.55	gold quality
stromal cell of endometrium	CL:0002255	94.52	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.35	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.33	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-3929	no	425.42
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

27 targeting SF3B4, 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-4533	100.00	69.48	2758
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-379-3P	99.69	69.60	1524
HSA-MIR-411-3P	99.69	69.63	1524
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-133A-3P	99.27	71.53	1270
HSA-MIR-133B	99.27	71.53	1270
HSA-MIR-194-5P	99.01	69.65	1465
HSA-MIR-509-3P	98.12	67.25	612
HSA-MIR-5681A	97.99	67.17	1658
HSA-MIR-10526-3P	97.86	64.97	1342
HSA-MIR-510-5P	97.66	65.82	916
HSA-MIR-5699-5P	97.36	67.03	1014
HSA-MIR-875-5P	96.74	66.48	579

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 27)

• determined the three-dimensional structure of the human SF3b complex by single-particle electron cryomicroscopy at a resolution of less than 10 angstroms, allowing identification of protein domains with known structural folds (PMID:12738865)
• SAP49 is regulated by the BMPR-IA tumor suppressor (PMID:15351706)
• SF3b4, known to be localized in the nucleus and involved in RNA splicing, binds BMPR-IA and specifically inhibits BMP-mediated osteochondral cell differentiation (PMID:17513295)
• Inhibiting the induction of two proteins involved in two of the most significantly upregulated cellular processes, ribosome biogenesis (eIF6) and hnRNA splicing (SF3B2/SF3B4), showed that human T cells can enter the cell cycle without growing in size. (PMID:22415777)
• These results suggest that most cases of Nager syndrome are caused by haploinsufficiency of SF3B4. (PMID:22541558)
• SF3B4 mutation is associated with Nager syndrome. (PMID:23568615)
• SF3B4 haploinsufficiency confirmed as the major cause of Nager syndrome. (PMID:24003905)
• High SF3B4 expression is associated with hepatocellular carcinoma. (PMID:25731616)
• Overexpression of SF3B4, that is due to DNA copy number increase, is suggested to play a role in progression of HCC (PMID:27127115)
• SF3B4 mutations identified in Rodriguez Acrofacial Dysostosis patients disrupted mRNA splicing and reduced expression of DLX5, DLX6, SOX9, and SOX6 in cultured chondrocytes. (PMID:27622494)
• We identified two heterozygous frameshift mutations in the SF3B4 gene in three of the four fetuses investigated. The observed mutation was apparently de novo in one fetus for whom parental DNA was available. Thus, Acrofacial dysostosis syndrome of Rodriguez is an autosomal dominant condition and the recurrences identified in the initial report were likely due to gonadal mosaicism. (PMID:27642715)
• Chemical shift mapping showed that the SF3b145 fragment spanning residues 598-631 interacts with SF3b49 RRM1, which adopts a canonical RRM fold with a topology of beta1-alpha1-beta2-beta3-alpha2-beta4. (PMID:27862552)
• A novel synonymous variant within exon 3 of the SF3B4 gene was identified in three members of a family affected by Nager syndrome. (PMID:27966544)
• splicing factor 3b subunit 4 was found to inhibit the activity of signal transducer and activator of transcription 3 signaling via downregulating the phosphorylation of signal transducer and activator of transcription 3 on a tyrosine residue at position 705. (PMID:28351319)
• SF3B4 indicates early-stage hepatocellular carcinoma in precancerous lesions, and also functions as an early-stage driver in the development of liver cancer. (PMID:29397868)
• MiRNA-133b not only regulates the endogenous expression of SF3B4 but also modulates SF3B4-mediated AS efficiency in HCC tumorigenesis. (PMID:30391496)
• A unique system comprising a p180-SF3b4-mRNA complex facilitates the selective assembly of polyribosomes on the endoplasmic reticulum. (PMID:31004060)
• Publicly available data from paired normal and tumor tissues in hepatocellular carcinoma (HCC) and results from patients with HCC suggest that SRSF3 and SF3B4 possess an inverse relationship. SRSF3 is a key molecule for determining SF3B4 levels in HCC cells (PMID:32234894)
• Nager syndrome in patient lacking acrofacial dysostosis: Expanding the phenotypic spectrum of SF3B4-related disease. (PMID:33559401)
• Enabled homolog (ENAH) regulated by RNA binding protein splicing factor 3b subunit 4 (SF3B4) exacerbates the proliferation, invasion and migration of hepatocellular carcinoma cells via Notch signaling pathway. (PMID:35030977)
• SF3B4 promotes ovarian cancer progression by regulating alternative splicing of RAD52. (PMID:35210412)
• The Role of Splicing Factor SF3B4 in Congenital Diseases and Tumors. (PMID:35220998)
• SF3B4 Depletion Retards the Growth of A549 Non-Small Cell Lung Cancer Cells via UBE4B-Mediated Regulation of p53/p21 and p27 Expression. (PMID:35996826)
• SF3B4 promotes Twist1 expression and clear cell renal cell carcinoma progression by facilitating the export of KLF 16 mRNA from the nucleus to the cytoplasm. (PMID:36639679)
• SETDB1 promotes progression through upregulation of SF3B4 expression and regulates the immunity in ovarian cancer. (PMID:38317200)
• METTL3-mediated the m6A modification of SF3B4 facilitates the development of non-small cell lung cancer by enhancing LSM4 expression. (PMID:38462740)
• SF3B4 Regulates Cellular Senescence and Suppresses Therapy-induced Senescence of Cancer Cells. (PMID:39467623)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	sf3b4	ENSDARG00000018574
mus_musculus	Sf3b4	ENSMUSG00000068856
rattus_norvegicus	Sf3b4	ENSRNOG00000021181
drosophila_melanogaster	Spx	FBGN0015818
caenorhabditis_elegans		WBGENE00004723

Paralogs (24): ELAVL1 (ENSG00000066044), PABPC1 (ENSG00000070756), RBMS2 (ENSG00000076067), PABPC4 (ENSG00000090621), PABPC1L (ENSG00000101104), ELAVL2 (ENSG00000107105), RBM24 (ENSG00000112183), TARDBP (ENSG00000120948), HNRNPR (ENSG00000125944), RBM38 (ENSG00000132819), SYNCRIP (ENSG00000135316), RBMS3 (ENSG00000144642), PABPC3 (ENSG00000151846), RBMS1 (ENSG00000153250), RBM45 (ENSG00000155636), ELAVL4 (ENSG00000162374), PABPC5 (ENSG00000174740), PUF60 (ENSG00000179950), PABPC1L2B (ENSG00000184388), PABPC1L2A (ENSG00000186288), RBM34 (ENSG00000188739), ELAVL3 (ENSG00000196361), RBM14 (ENSG00000239306), PABPC4L (ENSG00000254535)

Protein

Protein identifiers

Splicing factor 3B subunit 4 — Q15427 (reviewed: Q15427)

Alternative names: Pre-mRNA-splicing factor SF3b 49 kDa subunit, Spliceosome-associated protein 49

All UniProt accessions (2): Q15427, Q5SZ64

UniProt curated annotations — full annotation on UniProt →

Function. Component of the 17S U2 SnRNP complex of the spliceosome, a large ribonucleoprotein complex that removes introns from transcribed pre-mRNAs. The 17S U2 SnRNP complex (1) directly participates in early spliceosome assembly and (2) mediates recognition of the intron branch site during pre-mRNA splicing by promoting the selection of the pre-mRNA branch-site adenosine, the nucleophile for the first step of splicing. Within the 17S U2 SnRNP complex, SF3B4 is part of the SF3B subcomplex, which is required for ‘A’ complex assembly formed by the stable binding of U2 snRNP to the branchpoint sequence in pre-mRNA. Sequence independent binding of SF3A and SF3B subcomplexes upstream of the branch site is essential, it may anchor U2 snRNP to the pre-mRNA. May also be involved in the assembly of the ‘E’ complex. Also acts as a component of the minor spliceosome, which is involved in the splicing of U12-type introns in pre-mRNAs.

Subunit / interactions. Component of the 17S U2 SnRNP complex, a ribonucleoprotein complex that contains small nuclear RNA (snRNA) U2 and a number of specific proteins. Part of the SF3B subcomplex of the 17S U2 SnRNP complex. SF3B associates with the splicing subcomplex SF3A and a 12S RNA unit to form the U2 small nuclear ribonucleoproteins complex (U2 snRNP). SF3B4 has been found in complex spliceosome ‘B’ and ‘C’ as well. Component of the minor (U12-type spliceosome) spliceosome. Found in a complex with PRMT9, SF3B2 and SF3B4.

Subcellular location. Nucleus.

Disease relevance. Acrofacial dysostosis 1, Nager type (AFD1) [MIM:154400] A form of acrofacial dysostosis, a group of disorders which are characterized by malformation of the craniofacial skeleton and the limbs. The major facial features of AFD1 include downslanted palpebral fissures, midface retrusion, and micrognathia, the latter of which often requires the placement of a tracheostomy in early childhood. Limb defects typically involve the anterior (radial) elements of the upper limbs and manifest as small or absent thumbs, triphalangeal thumbs, radial hyoplasia or aplasia, and radioulnar synostosis. Phocomelia of the upper limbs and, occasionally, lower-limb defects have also been reported. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the SF3B4 family.

RefSeq proteins (1): NP_005841* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000504	RRM_dom	Domain
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR034158	SF3B4_RRM1	Domain
IPR034159	SF3B4_RRM2	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily
IPR052084	SF3B4_spliceosome_assoc	Family

Pfam: PF00076

UniProt features (35 total): strand 14, compositionally biased region 6, helix 5, turn 3, modified residue 2, domain 2, initiator methionine 1, chain 1, region of interest 1

Structure

Experimental structures (PDB)

45 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
7EVO	ELECTRON MICROSCOPY	2.5
8H6L	ELECTRON MICROSCOPY	2.6
8H6K	ELECTRON MICROSCOPY	2.7
8HK1	ELECTRON MICROSCOPY	2.7
7DVQ	ELECTRON MICROSCOPY	2.89
7VPX	ELECTRON MICROSCOPY	3
8I0R	ELECTRON MICROSCOPY	3
8I0T	ELECTRON MICROSCOPY	3
8I0V	ELECTRON MICROSCOPY	3
7ONB	ELECTRON MICROSCOPY	3.1
7QTT	ELECTRON MICROSCOPY	3.1
8H6E	ELECTRON MICROSCOPY	3.2
8H6J	ELECTRON MICROSCOPY	3.25
9ZE2	ELECTRON MICROSCOPY	3.26
6QX9	ELECTRON MICROSCOPY	3.28
8I0U	ELECTRON MICROSCOPY	3.3
8I0P	ELECTRON MICROSCOPY	3.4
9ZE0	ELECTRON MICROSCOPY	3.43
9ZEC	ELECTRON MICROSCOPY	3.61
6AHD	ELECTRON MICROSCOPY	3.8
9ZE3	ELECTRON MICROSCOPY	3.93
9ZED	ELECTRON MICROSCOPY	3.94
8QZS	ELECTRON MICROSCOPY	4.1
8I0S	ELECTRON MICROSCOPY	4.2
8R09	ELECTRON MICROSCOPY	4.3
8R0B	ELECTRON MICROSCOPY	4.4
7ABH	ELECTRON MICROSCOPY	4.5
8Y7E	ELECTRON MICROSCOPY	4.66
5Z58	ELECTRON MICROSCOPY	4.9
5Z56	ELECTRON MICROSCOPY	5.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15427-F1	74.45	0.38

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 (2): 2, 56

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-72163	mRNA Splicing - Major Pathway
R-HSA-72165	mRNA Splicing - Minor Pathway
R-HSA-9770562	mRNA Polyadenylation
R-HSA-9918481	Dengue Virus-Host Interactions
R-HSA-9943411	CHD1 and CHD2 subfamily
R-HSA-72172	mRNA Splicing
R-HSA-72203	Processing of Capped Intron-Containing Pre-mRNA
R-HSA-8953854	Metabolism of RNA

MSigDB gene sets: 379 (showing top): ENK_UV_RESPONSE_KERATINOCYTE_UP, TGACCTY_ERR1_Q2, PATIL_LIVER_CANCER, ACCAATC_MIR509, REACTOME_MRNA_3_END_PROCESSING, REACTOME_PROCESSING_OF_CAPPED_INTRON_CONTAINING_PRE_MRNA, GOBP_PROTEIN_RNA_COMPLEX_ORGANIZATION, GOBP_RNA_SPLICING, REACTOME_MRNA_SPLICING, DODD_NASOPHARYNGEAL_CARCINOMA_UP, NRF2_01, DOUGLAS_BMI1_TARGETS_UP, GOBP_RIBONUCLEOPROTEIN_COMPLEX_BIOGENESIS, GOBP_SPLICEOSOMAL_SNRNP_ASSEMBLY, REACTOME_METABOLISM_OF_RNA

GO Biological Process (5): RNA splicing, via transesterification reactions (GO:0000375), mRNA splicing, via spliceosome (GO:0000398), mRNA processing (GO:0006397), RNA splicing (GO:0008380), U2-type prespliceosome assembly (GO:1903241)

GO Molecular Function (4): RNA binding (GO:0003723), splicing factor binding (GO:1990935), nucleic acid binding (GO:0003676), protein binding (GO:0005515)

GO Cellular Component (8): nucleus (GO:0005634), nucleoplasm (GO:0005654), spliceosomal complex (GO:0005681), U2-type spliceosomal complex (GO:0005684), U2 snRNP (GO:0005686), U12-type spliceosomal complex (GO:0005689), U2-type precatalytic spliceosome (GO:0071005), precatalytic spliceosome (GO:0071011)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
mRNA Splicing	2
mRNA 3’-end processing	1
Dengue Virus Infection	1
CHD chromatin remodelers	1
Processing of Capped Intron-Containing Pre-mRNA	1
Metabolism of RNA	1

GO top-level categories

Rollup of top GO terms by namespace:

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

Protein interactions and networks

STRING

2172 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SF3B4	SF3B2	Q13435	999
SF3B4	SF3B1	O75533	995
SF3B4	SF3B3	Q15393	995
SF3B4	SF3B5	Q9BWJ5	995
SF3B4	PHF5A	Q7RTV0	994
SF3B4	SF3B6	Q9Y3B4	993
SF3B4	SF3A3	Q12874	931
SF3B4	SNRPC	P09234	866
SF3B4	SF3A2	Q15428	851
SF3B4	EFTUD2	Q15029	803
SF3B4	SF3A1	Q15459	782
SF3B4	TCERG1	O14776	780
SF3B4	SNRPB	P14678	775
SF3B4	SNRPA1	P09661	762
SF3B4	U2AF2	P26368	755

IntAct

286 interactions, top by confidence:

A	B	Type	Score
SF3B2	SF3B4	psi-mi:“MI:0915”(physical association)	0.910
SF3B2	SF3B4	psi-mi:“MI:0914”(association)	0.910
SF3B4	SF3B2	psi-mi:“MI:0915”(physical association)	0.910
RBM10	SF3B4	psi-mi:“MI:0915”(physical association)	0.800
NCK2	SF3B4	psi-mi:“MI:0915”(physical association)	0.780
MAPK9	SF3B4	psi-mi:“MI:0915”(physical association)	0.780
SF3B4	MAPK9	psi-mi:“MI:0915”(physical association)	0.780
SF3B4	NCK2	psi-mi:“MI:0915”(physical association)	0.780
PRMT9	SF3B2	psi-mi:“MI:0914”(association)	0.750
HNRNPUL1	SF3B4	psi-mi:“MI:0915”(physical association)	0.740
SF3B4	TCAF1	psi-mi:“MI:0915”(physical association)	0.740
TCAF1	SF3B4	psi-mi:“MI:0915”(physical association)	0.740
SF3B4	HNRNPUL1	psi-mi:“MI:0915”(physical association)	0.740
CCDC97	SF3B1	psi-mi:“MI:0914”(association)	0.730
PHF5A	SF3B1	psi-mi:“MI:0914”(association)	0.730
CWF19L2	SF3B4	psi-mi:“MI:0915”(physical association)	0.720
SF3B4	BAG3	psi-mi:“MI:0915”(physical association)	0.720
SF3B4	CWF19L2	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (661): SF3B4 (Affinity Capture-MS), SF3B4 (Two-hybrid), SF3B4 (Two-hybrid), SF3B4 (Two-hybrid), SF3B4 (Two-hybrid), SF3B4 (Two-hybrid), SF3B4 (Two-hybrid), SF3B4 (Two-hybrid), SF3B4 (Two-hybrid), BAIAP2 (Two-hybrid), SF3B2 (Two-hybrid), HNRNPUL1 (Two-hybrid), SS18L1 (Two-hybrid), PPP1R16B (Two-hybrid), HSPB7 (Two-hybrid)

ESM2 similar proteins: A7EYK3, A7SEP9, A8NYM5, A8XW44, C0NN85, C3Z1P5, C5XYW4, C5XZK6, C7YRT4, D0NHA2, D3B3B7, D5GDH4, E0VI98, E3KIY6, E3LAN7, E3X5D6, F6HQ26, O43670, P23246, P90815, Q09442, Q0P5D2, Q15427, Q16630, Q16IW3, Q1K7T5, Q1RLC9, Q298E0, Q4N6K2, Q4P2Q5, Q4UJ14, Q4WQM6, Q55A45, Q56XE4, Q5BBX9, Q5KC16, Q5NVH8, Q5R8K4, Q63627, Q6AYL5

Diamond homologs: A0A0D1DWZ5, A0JM51, A1CRM1, A1D4K4, A2A5N3, A2Q848, A3LXL0, A4IIM2, A4QUF0, A5DW14, F4HT49, O04319, O14102, O22173, O57406, O64380, O95319, O97018, P04147, P0CB38, P0CP46, P0CP47, P20965, P21187, P28659, P29558, P31209, P32588, P39697, P42731, P60047, P60048, P60049, P60050, Q08E07, Q09442, Q0CR95, Q0U1G2, Q13310, Q15427

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
SF3B4	“form complex”	SF3b	binding
SF3B4	“form complex”	“U2 snRNP complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 119 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
mRNA Polyadenylation	19	21.1×	4e-18
mRNA Splicing	15	20.9×	4e-14
CHD1 and CHD2 subfamily	15	20.6×	4e-14
Processing of Capped Intron-Containing Pre-mRNA	17	17.7×	8e-15
mRNA Splicing - Minor Pathway	6	17.0×	9e-05
mRNA Splicing - Major Pathway	23	15.9×	4e-19
FCGR3A-mediated phagocytosis	5	11.8×	4e-03
Metabolism of RNA	20	10.6×	1e-13

GO biological processes:

GO term	Partners	Fold	FDR
U2-type prespliceosome assembly	11	67.3×	2e-15
RNA splicing, via transesterification reactions	5	30.6×	7e-05
mRNA splicing, via spliceosome	18	16.2×	1e-14
RNA splicing	13	11.2×	3e-08
mRNA processing	13	10.0×	9e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	38
Likely pathogenic	6
Uncertain significance	46
Likely benign	30
Benign	16

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1027377	NM_005850.5(SF3B4):c.763_781del (p.Pro255fs)	Pathogenic
1323581	NM_005850.5(SF3B4):c.35-1G>A	Pathogenic
1338398	NM_005850.5(SF3B4):c.132del (p.Met44fs)	Pathogenic
1994811	NM_005850.5(SF3B4):c.160C>T (p.Gln54Ter)	Pathogenic
208827	NM_005850.5(SF3B4):c.1252_1258del (p.Leu418fs)	Pathogenic
208828	NM_005850.5(SF3B4):c.1232del (p.Pro411fs)	Pathogenic
208829	NM_005850.5(SF3B4):c.1199del (p.Pro400fs)	Pathogenic
208830	NM_005850.5(SF3B4):c.1148dup (p.His383fs)	Pathogenic
208833	NM_005850.5(SF3B4):c.864del (p.His288fs)	Pathogenic
208834	NM_005850.5(SF3B4):c.836_837insGGGTATG (p.Thr280fs)	Pathogenic
208835	NM_005850.5(SF3B4):c.827dup (p.Ser277fs)	Pathogenic
208836	NM_005850.5(SF3B4):c.796dup (p.Met266fs)	Pathogenic
208837	NM_005850.5(SF3B4):c.769del (p.Ile257fs)	Pathogenic
208838	NM_005850.5(SF3B4):c.661_664dup (p.Asn222fs)	Pathogenic
208839	NM_005850.5(SF3B4):c.625C>T (p.Gln209Ter)	Pathogenic
208840	NM_005850.5(SF3B4):c.452C>A (p.Ser151Ter)	Pathogenic
208841	NM_005850.5(SF3B4):c.88del (p.Trp30fs)	Pathogenic
212156	NM_005850.5(SF3B4):c.1230_1249del (p.Pro411fs)	Pathogenic
212157	NM_005850.5(SF3B4):c.193G>T (p.Glu65Ter)	Pathogenic
212158	NM_005850.5(SF3B4):c.45_46del (p.Tyr16fs)	Pathogenic
212159	NM_005850.5(SF3B4):c.731_743del (p.Pro244fs)	Pathogenic
2430267	NM_005850.5(SF3B4):c.417C>T (p.Gly139=)	Pathogenic
280303	NM_005850.5(SF3B4):c.811del (p.Ala271fs)	Pathogenic
31652	NM_005850.5(SF3B4):c.1147del (p.His383fs)	Pathogenic
31653	NM_005850.5(SF3B4):c.913+1G>A	Pathogenic
3253581	NM_005850.5(SF3B4):c.872C>G (p.Ser291Ter)	Pathogenic
3340592	NM_005850.5(SF3B4):c.737dup (p.Val247fs)	Pathogenic
3363154	NM_005850.5(SF3B4):c.788dup (p.Pro264fs)	Pathogenic
3382165	NM_005850.5(SF3B4):c.512dup (p.Ile172fs)	Pathogenic
3663874	NM_005850.5(SF3B4):c.722del (p.Gly241fs)	Pathogenic

SpliceAI

411 predictions. Top by Δscore:

Variant	Effect	Δscore
1:149923729:CCT:C	acceptor_loss	1.0000
1:149923730:CT:C	acceptor_loss	1.0000
1:149924010:CATCC:C	acceptor_gain	1.0000
1:149924011:ATCC:A	acceptor_gain	1.0000
1:149924012:TCC:T	acceptor_gain	1.0000
1:149924013:CC:C	acceptor_gain	1.0000
1:149924013:CCC:C	acceptor_gain	1.0000
1:149924014:CC:C	acceptor_gain	1.0000
1:149924015:C:CA	acceptor_loss	1.0000
1:149924015:C:CC	acceptor_gain	1.0000
1:149924015:C:T	acceptor_gain	1.0000
1:149924017:A:AC	acceptor_gain	1.0000
1:149924017:A:C	acceptor_gain	1.0000
1:149924023:A:AC	acceptor_gain	1.0000
1:149924028:A:AC	acceptor_gain	1.0000
1:149924028:A:C	acceptor_gain	1.0000
1:149925832:CTAC:C	donor_loss	1.0000
1:149925833:TA:T	donor_loss	1.0000
1:149926038:CATGC:C	acceptor_gain	1.0000
1:149926040:TGC:T	acceptor_gain	1.0000
1:149926042:CC:C	acceptor_loss	1.0000
1:149926371:TTTA:T	donor_loss	1.0000
1:149926373:TA:T	donor_loss	1.0000
1:149926375:C:CA	donor_loss	1.0000
1:149926409:C:CT	donor_gain	1.0000
1:149926914:ATAGC:A	acceptor_gain	1.0000
1:149926915:TAGC:T	acceptor_gain	1.0000
1:149926916:AGC:A	acceptor_gain	1.0000
1:149926917:GC:G	acceptor_gain	1.0000
1:149926917:GCC:G	acceptor_loss	1.0000

AlphaMissense

2728 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:149926449:A:C	F211L	1.000
1:149926449:A:T	F211L	1.000
1:149926450:A:C	F211C	1.000
1:149926450:A:G	F211S	1.000
1:149926451:A:C	F211V	1.000
1:149926451:A:G	F211L	1.000
1:149926451:A:T	F211I	1.000
1:149926460:G:C	H208D	1.000
1:149926493:C:G	A197P	1.000
1:149926495:G:T	A196E	1.000
1:149926496:C:G	A196P	1.000
1:149926496:C:T	A196T	1.000
1:149926498:A:G	L195P	1.000
1:149926498:A:T	L195Q	1.000
1:149926501:A:G	L194P	1.000
1:149926504:C:A	R193L	1.000
1:149926504:C:G	R193P	1.000
1:149926505:G:C	R193G	1.000
1:149926506:T:A	E192D	1.000
1:149926506:T:G	E192D	1.000
1:149926507:T:A	E192V	1.000
1:149926508:C:T	E192K	1.000
1:149926510:G:T	A191D	1.000
1:149926517:A:G	S189P	1.000
1:149926519:C:A	G188V	1.000
1:149926519:C:G	G188A	1.000
1:149926519:C:T	G188D	1.000
1:149926520:C:A	G188C	1.000
1:149926520:C:G	G188R	1.000
1:149926520:C:T	G188S	1.000

dbSNP variants (sampled 300 via entrez): RS1000623324 (1:149929590 T>C,G), RS1000743503 (1:149929236 T>C), RS1001907372 (1:149928480 C>A,G), RS1002256578 (1:149928737 G>A,C,T), RS1003314537 (1:149927545 T>C), RS1005376519 (1:149928703 A>G), RS1006431478 (1:149927498 T>A,C,G), RS1006693610 (1:149927944 G>A,C,T), RS1008116925 (1:149926617 C>G,T), RS1009403690 (1:149925331 T>G), RS1009905990 (1:149922863 G>A), RS1010278955 (1:149927923 G>A,C), RS1011282363 (1:149926578 A>G), RS1012784605 (1:149926123 T>C), RS1014722027 (1:149925339 T>C)

Disease associations

OMIM: gene MIM:605593 | disease phenotypes: MIM:154400, MIM:156500

GenCC curated gene-disease

Disease	Classification	Inheritance
Nager acrofacial dysostosis	Definitive	Autosomal dominant
acrofacial dysostosis Rodriguez type	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
SF3B4-related acrofacial dysostosis	Definitive	AD

Mondo (5): Nager acrofacial dysostosis (MONDO:0007943), SF3B4-related acrofacial dysostosis (MONDO:0800483), Schmid metaphyseal chondrodysplasia (MONDO:0007983), intellectual disability (MONDO:0001071), acrofacial dysostosis Rodriguez type (MONDO:0008714)

Orphanet (3): Nager syndrome (Orphanet:245), Metaphyseal chondrodysplasia, Schmid type (Orphanet:174), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

110 total (30 of 110 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000122	Unilateral renal agenesis
HP:0000130	Abnormality of the uterus
HP:0000154	Wide mouth
HP:0000174	Abnormal palate morphology
HP:0000175	Cleft palate
HP:0000185	Cleft soft palate
HP:0000204	Cleft upper lip
HP:0000211	Trismus
HP:0000220	Velopharyngeal insufficiency
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000272	Malar flattening
HP:0000278	Retrognathia
HP:0000308	Microretrognathia
HP:0000324	Facial asymmetry
HP:0000327	Hypoplasia of the maxilla
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000378	Cupped ear
HP:0000384	Preauricular skin tag
HP:0000402	Stenosis of the external auditory canal
HP:0000405	Conductive hearing impairment
HP:0000413	Atresia of the external auditory canal
HP:0000426	Prominent nasal bridge
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures

GWAS associations

25 associations (top):

Study	Trait	p-value
GCST000175_50	Height	1.000000e-10
GCST000817_106	Height	5.000000e-32
GCST002644_6	Birth length	8.000000e-06
GCST002646_2	Infant length	2.000000e-16
GCST004063_100	Waist circumference adjusted for body mass index	1.000000e-08
GCST004063_108	Waist circumference adjusted for body mass index	1.000000e-13
GCST004063_149	Waist circumference adjusted for body mass index	2.000000e-07
GCST004500_8	Waist circumference adjusted for BMI (adjusted for smoking behaviour)	3.000000e-14
GCST004500_81	Waist circumference adjusted for BMI (adjusted for smoking behaviour)	2.000000e-10
GCST004500_91	Waist circumference adjusted for BMI (adjusted for smoking behaviour)	4.000000e-07
GCST004501_130	Waist circumference adjusted for BMI (joint analysis main effects and smoking interaction)	4.000000e-14
GCST004501_131	Waist circumference adjusted for BMI (joint analysis main effects and smoking interaction)	1.000000e-09
GCST004501_132	Waist circumference adjusted for BMI (joint analysis main effects and smoking interaction)	5.000000e-07
GCST004504_95	Waist circumference adjusted for BMI in non-smokers	2.000000e-07
GCST004504_96	Waist circumference adjusted for BMI in non-smokers	3.000000e-07
GCST004504_97	Waist circumference adjusted for BMI in non-smokers	4.000000e-12
GCST007294_101	Body fat distribution (trunk fat ratio)	2.000000e-87
GCST007294_115	Body fat distribution (trunk fat ratio)	3.000000e-22
GCST007294_154	Body fat distribution (trunk fat ratio)	4.000000e-99
GCST007295_122	Body fat distribution (leg fat ratio)	1.000000e-76
GCST007295_14	Body fat distribution (leg fat ratio)	4.000000e-23
GCST007295_98	Body fat distribution (leg fat ratio)	5.000000e-92
GCST007485_2	Anthropometric traits	1.000000e-85
GCST007490_5	Anthropometric traits (multi-trait analysis)	1.000000e-53
GCST008839_163	Height	6.000000e-39

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0006784	body height at birth
EFO:0006785	infant body height
EFO:0007789	BMI-adjusted waist circumference
EFO:0004318	smoking behavior
EFO:0004341	body fat distribution
EFO:0004324	body weights and measures

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C538183	Acrofacial dysostosis Rodriguez type (supp.)
C538184	Acrofacial dysostosis, Nager type (supp.)
C537352	Metaphyseal chondrodysplasia Schmid type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066181 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects cotreatment, increases abundance, increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
aristolochic acid I	increases expression, decreases expression	1
bisphenol F	increases expression	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
deoxynivalenol	increases expression	1
sodium arsenate	decreases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
tetrabromobisphenol A	decreases expression	1
pyrrolidine dithiocarbamic acid	decreases reaction, affects cotreatment, decreases expression	1
ochratoxin A	decreases expression	1
potassium chromate(VI)	increases expression, affects cotreatment	1
nivalenol	increases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
cyclic 3’,5’-uridine monophosphate	affects binding	1
epigallocatechin gallate	affects cotreatment, increases expression	1
15-acetyldeoxynivalenol	increases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
MT19c compound	decreases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	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
CHEMBL5697315	Binding	Inhibition of SF3B4 (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)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT04931056	Not specified	COMPLETED	A Post Market Clinical Follow-up Study on Biomet Microfixation HTR PEKK (Midface), Facial & Mandibular Plates.
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability