SON

Summary

SON (SON DNA and RNA binding protein, HGNC:11183) is a protein-coding gene on chromosome 21q22.11, encoding Protein SON (P18583). RNA-binding protein that acts as a mRNA splicing cofactor by promoting efficient splicing of transcripts that possess weak splice sites. It is a common-essential gene (DepMap: required in 95.8% of cancer cell lines) and haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a protein that contains multiple simple repeats. The encoded protein binds RNA and promotes pre-mRNA splicing, particularly of transcripts with poor splice sites. The protein also recognizes a specific DNA sequence found in the human hepatitis B virus (HBV) and represses HBV core promoter activity. There is a pseudogene for this gene on chromosome 1. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 6651 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ZTTK syndrome (Definitive, ClinGen)
• GWAS associations: 2
• Clinical variants (ClinVar): 1,754 total — 105 pathogenic, 37 likely-pathogenic
• Phenotypes (HPO): 140
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 95.8% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_138927

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11183
Approved symbol	SON
Name	SON DNA and RNA binding protein
Location	21q22.11
Locus type	gene with protein product
Status	Approved
Aliases	DBP-5, NREBP, KIAA1019, BASS1, FLJ21099, FLJ33914
Ensembl gene	ENSG00000159140
Ensembl biotype	protein_coding
OMIM	182465
Entrez	6651

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 7 protein_coding, 6 retained_intron, 5 protein_coding_CDS_not_defined, 4 nonsense_mediated_decay

ENST00000300278, ENST00000356577, ENST00000381679, ENST00000381692, ENST00000421541, ENST00000429093, ENST00000436227, ENST00000455528, ENST00000457208, ENST00000465834, ENST00000467616, ENST00000470533, ENST00000473102, ENST00000474355, ENST00000475072, ENST00000477419, ENST00000478183, ENST00000484294, ENST00000491794, ENST00000492229, ENST00000695559, ENST00000704334

RefSeq mRNA: 6 — MANE Select: NM_138927 NM_001291411, NM_001291412, NM_001412132, NM_001412133, NM_032195, NM_138927

CCDS: CCDS13629, CCDS13631, CCDS74784, CCDS77624

Canonical transcript exons

ENST00000356577 — 12 exons

Exon	Start	End
ENSE00001043468	33557156	33557316
ENSE00001043475	33559230	33559376
ENSE00001178085	33559587	33559775
ENSE00001314216	33549476	33555391
ENSE00001372796	33567157	33567267
ENSE00001379673	33568971	33569087
ENSE00001938879	33576365	33577481
ENSE00001948678	33543038	33543169
ENSE00003486708	33575778	33575893
ENSE00003496844	33573308	33573455
ENSE00003612832	33575596	33575667
ENSE00003672267	33546213	33546379

Expression profiles

Bgee: expression breadth ubiquitous, 304 present calls, max score 99.64.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 153.1006 / max 4449.6204, expressed in 1824 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
188877	148.4711	1823
188880	2.8236	1189
188873	0.7116	315
188874	0.5545	246
209300	0.3059	85
188875	0.1323	57
188876	0.1016	39

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pylorus	UBERON:0001166	99.64	gold quality
tendon of biceps brachii	UBERON:0008188	99.63	gold quality
cardia of stomach	UBERON:0001162	99.56	gold quality
nipple	UBERON:0002030	99.43	gold quality
trabecular bone tissue	UBERON:0002483	99.34	gold quality
renal medulla	UBERON:0000362	99.28	gold quality
pericardium	UBERON:0002407	99.26	gold quality
right uterine tube	UBERON:0001302	99.24	gold quality
trigeminal ganglion	UBERON:0001675	99.20	gold quality
seminal vesicle	UBERON:0000998	99.19	gold quality
fundus of stomach	UBERON:0001160	99.19	gold quality
mucosa of stomach	UBERON:0001199	99.18	gold quality
mucosa of paranasal sinus	UBERON:0005030	99.17	gold quality
ventricular zone	UBERON:0003053	99.16	gold quality
dorsal root ganglion	UBERON:0000044	99.14	gold quality
right lobe of thyroid gland	UBERON:0001119	99.14	gold quality
body of uterus	UBERON:0009853	99.14	gold quality
right ovary	UBERON:0002118	99.12	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.11	gold quality
urethra	UBERON:0000057	99.10	gold quality
pituitary gland	UBERON:0000007	99.07	gold quality
medial globus pallidus	UBERON:0002477	99.06	gold quality
lower esophagus	UBERON:0013473	99.06	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.06	gold quality
left ovary	UBERON:0002119	99.05	gold quality
inferior vagus X ganglion	UBERON:0005363	99.04	gold quality
left uterine tube	UBERON:0001303	99.03	gold quality
left lobe of thyroid gland	UBERON:0001120	99.02	gold quality
corpus callosum	UBERON:0002336	99.01	gold quality
tibia	UBERON:0000979	99.00	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	1417.79
E-CURD-122	yes	32.36
E-MTAB-10042	yes	4.72
E-CURD-53	no	577.55
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

7 targets.

Target	Regulation
AVP
COMP
GHSR
HBG2
LEP
PRKAA2
RB1

Upstream regulators (CollecTRI, top): CUX1

miRNA regulators (miRDB)

79 targeting SON, 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-3163	100.00	77.23	8605
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-4789-3P	99.99	70.75	2484
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-4420	99.82	70.08	1624
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-548AG	99.77	69.25	1492
HSA-MIR-548AI	99.69	69.24	1494
HSA-MIR-548BA	99.69	69.14	1514
HSA-MIR-570-5P	99.69	69.24	1494
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-466	99.67	70.85	2863

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 95.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 26)

• SON is an indispensable factor for cell growth, and AML1-ETO binding to SON may trigger signals inhibiting leukemogenesis. (PMID:18952841)
• Data suggest that Son is essential for appropriate subnuclear organization of pre-mRNA splicing factors and for promoting normal cell cycle progression. (PMID:20053686)
• The identification of the RNA/DNA-binding protein SON as a component of spliceosome that plays pleiotropic roles during mitotic progression, is reported. (PMID:20581448)
• Results reveal a mechanism for controlling cell-cycle progression through SON-dependent constitutive splicing at suboptimal splice sites, with strong implications for its role in cancer and other human diseases. (PMID:21504830)
• The data show that Son-regulated splicing encompasses all known types of alternative splicing, the most common being alternative splicing of cassette exons. (PMID:22193954)
• Studied knockdown screening of 78 MAPK-associated molecules associated with proliferation of pancreatic cancer cells in vitro. Knockdown of SON substantially suppressed pancreatic cancer cell proliferation and survival in vitro and tumorigenicity in vivo. (PMID:23227827)
• SON protein regulates GATA-2 through transcriptional control of the microRNA 23a27a24-2 cluster (PMID:23322776)
• identify the spliceosome-associated factor SON as a factor essential for the maintenance of hESCs (PMID:24013217)
• Here, we summarize available information from several early studies on SON, and highlight recent discoveries describing molecular mechanisms of SON-mediated gene regulation. (PMID:24030980)
• progenitors. Our findings define SON as a fine-tuner of the MLL-menin interaction and reveal short SON overexpression as a marker indicating aberrant transcriptional initiation in leukemia. (PMID:26990989)
• we have established that haploinsufficiency of SON causes a new recognizable syndrome of intellectual disability. SON is located within 21q22.11, a critical region for Braddock-Carey syndrome, therefore, we suggest that the intellectual disability observed in Braddock-Carey syndrome could be accounted for by haploinsufficiency of SON. (PMID:27256762)
• description of seven unrelated individuals with de novo variants in SON and propose that deleterious variants in SON are associated with a severe multisystem disorder characterized by developmental delay, persistent feeding difficulties, and congenital malformations, including brain anomalies (PMID:27545676)
• data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development. (PMID:27545680)
• We found that SON and SC35 (also known as SRSF2) localize to the central region of the speckle, whereas MALAT1 and small nuclear (sn)RNAs are enriched at the speckle periphery. (PMID:29133588)
• SON haploinsufficiency causes impaired pre-mRNA splicing of CAKUT genes and heterogeneous renal phenotypes. (PMID:31005274)
• SON DNA-binding protein mediates macrophage autophagy and responses to intracellular infection. (PMID:32484234)
• Phenotypic expansion in Zhu-Tokita-Takenouchi-Kim syndrome caused by de novo variants in the SON gene. (PMID:32705777)
• SON and SRRM2 are essential for nuclear speckle formation. (PMID:33095160)
• SON inhibits megakaryocytic differentiation via repressing RUNX1 and the megakaryocytic gene expression program in acute megakaryoblastic leukemia. (PMID:33247227)
• ZTTK syndrome: Clinical and molecular findings of 15 cases and a review of the literature. (PMID:34331327)
• The SON RNA splicing factor is required for intracellular trafficking structures that promote centriole assembly and ciliogenesis. (PMID:34406792)
• Establishing the phenotypic spectrum of ZTTK syndrome by analysis of 52 individuals with variants in SON. (PMID:34521999)
• SON drives oncogenic RNA splicing in glioblastoma by regulating PTBP1/PTBP2 switching and RBFOX2 activity. (PMID:34548489)
• Expanding the mutational spectrum of ZTTK syndrome: A de novo variant with global developmental delay and malnutrition in a Chinese patient. (PMID:37488749)
• SON is an essential m[6]A target for hematopoietic stem cell fate. (PMID:38065069)
• SON is an essential RNA splicing factor promoting ErbB2 and ErbB3 expression in breast cancer. (PMID:39313574)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	sona	ENSDARG00000055389
		ENSDARG00000114730
mus_musculus	Son	ENSMUSG00000022961
rattus_norvegicus	Son	ENSRNOG00000002021
drosophila_melanogaster	Son	FBGN0037716
caenorhabditis_elegans	D1037.1	WBGENE00017025

Protein

Protein identifiers

Protein SON — P18583 (reviewed: P18583)

Alternative names: Bax antagonist selected in saccharomyces 1, Negative regulatory element-binding protein, Protein DBP-5, SON3

All UniProt accessions (8): A0A8Q3SI10, A0A994J4Y9, P18583, H7C1M2, H7C1S4, H7C257, H7C2G8, J3QSZ5

UniProt curated annotations — full annotation on UniProt →

Function. RNA-binding protein that acts as a mRNA splicing cofactor by promoting efficient splicing of transcripts that possess weak splice sites. Specifically promotes splicing of many cell-cycle and DNA-repair transcripts that possess weak splice sites, such as TUBG1, KATNB1, TUBGCP2, AURKB, PCNT, AKT1, RAD23A, and FANCG. Probably acts by facilitating the interaction between Serine/arginine-rich proteins such as SRSF2 and the RNA polymerase II. Also binds to DNA; binds to the consensus DNA sequence: 5’-GA[GT]AN[CG][AG]CC-3’. May indirectly repress hepatitis B virus (HBV) core promoter activity and transcription of HBV genes and production of HBV virions. Essential for correct RNA splicing of multiple genes critical for brain development, neuronal migration and metabolism, including TUBG1, FLNA, PNKP, WDR62, PSMD3, PCK2, PFKL, IDH2, and ACY1.

Subunit / interactions. Interacts with SRSF2. Associates with the spliceosome. Interacts with the AML1-MTG8 (AML1-ETO) fusion protein, possibly leading to trigger signals inhibiting leukemogenesis. Interacts with USH1G.

Subcellular location. Nucleus speckle.

Tissue specificity. Widely expressed, with the higher expression seen in leukocyte and heart.

Disease relevance. ZTTK syndrome (ZTTKS) [MIM:617140] An autosomal dominant syndrome characterized by intellectual disability, developmental delay, malformations of the cerebral cortex, epilepsy, vision problems, musculo-skeletal abnormalities, and congenital malformations. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Contains 8 types of repeats which are distributed in 3 regions.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Isoforms (10)

UniProt ID	Names	Canonical?
P18583-1	F	yes
P18583-2	A
P18583-3	B
P18583-4	C
P18583-5	D
P18583-6	E
P18583-7	G
P18583-8	H
P18583-9	I
P18583-10	J

RefSeq proteins (6): NP_001278340, NP_001278341, NP_001399061, NP_001399062, NP_115571, NP_620305* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000467	G_patch_dom	Domain
IPR014720	dsRBD_dom	Domain
IPR032922
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily

Pfam: PF01585, PF14709, PF17069

UniProt features (141 total): modified residue 42, repeat 23, compositionally biased region 17, region of interest 16, splice variant 15, sequence conflict 13, sequence variant 7, cross-link 4, domain 2, initiator methionine 1, chain 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
7CIQ	X-RAY DIFFRACTION	1.59
7CIR	X-RAY DIFFRACTION	1.81
7DYN	X-RAY DIFFRACTION	2
7CIS	X-RAY DIFFRACTION	2.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P18583-F1	36.48	0.02

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 (46): 2163, 2238, 64, 2055, 2092, 2149, 2, 16, 94, 142, 152, 154, 160, 283, 288, 400, 950, 959, 998, 1007 …

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 580 (showing top): GOBP_MITOTIC_CYTOKINESIS, GCACCTT_MIR18A_MIR18B, AAGCAAT_MIR137, MULLIGHAN_NPM1_SIGNATURE_3_UP, MODULE_169, DACOSTA_UV_RESPONSE_VIA_ERCC3_XPCS_DN, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, TTTGTAG_MIR520D, AAGCCAT_MIR135A_MIR135B, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, HSIAO_HOUSEKEEPING_GENES, BROWNE_HCMV_INFECTION_16HR_UP, MORF_HDAC2, ATGTTAA_MIR302C, LINDGREN_BLADDER_CANCER_CLUSTER_2A_DN

GO Biological Process (8): microtubule cytoskeleton organization (GO:0000226), mitotic cytokinesis (GO:0000281), mRNA processing (GO:0006397), RNA splicing (GO:0008380), negative regulation of apoptotic process (GO:0043066), regulation of RNA splicing (GO:0043484), regulation of mRNA splicing, via spliceosome (GO:0048024), regulation of cell cycle (GO:0051726)

GO Molecular Function (4): DNA binding (GO:0003677), RNA binding (GO:0003723), nucleic acid binding (GO:0003676), protein binding (GO:0005515)

GO Cellular Component (2): nuclear speck (GO:0016607), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA processing	2
nucleic acid binding	2
binding	2
cytoskeleton organization	1
microtubule-based process	1
mitotic cell cycle	1
cytoskeleton-dependent cytokinesis	1
mitotic cell cycle process	1
mRNA metabolic process	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
RNA splicing	1
regulation of gene expression	1
regulation of primary metabolic process	1
mRNA splicing, via spliceosome	1
regulation of RNA splicing	1
regulation of mRNA processing	1
cell cycle	1
regulation of cellular process	1
nuclear ribonucleoprotein granule	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2299 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SON	GLE1	Q53GS7	927
SON	DONSON	Q9NYP3	773
SON	RBBP6	Q7Z6E9	769
SON	PIP5K1C	O60331	706
SON	PIP4K2A	P48426	639
SON	ARID4A	P29374	587
SON	SRSF2	Q01130	586
SON	NXF1	Q9UBU9	574
SON	KDM5A	P29375	555
SON	DDX4	Q9NQI0	551
SON	PPP1CC	P36873	512
SON	DDX3Y	O15523	502
SON	GART	P22102	475
SON	NXT1	Q9UKK6	468
SON	SACK1H	Q6ZRV2	461

IntAct

127 interactions, top by confidence:

A	B	Type	Score
PIK3CA	PIK3R2	psi-mi:“MI:0914”(association)	0.900
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
SF3B1	SAP18	psi-mi:“MI:0914”(association)	0.640
PNN	CASC3	psi-mi:“MI:0914”(association)	0.640
YWHAG	SON	psi-mi:“MI:0915”(physical association)	0.590
NCBP3	SAP18	psi-mi:“MI:0914”(association)	0.530
SRPK2	RRP9	psi-mi:“MI:0914”(association)	0.530
CPSF6	DDX39A	psi-mi:“MI:0914”(association)	0.480
SON	RUNX1T1	psi-mi:“MI:0915”(physical association)	0.400
SON	YWHAB	psi-mi:“MI:0915”(physical association)	0.400
NS	SON	psi-mi:“MI:0915”(physical association)	0.370
SON	NS1	psi-mi:“MI:0915”(physical association)	0.370
SON	NS	psi-mi:“MI:0915”(physical association)	0.370
PRPF40A	SON	psi-mi:“MI:0915”(physical association)	0.370
SON	SNIP1	psi-mi:“MI:0915”(physical association)	0.370
DDX41	DDX39A	psi-mi:“MI:0914”(association)	0.350
PB2	HAX1	psi-mi:“MI:0914”(association)	0.350
PB2	ESYT2	psi-mi:“MI:0914”(association)	0.350
	HAX1	psi-mi:“MI:0914”(association)	0.350
PB1	ESYT2	psi-mi:“MI:0914”(association)	0.350
PB2	IPO5	psi-mi:“MI:0914”(association)	0.350
MKI67	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
MAPT	LANCL1	psi-mi:“MI:0914”(association)	0.350
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (257): SON (Affinity Capture-MS), SON (Affinity Capture-MS), SON (Affinity Capture-MS), SON (Affinity Capture-MS), SON (Affinity Capture-MS), SON (Affinity Capture-MS), SON (Affinity Capture-MS), SON (Affinity Capture-MS), SON (Affinity Capture-MS), SON (Affinity Capture-MS), SON (Co-fractionation), SON (Co-fractionation), SON (Affinity Capture-MS), SON (Proximity Label-MS), SON (Biochemical Activity)

ESM2 similar proteins: A0A087WUL8, A0A0J9YWL9, A0A0J9YY54, A0A0U1RQI7, A6NJ88, A6QL64, B4DH59, D3ZVV1, E9Q6E9, F1LWT0, O04492, O88799, P0DKJ7, P0DKJ8, P0DKL2, P0DPF3, P18583, P53353, Q08AG5, Q0P6D6, Q2EG98, Q3BBV2, Q4ZJZ1, Q5HY64, Q5JPF3, Q5QGU6, Q5TAG4, Q5TI25, Q5XHX6, Q6P3W6, Q6P902, Q6XPR3, Q6ZQX7, Q86T75, Q86VE3, Q86VQ3, Q8N2N9, Q8N660, Q8N693, Q96EQ9

Diamond homologs: P18583, Q9QX47, Q9UTK6, A0JMV4, A4IGK4, A4L691, Q28H71, Q6DDU9, Q9CZX5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
RBM15	up-regulates	SON	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 134 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
Transport of Mature Transcript to Cytoplasm	10	41.8×	9e-13
RNA Polymerase II Transcription Termination	13	31.4×	7e-15
mRNA 3’-end processing	14	30.3×	8e-16
mRNA Splicing	19	22.9×	5e-19
Transport of Mature mRNA derived from an Intron-Containing Transcript	12	20.1×	3e-11
mRNA Polyadenylation	20	19.3×	1e-18
Processing of Capped Intron-Containing Pre-mRNA	21	19.0×	3e-19
Nonsense-Mediated Decay (NMD)	7	17.9×	3e-06

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of mRNA splicing, via spliceosome	6	41.4×	6e-07
regulation of mRNA processing	5	40.0×	1e-05
spliceosomal complex assembly	5	27.1×	9e-05
nuclear-transcribed mRNA catabolic process, nonsense-mediated decay	6	25.3×	1e-05
mRNA export from nucleus	8	21.3×	6e-07
regulation of alternative mRNA splicing, via spliceosome	9	19.8×	2e-07
mRNA splicing, via spliceosome	21	17.3×	2e-17
RNA splicing	18	14.3×	2e-13

Disease & clinical

Clinical variants and AI predictions

ClinVar

1754 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	105
Likely pathogenic	37
Uncertain significance	757
Likely benign	624
Benign	103

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1013462	NM_138927.4(SON):c.2727dup (p.Ser910fs)	Pathogenic
1074571	NC_000021.8:g.(?_34923768)_34933642del	Pathogenic
1076051	NM_138927.4(SON):c.4510del (p.Glu1504fs)	Pathogenic
1098838	NM_138927.4(SON):c.3334del (p.Arg1112fs)	Pathogenic
1215480	NM_138927.4(SON):c.5459_5460del (p.Ser1820fs)	Pathogenic
1285461	NM_138927.4(SON):c.3617_3618del (p.Glu1206fs)	Pathogenic
1319177	NM_138927.4(SON):c.1024C>T (p.Gln342Ter)	Pathogenic
1323632	NM_138927.4(SON):c.2965del (p.Arg989fs)	Pathogenic
1323633	NM_138927.4(SON):c.78-1G>A	Pathogenic
1343134	NM_138927.4(SON):c.4198_4201del (p.Pro1400fs)	Pathogenic
1389406	NM_138927.4(SON):c.4895T>G (p.Leu1632Ter)	Pathogenic
1456728	NM_138927.4(SON):c.1707_1722del (p.Pro570fs)	Pathogenic
1459132	NM_138927.4(SON):c.3585G>A (p.Trp1195Ter)	Pathogenic
1699122	NM_138927.4(SON):c.3968_3975delinsGTTGGT (p.Ser1323fs)	Pathogenic
1699464	NM_138927.4(SON):c.2357_2358dup (p.Ala787Ter)	Pathogenic
1699617	NM_138927.4(SON):c.394C>T (p.Gln132Ter)	Pathogenic
1708239	NM_138927.4(SON):c.3156del (p.Met1053fs)	Pathogenic
1709146	NM_138927.4(SON):c.4480C>T (p.Gln1494Ter)	Pathogenic
1723129	NM_138927.4(SON):c.117del (p.Ile41fs)	Pathogenic
1802578	NM_138927.4(SON):c.2910del (p.Pro969_Tyr970insTer)	Pathogenic
1806327	NM_138927.4(SON):c.1892_1910del (p.Glu631fs)	Pathogenic
2118270	NM_138927.4(SON):c.3241C>T (p.Arg1081Ter)	Pathogenic
2231104	NM_138927.4(SON):c.3088_3094del (p.Glu1030fs)	Pathogenic
2276959	NM_138927.4(SON):c.3287dup (p.Tyr1096Ter)	Pathogenic
2505239	NM_138927.4(SON):c.6321+1del	Pathogenic
2631292	NM_138927.4(SON):c.2381del (p.Gln794fs)	Pathogenic
265774	NM_138927.4(SON):c.5549_5550del (p.Arg1850fs)	Pathogenic
265776	NM_138927.4(SON):c.4640del (p.His1547fs)	Pathogenic
2699199	NM_138927.4(SON):c.1157dup (p.Pro387fs)	Pathogenic
280834	NM_138927.4(SON):c.1136C>A (p.Ser379Ter)	Pathogenic

SpliceAI

53 predictions. Top by Δscore:

Variant	Effect	Δscore
21:33575307:A:AC	donor_gain	0.8100
21:33575261:CTTG:C	donor_gain	0.7700
21:33575263:TG:T	donor_gain	0.7400
21:33575126:T:TA	donor_gain	0.7300
21:33575259:CTCT:C	donor_gain	0.7100
21:33575260:TCTT:T	donor_gain	0.7100
21:33575328:G:A	donor_gain	0.7100
21:33575186:C:CT	donor_gain	0.6700
21:33575312:A:C	donor_gain	0.6600
21:33575283:G:A	donor_gain	0.6400
21:33575264:G:T	donor_gain	0.6200
21:33575194:C:CA	donor_gain	0.5800
21:33575310:A:AC	donor_gain	0.5800
21:33575311:C:CC	donor_gain	0.5800
21:33575235:CA:C	donor_gain	0.5700
21:33575311:CAGG:C	donor_gain	0.5500
21:33575230:T:TC	donor_gain	0.5400
21:33575338:A:AC	donor_gain	0.5300
21:33575339:C:CC	donor_gain	0.5300
21:33575187:C:CT	donor_gain	0.5200
21:33575292:T:TA	donor_gain	0.5100
21:33575325:TG:T	donor_gain	0.5100
21:33575166:G:C	donor_gain	0.5000
21:33575262:TTG:T	donor_gain	0.5000
21:33575293:C:CA	donor_gain	0.4900
21:33575157:T:TA	donor_gain	0.4800
21:33575236:A:T	donor_gain	0.4400
21:33575336:A:T	donor_gain	0.4200
21:33575172:A:AC	donor_gain	0.4100
21:33575229:T:TA	donor_gain	0.4100

AlphaMissense

15678 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:33557168:T:C	L2058S	1.000
21:33557171:T:C	L2059P	1.000
21:33557179:G:C	A2062P	1.000
21:33557180:C:A	A2062D	1.000
21:33557185:G:C	A2064P	1.000
21:33557191:G:C	A2066P	1.000
21:33557309:T:C	L2105P	1.000
21:33559233:T:C	C2109R	1.000
21:33559641:T:C	F2175L	1.000
21:33559642:T:C	F2175S	1.000
21:33559642:T:G	F2175C	1.000
21:33559643:C:A	F2175L	1.000
21:33559643:C:G	F2175L	1.000
21:33559701:T:A	W2195R	1.000
21:33559701:T:C	W2195R	1.000
21:33559703:G:C	W2195C	1.000
21:33559703:G:T	W2195C	1.000
21:33567188:G:C	R2230P	1.000
21:33567197:C:A	A2233D	1.000
21:33567209:T:C	L2237P	1.000
21:33567256:G:C	A2253P	1.000
21:33567257:C:A	A2253D	1.000
21:33567260:A:C	Q2254P	1.000
21:33568977:G:C	A2259P	1.000
21:33568980:T:A	W2260R	1.000
21:33568980:T:C	W2260R	1.000
21:33568982:G:C	W2260C	1.000
21:33568982:G:T	W2260C	1.000
21:33568983:G:C	A2261P	1.000
21:33569010:T:C	F2270L	1.000

dbSNP variants (sampled 300 via entrez): RS1000081945 (21:33560822 C>T), RS1000166491 (21:33544996 A>G), RS1000256731 (21:33566105 A>G), RS1000440467 (21:33548774 T>C), RS1000481032 (21:33560455 C>G), RS1000614405 (21:33543950 T>A), RS1000615808 (21:33548074 C>T), RS1000638811 (21:33560758 C>A,T), RS1000670102 (21:33560498 A>G), RS1000673494 (21:33544194 A>C), RS1000799196 (21:33567005 CTCTT>C), RS1000844351 (21:33542639 C>T), RS1000853266 (21:33566809 C>G), RS1000863720 (21:33567595 G>A), RS1000909811 (21:33553828 G>C)

Disease associations

OMIM: gene MIM:182465 | disease phenotypes: MIM:617140, MIM:270685

GenCC curated gene-disease

Disease	Classification	Inheritance
ZTTK syndrome	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
ZTTK syndrome	Definitive	AD

Mondo (3): ZTTK syndrome (MONDO:0014936), intellectual disability (MONDO:0001071), hereditary spastic paraplegia 17 (MONDO:0010043)

Orphanet (3): ZTTK syndrome (Orphanet:500150), Autosomal dominant spastic paraplegia type 17 (Orphanet:100998), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

140 total (30 of 140 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000085	Horseshoe kidney
HP:0000103	Polyuria
HP:0000119	Abnormality of the genitourinary system
HP:0000122	Unilateral renal agenesis
HP:0000160	Narrow mouth
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000176	Submucous cleft hard palate
HP:0000193	Bifid uvula
HP:0000218	High palate
HP:0000233	Thin vermilion border
HP:0000256	Macrocephaly
HP:0000286	Epicanthus
HP:0000293	Full cheeks
HP:0000319	Smooth philtrum
HP:0000322	Short philtrum
HP:0000324	Facial asymmetry
HP:0000327	Hypoplasia of the maxilla
HP:0000341	Narrow forehead
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000411	Protruding ear
HP:0000431	Wide nasal bridge
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000494	Downslanted palpebral fissures
HP:0000529	Progressive visual loss
HP:0000540	Hypermetropia
HP:0000545	Myopia

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST008479_14	Psoriasis	1.000000e-08
GCST012489_133	Heel bone mineral density x serum urate levels interaction	1.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C536644	Spastic paraplegia 17 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725088 (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

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
7.85	Kd	14	nM	MOLIBRESIB
7.30	IC50	50	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	2179193: Binding affinity against SON (unknown origin) assessed as apparent dissociation constant incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	kd	0.0140	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	3
Cisplatin	decreases expression	2
Estradiol	decreases expression, increases expression	2
Tobacco Smoke Pollution	increases expression	2
Cadmium Chloride	decreases expression, increases expression	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
chloroacetaldehyde	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
deoxynivalenol	increases expression	1
sodium arsenate	decreases expression	1
trichostatin A	decreases expression	1
afimoxifene	decreases expression	1
cobaltous chloride	increases expression	1
coumarin	affects phosphorylation	1
beta-methylcholine	affects expression	1
tamibarotene	affects expression	1
di-n-butylphosphoric acid	affects expression	1
mono(2-ethyl-5-oxohexyl)phthalate	affects expression	1
acyline	increases expression	1
N-butyrylglucosamine	increases expression	1
2-amino-14,16-dimethyloctadecan-3-ol	decreases expression	1
bisphenol S	increases expression	1
jinfukang	decreases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	decreases expression	1
Arsenic Trioxide	increases response to substance	1
Fulvestrant	decreases 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
CHEMBL5697406	Binding	Inhibition of SON (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)

197 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)
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
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders