SCAF4

Summary

SCAF4 (SR-related CTD associated factor 4, HGNC:19304) is a protein-coding gene on chromosome 21q22.11, encoding SR-related and CTD-associated factor 4 (O95104). Anti-terminator protein required to prevent early mRNA termination during transcription. It is a selective cancer dependency (DepMap: 15.2% of cell lines).

This gene likely encodes a member of the arginine/serine-rich splicing factor family. A similar protein in Rat appears to bind the large subunit of RNA polymerase II and provide a link between transcription and pre-mRNA splicing. Alternatively spliced transcript variants have been described.

Source: NCBI Gene 57466 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 351 total — 24 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 40
• Cancer dependency (DepMap): dependent in 15.2% of screened cell lines
• MANE Select transcript: NM_020706

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19304
Approved symbol	SCAF4
Name	SR-related CTD associated factor 4
Location	21q22.11
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1172, DKFZp434E098, SRA4
Ensembl gene	ENSG00000156304
Ensembl biotype	protein_coding
OMIM	616023
Entrez	57466

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 18 protein_coding, 3 retained_intron

ENST00000286835, ENST00000399804, ENST00000434667, ENST00000467731, ENST00000472318, ENST00000485790, ENST00000908755, ENST00000908756, ENST00000908757, ENST00000908758, ENST00000908759, ENST00000908760, ENST00000908761, ENST00000908762, ENST00000908763, ENST00000908764, ENST00000908765, ENST00000931674, ENST00000931675, ENST00000931676, ENST00000949917

RefSeq mRNA: 3 — MANE Select: NM_020706 NM_001145444, NM_001145445, NM_020706

CCDS: CCDS33537, CCDS46644, CCDS54482

Canonical transcript exons

ENST00000286835 — 20 exons

Exon	Start	End
ENSE00001025679	31696569	31696750
ENSE00001025680	31685049	31685240
ENSE00003518978	31692349	31692449
ENSE00003525870	31706274	31706357
ENSE00003537037	31685398	31685484
ENSE00003539850	31702244	31702379
ENSE00003559960	31685568	31685733
ENSE00003573674	31700995	31701171
ENSE00003583230	31694813	31694980
ENSE00003593983	31694204	31694289
ENSE00003626347	31703765	31703926
ENSE00003649452	31701776	31701918
ENSE00003650509	31688307	31688464
ENSE00003652132	31691817	31691930
ENSE00003654271	31690797	31690953
ENSE00003661688	31693294	31693484
ENSE00003682168	31696113	31696221
ENSE00003685771	31705423	31705467
ENSE00003888833	31671000	31672354
ENSE00003892481	31731663	31732118

Expression profiles

Bgee: expression breadth ubiquitous, 267 present calls, max score 96.21.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.0014 / max 403.3496, expressed in 1821 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
190177	26.4058	1813
190175	6.6647	1728
190176	0.7131	404
190174	0.2178	82

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	96.21	gold quality
buccal mucosa cell	CL:0002336	95.65	gold quality
sperm	CL:0000019	93.65	gold quality
ventricular zone	UBERON:0003053	90.35	gold quality
male germ cell	CL:0000015	89.88	gold quality
medial globus pallidus	UBERON:0002477	89.09	gold quality
skin of abdomen	UBERON:0001416	88.61	gold quality
skin of leg	UBERON:0001511	88.45	gold quality
left ovary	UBERON:0002119	88.31	gold quality
ganglionic eminence	UBERON:0004023	88.20	gold quality
colonic epithelium	UBERON:0000397	88.19	gold quality
right ovary	UBERON:0002118	88.06	gold quality
body of uterus	UBERON:0009853	87.98	gold quality
ectocervix	UBERON:0012249	87.87	gold quality
choroid plexus epithelium	UBERON:0003911	87.69	gold quality
small intestine Peyer’s patch	UBERON:0003454	87.58	gold quality
popliteal artery	UBERON:0002250	87.34	gold quality
tibial artery	UBERON:0007610	87.34	gold quality
leukocyte	CL:0000738	87.26	gold quality
monocyte	CL:0000576	87.25	gold quality
mononuclear cell	CL:0000842	87.23	gold quality
sural nerve	UBERON:0015488	87.22	gold quality
right lung	UBERON:0002167	87.20	gold quality
gastrocnemius	UBERON:0001388	86.90	gold quality
mucosa of transverse colon	UBERON:0004991	86.89	gold quality
esophagus mucosa	UBERON:0002469	86.81	gold quality
aorta	UBERON:0000947	86.69	gold quality
lymph node	UBERON:0000029	86.66	gold quality
transverse colon	UBERON:0001157	86.63	gold quality
right lobe of liver	UBERON:0001114	86.62	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.94
E-GEOD-99795	no	96.84

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

46 targeting SCAF4, 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-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-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-508-5P	99.41	64.25	1248

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 15.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 8)

• Describes function of the CTD-interacting domain of human SCAF8, human SCAF4, and similar proteins in S. cerevisiae. (PMID:18550522)
• Report frequency of SFRS15 SNPs in diabetic nephropathy. (PMID:24821155)
• Together, SCAF4 and SCAF8 coordinate the transition between elongation and termination, ensuring correct polyA site selection and RNAPII transcriptional termination in human cells. (PMID:31104839)
• Variants in SCAF4 Cause a Neurodevelopmental Disorder and Are Associated with Impaired mRNA Processing. (PMID:32730804)
• Structural basis for the recognition of the S2, S5-phosphorylated RNA polymerase II CTD by the mRNA anti-terminator protein hSCAF4. (PMID:34897689)
• SCAF4 variants associated with focal epilepsy accompanied by multisystem disorders. (PMID:37394306)
• SCAF4 variants are associated with epilepsy with neurodevelopmental disorders. (PMID:37891035)
• Describes identification of rat serine/arginine-rich splicing factors that interact with RNA polymerase II, including rA1, rA4, rA8, and rA9. (PMID:8692929)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	scaf4b	ENSDARG00000018854
danio_rerio	scaf4a	ENSDARG00000077093
mus_musculus	Scaf4	ENSMUSG00000022983
rattus_norvegicus	Scaf4	ENSRNOG00000002104
drosophila_melanogaster	Isha	FBGN0034598
caenorhabditis_elegans	nrd-1	WBGENE00017004

Paralogs (1): SCAF8 (ENSG00000213079)

Protein

Protein identifiers

SR-related and CTD-associated factor 4 — O95104 (reviewed: O95104)

Alternative names: CTD-binding SR-like protein RA4, Splicing factor, arginine/serine-rich 15

All UniProt accessions (1): O95104

UniProt curated annotations — full annotation on UniProt →

Function. Anti-terminator protein required to prevent early mRNA termination during transcription. Together with SCAF8, acts by suppressing the use of early, alternative poly(A) sites, thereby preventing the accumulation of non-functional truncated proteins. Mechanistically, associates with the phosphorylated C-terminal heptapeptide repeat domain (CTD) of the largest RNA polymerase II subunit (POLR2A), and subsequently binds nascent RNA upstream of early polyadenylation sites to prevent premature mRNA transcript cleavage and polyadenylation. Independently of SCAF8, also acts as a suppressor of transcriptional readthrough.

Subunit / interactions. Interacts with POLR2A; via C-terminal heptapeptide repeat domain (CTD) phosphorylated at ‘Ser-2’ and ‘Ser-5’.

Subcellular location. Nucleus.

Disease relevance. Fliedner-Zweier syndrome (FZS) [MIM:620511] An autosomal dominant neurodevelopmental disorder characterized by variable features including mild intellectual disability, seizures, behavioral abnormalities, and various skeletal and structural anomalies. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (3)

UniProt ID	Names	Canonical?
O95104-1	1	yes
O95104-2	2
O95104-3	3

RefSeq proteins (3): NP_001138916, NP_001138917, NP_065757* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000504	RRM_dom	Domain
IPR006569	CID_dom	Domain
IPR008942	ENTH_VHS	Homologous_superfamily
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR034369	SCAF4_RRM	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily
IPR051485	SR-CTD_assoc_factor	Family

Pfam: PF00076, PF04818

UniProt features (60 total): sequence conflict 17, helix 12, compositionally biased region 9, sequence variant 6, region of interest 6, modified residue 4, domain 2, splice variant 2, chain 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6XKB	X-RAY DIFFRACTION	1.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95104-F1	54.53	0.20

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 (4): 49, 154, 656, 1004

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 216 (showing top): WANG_CLIM2_TARGETS_UP, GOBP_DNA_TEMPLATED_TRANSCRIPTION_TERMINATION, NFKB_Q6, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, NFKB_C, BLALOCK_ALZHEIMERS_DISEASE_UP, OCT1_06, GOBP_TERMINATION_OF_RNA_POLYMERASE_II_TRANSCRIPTION, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_DISASSEMBLY, AACTTT_UNKNOWN, GOBP_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_DISASSEMBLY, chr21q22, LAIHO_COLORECTAL_CANCER_SERRATED_DN, GOMF_PHOSPHOPROTEIN_BINDING, KRIGE_RESPONSE_TO_TOSEDOSTAT_24HR_UP

GO Biological Process (1): negative regulation of termination of RNA polymerase II transcription, poly(A)-coupled (GO:2000805)

GO Molecular Function (3): RNA binding (GO:0003723), RNA polymerase II C-terminal domain phosphoserine binding (GO:1990269), nucleic acid binding (GO:0003676)

GO Cellular Component (2): nucleus (GO:0005634), nucleoplasm (GO:0005654)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
termination of RNA polymerase II transcription, poly(A)-coupled	1
negative regulation of termination of RNA polymerase II transcription	1
regulation of termination of RNA polymerase II transcription, poly(A)-coupled	1
nucleic acid binding	1
phosphoserine residue binding	1
RNA polymerase II C-terminal domain binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1832 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SCAF4	ZCCHC17	Q9NP64	663
SCAF4	PCF11	O94913	642
SCAF4	CDC5L	Q99459	572
SCAF4	SF3B4	Q15427	559
SCAF4	CDK12	Q9NYV4	522
SCAF4	NCBP2	P52298	512
SCAF4	MED13L	Q71F56	507
SCAF4	PCBP2	Q15366	506
SCAF4	SETX	Q7Z333	500
SCAF4	C21orf58	P58505	500
SCAF4	SCAF1	Q9H7N4	500
SCAF4	RPRD2	Q5VT52	490
SCAF4	ELOF1	P60002	482
SCAF4	DDX39A	O00148	481
SCAF4	HUNK	P57058	480

IntAct

70 interactions, top by confidence:

A	B	Type	Score
POLR2J	POLR1C	psi-mi:“MI:0914”(association)	0.830
POLR2D	MED19	psi-mi:“MI:0914”(association)	0.730
POLR2E	MED19	psi-mi:“MI:0914”(association)	0.730
KLHL22	TMEM223	psi-mi:“MI:0914”(association)	0.640
QPRT	PIK3C2A	psi-mi:“MI:0914”(association)	0.640
SUMO1	CBX4	psi-mi:“MI:0914”(association)	0.600
SUPT5H	POLR2D	psi-mi:“MI:0914”(association)	0.530
MAGEB2	POLRMT	psi-mi:“MI:0914”(association)	0.530
CLEC3A	ZZEF1	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
SCAF4	WBP4	psi-mi:“MI:0915”(physical association)	0.400
SCAF4		psi-mi:“MI:0915”(physical association)	0.370
SCAF4	TP63	psi-mi:“MI:0915”(physical association)	0.370
PPP4R3A	COG4	psi-mi:“MI:0914”(association)	0.350
CCNB2	SCAF4	psi-mi:“MI:0914”(association)	0.350
LARP7		psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
POLR2M	MED19	psi-mi:“MI:0914”(association)	0.350
rep	NOP56	psi-mi:“MI:0914”(association)	0.350
rep	POLRMT	psi-mi:“MI:0914”(association)	0.350
SRPK3	SNRPGP15	psi-mi:“MI:0914”(association)	0.350
SRPK2	SNRPGP15	psi-mi:“MI:0914”(association)	0.350
LIN28A	MEX3A	psi-mi:“MI:0914”(association)	0.350
LIN28A	AGPS	psi-mi:“MI:0914”(association)	0.350
MTDH	NOP56	psi-mi:“MI:0914”(association)	0.350
FUS	SUPT5H	psi-mi:“MI:0914”(association)	0.350

BioGRID (166): SCAF4 (Affinity Capture-MS), SCAF4 (Affinity Capture-MS), SCAF4 (Affinity Capture-MS), SCAF4 (Affinity Capture-MS), CDK12 (Co-fractionation), SCAF4 (Affinity Capture-MS), SCAF4 (Affinity Capture-MS), SCAF4 (Affinity Capture-MS), SCAF4 (Affinity Capture-MS), SCAF4 (Affinity Capture-MS), SCAF4 (Affinity Capture-MS), SCAF4 (Affinity Capture-MS), SCAF4 (Affinity Capture-MS), SCAF4 (Affinity Capture-MS), SCAF4 (Proximity Label-MS)

ESM2 similar proteins: A2VDB3, A7EQA8, A7Z019, O44498, O94842, O95104, O95835, P0CB49, P34333, P34428, P46582, P51531, P51532, P97868, Q08D57, Q09345, Q09556, Q17308, Q1LY77, Q20374, Q3TKT4, Q3TLH4, Q4V7X9, Q5F3P8, Q5HZJ0, Q63623, Q63627, Q66J90, Q66KL9, Q6DIC0, Q6DID3, Q6DRG1, Q6GLQ4, Q7TSH6, Q7Z6E9, Q8BYR2, Q8CGZ0, Q8IWX8, Q8K1P7, Q8NE35

Diamond homologs: O95104, Q63623, Q63627, Q6DID3, Q7TSH6, Q9LNV5, Q9SX80, Q9UPN6, Q9ZW36, A4IIM2, B8BCZ8, F4I3B3, O13759, O57406, O59800, O95319, P0CR50, P0CR51, P28659, P31483, P32831, P38241, P52912, P70318, Q00539, Q01085, Q0J9Y2, Q0WW84, Q1JQ73, Q28HE9, Q3B7L8, Q4PGU6, Q4QQT3, Q4R4J1, Q4V7D7, Q4W9V0, Q5A5N5, Q5AX35, Q5F3T7, Q5R8Y8

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 93 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
Pausing and recovery of Tat-mediated HIV elongation	5	28.3×	3e-05
Tat-mediated HIV elongation arrest and recovery	5	28.3×	3e-05
HIV elongation arrest and recovery	5	26.6×	3e-05
Pausing and recovery of HIV elongation	5	26.6×	3e-05
HIV Transcription Elongation	5	25.8×	3e-05
RNA Polymerase II Transcription Termination	7	23.6×	8e-07
mRNA Splicing - Minor Pathway	6	20.7×	2e-05
Formation of HIV-1 elongation complex containing HIV-1 Tat	5	20.0×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
RNA splicing	11	11.6×	1e-06
mRNA splicing, via spliceosome	9	9.8×	9e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	24
Likely pathogenic	15
Uncertain significance	230
Likely benign	51
Benign	1

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1334441	NM_020706.2(SCAF4):c.374_375dup (p.Glu126fs)	Pathogenic
1343211	NM_020706.2(SCAF4):c.790del (p.Arg264fs)	Pathogenic
1698044	NM_020706.2(SCAF4):c.1450C>T (p.Arg484Ter)	Pathogenic
1699102	NM_020706.2(SCAF4):c.749del (p.Pro250fs)	Pathogenic
1708237	NM_020706.2(SCAF4):c.1068+3A>G	Pathogenic
1804040	NM_020706.2(SCAF4):c.1295_1296del (p.Arg432fs)	Pathogenic
2227100	NM_020706.2(SCAF4):c.852del (p.Val285fs)	Pathogenic
2263747	NM_020706.2(SCAF4):c.1411C>T (p.Arg471Ter)	Pathogenic
2382716	NM_020706.2(SCAF4):c.1648dup (p.Met550fs)	Pathogenic
2664961	NM_020706.2(SCAF4):c.1669dup (p.Tyr557fs)	Pathogenic
2854932	NM_020706.2(SCAF4):c.1216dup (p.Thr406fs)	Pathogenic
3253288	NM_020706.2(SCAF4):c.1423C>T (p.Arg475Ter)	Pathogenic
3363102	NM_020706.2(SCAF4):c.1457_1460del (p.Lys486fs)	Pathogenic
3437763	NM_020706.2(SCAF4):c.656_660dup (p.Asn221fs)	Pathogenic
3899522	NM_020706.2(SCAF4):c.1339C>T (p.Arg447Ter)	Pathogenic
4279862	NM_020706.2(SCAF4):c.2015del (p.Pro672fs)	Pathogenic
4686841	NM_020706.2(SCAF4):c.1693C>T (p.Arg565Ter)	Pathogenic
4731221	NM_020706.2(SCAF4):c.1801dup (p.Tyr601fs)	Pathogenic
4756037	NM_020706.2(SCAF4):c.1429C>T (p.Arg477Ter)	Pathogenic
4818971	NM_020706.2(SCAF4):c.176del (p.Lys59fs)	Pathogenic
973768	NM_020706.2(SCAF4):c.571C>T (p.Gln191Ter)	Pathogenic
989407	NM_020706.2(SCAF4):c.321+1G>T	Pathogenic
989408	NM_020706.2(SCAF4):c.1614+1G>C	Pathogenic
989409	NM_020706.2(SCAF4):c.1889G>A (p.Trp630Ter)	Pathogenic
1184957	NM_020706.2(SCAF4):c.1378C>T (p.Arg460Ter)	Likely pathogenic
14779	NM_000454.5(SOD1):c.217G>A (p.Gly73Ser)	Likely pathogenic
2628910	NM_020706.2(SCAF4):c.839_840del (p.Glu280fs)	Likely pathogenic
2632229	NM_020706.2(SCAF4):c.1465_1466del (p.Glu489fs)	Likely pathogenic
2634005	NM_020706.2(SCAF4):c.959+1G>T	Likely pathogenic
2663908	NM_020706.2(SCAF4):c.1457_1458del (p.Lys486fs)	Likely pathogenic

SpliceAI

2505 predictions. Top by Δscore:

Variant	Effect	Δscore
21:31685170:CACCA:C	acceptor_gain	1.0000
21:31685172:CCA:C	acceptor_gain	1.0000
21:31685173:CAC:C	acceptor_gain	1.0000
21:31685175:C:CC	acceptor_gain	1.0000
21:31685396:A:AC	donor_gain	1.0000
21:31685397:C:CC	donor_gain	1.0000
21:31688301:TCTCA:T	donor_loss	1.0000
21:31688302:CTCA:C	donor_loss	1.0000
21:31688303:TCACC:T	donor_loss	1.0000
21:31688304:CACCT:C	donor_loss	1.0000
21:31688305:A:AT	donor_loss	1.0000
21:31688460:CCAAT:C	acceptor_gain	1.0000
21:31688461:CAAT:C	acceptor_gain	1.0000
21:31688461:CAATC:C	acceptor_gain	1.0000
21:31688462:AAT:A	acceptor_gain	1.0000
21:31688463:AT:A	acceptor_gain	1.0000
21:31688464:TC:T	acceptor_loss	1.0000
21:31688465:C:CA	acceptor_loss	1.0000
21:31688465:C:CC	acceptor_gain	1.0000
21:31688472:C:CT	acceptor_gain	1.0000
21:31688473:G:C	acceptor_gain	1.0000
21:31688473:G:GC	acceptor_gain	1.0000
21:31688473:G:T	acceptor_gain	1.0000
21:31690871:CA:C	acceptor_gain	1.0000
21:31690965:T:TC	acceptor_gain	1.0000
21:31690968:G:GC	acceptor_gain	1.0000
21:31690974:A:AC	acceptor_gain	1.0000
21:31690974:A:C	acceptor_gain	1.0000
21:31690976:A:AC	acceptor_gain	1.0000
21:31691952:T:TC	acceptor_gain	1.0000

AlphaMissense

7453 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:31690826:C:T	G619E	1.000
21:31690827:C:G	G619R	1.000
21:31690827:C:T	G619R	1.000
21:31690829:C:T	G618E	1.000
21:31690830:C:G	G618R	1.000
21:31690830:C:T	G618R	1.000
21:31690886:A:T	V599D	1.000
21:31690889:C:A	G598V	1.000
21:31690889:C:T	G598D	1.000
21:31690890:C:A	G598C	1.000
21:31690890:C:G	G598R	1.000
21:31690890:C:T	G598S	1.000
21:31690903:C:A	W593C	1.000
21:31690903:C:G	W593C	1.000
21:31690904:C:G	W593S	1.000
21:31690905:A:G	W593R	1.000
21:31690905:A:T	W593R	1.000
21:31690912:C:A	K590N	1.000
21:31690912:C:G	K590N	1.000
21:31690914:T:C	K590E	1.000
21:31690928:A:T	I585K	1.000
21:31690931:C:T	G584E	1.000
21:31690932:C:G	G584R	1.000
21:31690932:C:T	G584R	1.000
21:31690936:G:C	N582K	1.000
21:31690936:G:T	N582K	1.000
21:31690943:G:T	A580D	1.000
21:31690944:C:G	A580P	1.000
21:31690944:C:T	A580T	1.000
21:31690945:C:A	W579C	1.000

dbSNP variants (sampled 300 via entrez): RS1000028384 (21:31729262 C>T), RS1000078094 (21:31693796 C>A,T), RS1000151364 (21:31708614 G>A), RS1000178624 (21:31690042 T>A,C,G), RS1000189018 (21:31683714 A>T), RS1000242164 (21:31698383 A>C,G), RS1000305741 (21:31680905 G>C), RS1000316210 (21:31698116 A>T), RS1000390355 (21:31696459 T>C), RS1000418453 (21:31724015 G>A), RS1000438277 (21:31708346 C>T), RS1000457461 (21:31703656 C>A,T), RS1000477505 (21:31709564 T>C), RS1000510044 (21:31709343 A>G), RS1000551056 (21:31692273 T>G)

Disease associations

OMIM: gene MIM:616023 | disease phenotypes: MIM:620511, MIM:105400, MIM:617755, MIM:616721

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Strong	Autosomal dominant
Fliedner-Zweier syndrome	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (8): neurodevelopmental disorder (MONDO:0700092), Fliedner-Zweier syndrome (MONDO:0957787), intellectual disability (MONDO:0001071), amyotrophic lateral sclerosis type 1 (MONDO:0007103), complex neurodevelopmental disorder (MONDO:0100038), multicystic dysplastic kidney (MONDO:0015988), neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (MONDO:0060596), SLC39A8-CDG (MONDO:0014746)

Orphanet (7): Rare syndromic intellectual disability (Orphanet:102369), Amyotrophic lateral sclerosis (Orphanet:803), Non-specific syndromic intellectual disability (Orphanet:528084), Multicystic dysplastic kidney (Orphanet:1851), BPTF-related intellectual disability-facial dysmorphism-skeletal anomalies syndrome (Orphanet:686482), SLC39A8-CDG (Orphanet:468699), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

40 total (30 of 40 shown, HPO-id order):

HPO	Term
HP:0000003	Multicystic kidney dysplasia
HP:0000006	Autosomal dominant inheritance
HP:0000122	Unilateral renal agenesis
HP:0000126	Hydronephrosis
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000286	Epicanthus
HP:0000343	Long philtrum
HP:0000414	Bulbous nose
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0000767	Pectus excavatum
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001276	Hypertonia
HP:0001382	Joint hypermobility
HP:0001513	Obesity
HP:0001629	Ventricular septal defect
HP:0001647	Bicuspid aortic valve
HP:0001763	Pes planus
HP:0001822	Hallux valgus
HP:0002023	Anal atresia
HP:0002079	Hypoplasia of the corpus callosum
HP:0002144	Tethered cord
HP:0002435	Meningocele
HP:0002575	Tracheoesophageal fistula

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST003256_1	Joint damage progression in ACPA-negative rheumatoid arthritis	4.000000e-09
GCST006612_18	LDL cholesterol	1.000000e-10
GCST009028_32	Adverse response to drug	4.000000e-07
GCST010243_69	Apolipoprotein B levels	4.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0005413	joint damage measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0009658	adverse effect
EFO:0004615	apolipoprotein B measurement

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
D021782	Multicystic Dysplastic Kidney	C12.050.351.875.558; C12.050.351.968.419.403.750; C12.200.706.629; C12.200.777.419.403.750; C12.800.629; C12.950.419.403.750; C16.131.939.629
D065886	Neurodevelopmental Disorders	F03.625
C531617	Amyotrophic lateral sclerosis 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects expression, affects cotreatment	6
Tobacco Smoke Pollution	affects expression, increases expression	3
methylmercuric chloride	decreases expression, increases expression	2
trichostatin A	affects cotreatment, affects expression	2
Cisplatin	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Cadmium Chloride	decreases expression, increases abundance	2
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
testosterone undecanoate	affects cotreatment, decreases expression	1
methylparaben	increases expression	1
sodium arsenite	affects binding, increases reaction, increases activity	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, affects expression	1
dorsomorphin	affects expression, affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
Irinotecan	decreases expression	1
Acetaminophen	increases expression	1
Aerosols	decreases expression	1
Atrazine	decreases expression	1
Cadmium	decreases expression, increases abundance	1
Citrinin	decreases expression	1
Dimethyl Sulfoxide	increases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Estradiol	increases expression	1
Formaldehyde	decreases expression	1
Lead	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
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
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
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
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
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
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
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)
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development