ASCC3

Summary

ASCC3 (activating signal cointegrator 1 complex subunit 3, HGNC:18697) is a protein-coding gene on chromosome 6q16.3, encoding Activating signal cointegrator 1 complex subunit 3 (Q8N3C0). ATPase involved both in DNA repair and rescue of stalled ribosomes. 3’-5’ DNA helicase involved in repair of alkylated DNA: promotes DNA unwinding to generate single-stranded substrate needed for ALKBH3, enabling ALKBH3 to process alkylated N3-methylcytosine (3mC) within double-…. It is a selective cancer dependency (DepMap: 35.6% of cell lines).

This gene encodes a protein that belongs to a family of helicases that are involved in the ATP-dependent unwinding of nucleic acid duplexes. The encoded protein is the largest subunit of the activating signal cointegrator 1 complex that is involved in DNA repair and resistance to alkylation damage. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 10973 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual developmental disorder, autosomal recessive 81 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 18
• Clinical variants (ClinVar): 412 total — 14 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 55
• Cancer dependency (DepMap): dependent in 35.6% of screened cell lines
• MANE Select transcript: NM_006828

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18697
Approved symbol	ASCC3
Name	activating signal cointegrator 1 complex subunit 3
Location	6q16.3
Locus type	gene with protein product
Status	Approved
Aliases	RNAH, ASC1p200, dJ121G13.4, dJ467N11.1
Ensembl gene	ENSG00000112249
Ensembl biotype	protein_coding
OMIM	614217
Entrez	10973

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 10 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000324696, ENST00000324723, ENST00000369143, ENST00000369162, ENST00000468245, ENST00000518006, ENST00000522650, ENST00000930695, ENST00000930696, ENST00000930697, ENST00000930698, ENST00000930699, ENST00000930700

RefSeq mRNA: 3 — MANE Select: NM_006828 NM_001284271, NM_006828, NM_022091

CCDS: CCDS5046, CCDS5047, CCDS75497

Canonical transcript exons

ENST00000369162 — 42 exons

Exon	Start	End
ENSE00000421601	100638601	100638821
ENSE00000421604	100627842	100627987
ENSE00000421608	100606740	100606860
ENSE00000760980	100509932	100510107
ENSE00000760982	100512709	100512918
ENSE00000760983	100516180	100516327
ENSE00000760984	100517991	100518142
ENSE00000760986	100589634	100589768
ENSE00000760987	100589948	100590059
ENSE00000760990	100601810	100601935
ENSE00000761034	100606951	100607088
ENSE00000761137	100642581	100642749
ENSE00000761138	100644031	100644129
ENSE00000840244	100540163	100540387
ENSE00000840250	100605568	100605700
ENSE00000840253	100625192	100625334
ENSE00000840254	100627590	100627710
ENSE00000840256	100629015	100629181
ENSE00000840257	100631128	100631213
ENSE00000840261	100646615	100646769
ENSE00000840262	100647226	100647451
ENSE00001448943	100508194	100509533
ENSE00003459154	100679618	100679752
ENSE00003463610	100805760	100805880
ENSE00003469982	100798713	100798838
ENSE00003471671	100655699	100655818
ENSE00003497006	100799431	100799572
ENSE00003512861	100725539	100725703
ENSE00003519711	100864064	100864214
ENSE00003531314	100766565	100766705
ENSE00003546807	100662345	100662536
ENSE00003552115	100715462	100715533
ENSE00003559587	100661806	100662030
ENSE00003588940	100651560	100651646
ENSE00003601498	100652725	100652889
ENSE00003621148	100848148	100848707
ENSE00003623173	100767145	100767345
ENSE00003643924	100650538	100650714
ENSE00003673073	100800300	100800504
ENSE00003679352	100867908	100868038
ENSE00003686466	100718075	100718251
ENSE00003845447	100881061	100881329

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 95.33.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 43.9651 / max 671.6247, expressed in 1815 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
74830	29.6249	1811
74829	13.6306	1765
74828	0.7096	420

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
decidua	UBERON:0002450	95.33	gold quality
secondary oocyte	CL:0000655	92.66	gold quality
calcaneal tendon	UBERON:0003701	90.94	gold quality
oocyte	CL:0000023	90.42	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.83	gold quality
stromal cell of endometrium	CL:0002255	89.67	gold quality
ventricular zone	UBERON:0003053	89.53	gold quality
adrenal tissue	UBERON:0018303	88.23	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.34	gold quality
islet of Langerhans	UBERON:0000006	87.03	gold quality
bone marrow cell	CL:0002092	86.44	gold quality
right coronary artery	UBERON:0001625	86.02	gold quality
cartilage tissue	UBERON:0002418	85.79	gold quality
placenta	UBERON:0001987	85.72	gold quality
epithelium of nasopharynx	UBERON:0001951	85.63	gold quality
rectum	UBERON:0001052	85.57	gold quality
adenohypophysis	UBERON:0002196	85.45	gold quality
monocyte	CL:0000576	85.00	gold quality
tendon	UBERON:0000043	84.89	gold quality
corpus epididymis	UBERON:0004359	84.85	gold quality
mononuclear cell	CL:0000842	84.84	gold quality
leukocyte	CL:0000738	84.80	gold quality
vagina	UBERON:0000996	84.72	gold quality
right lobe of liver	UBERON:0001114	84.47	gold quality
ectocervix	UBERON:0012249	84.46	gold quality
ascending aorta	UBERON:0001496	84.40	gold quality
pituitary gland	UBERON:0000007	84.39	gold quality
right adrenal gland	UBERON:0001233	84.36	gold quality
right adrenal gland cortex	UBERON:0035827	84.35	gold quality
urinary bladder	UBERON:0001255	84.29	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.28

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP53

miRNA regulators (miRDB)

82 targeting ASCC3, 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-126-5P	100.00	72.71	3180
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 35.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 7)

• DNA unwinding by ASCC3 helicase is coupled to ALKBH3-dependent DNA alkylation repair and cancer cell proliferation. (PMID:22055184)
• Silencing of ASCC3 resulted in upregulation of multiple antiviral interferon-stimulated genes, which correlated with inhibition of infection of several positive-strand RNA viruses. (PMID:23781071)
• ASCC3 Gene Polymorphism was associated with Chronic Hepatitis B. (PMID:26536629)
• UV exposure results in spatial restriction of transcription and slower elongation, with the result that only the promoter-proximal 20-25 kb are efficiently transcribed; these events underlie a switch to expression of short mRNA isoforms and preferential use of alternative last exons in a number of genes, including ASCC3. (PMID:28215706)
• The interaction of DNA repair factors ASCC2 and ASCC3 is affected by somatic cancer mutations. (PMID:33139697)
• ALKBH3 partner ASCC3 mediates P-body formation and selective clearance of MMS-induced 1-methyladenosine and 3-methylcytosine from mRNA. (PMID:34217309)
• ASCC3 promotes the immunosuppression and progression of non-small cell lung cancer by impairing the type I interferon response via CAND1-mediated ubiquitination inhibition of STAT3. (PMID:38148115)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ascc3	ENSDARG00000086678
mus_musculus	Ascc3	ENSMUSG00000038774
rattus_norvegicus	Ascc3	ENSRNOG00000037604
drosophila_melanogaster	obe	FBGN0038344
caenorhabditis_elegans		WBGENE00013189

Paralogs (8): MTREX (ENSG00000039123), POLQ (ENSG00000051341), DDX60 (ENSG00000137628), SNRNP200 (ENSG00000144028), HFM1 (ENSG00000162669), HELQ (ENSG00000163312), DDX60L (ENSG00000181381), SKIC2 (ENSG00000204351)

Protein

Protein identifiers

Activating signal cointegrator 1 complex subunit 3 — Q8N3C0 (reviewed: Q8N3C0)

Alternative names: ASC-1 complex subunit p200, Helicase, ATP binding 1, Trip4 complex subunit p200

All UniProt accessions (3): Q8N3C0, E5RFZ0, J3KNJ4

UniProt curated annotations — full annotation on UniProt →

Function. ATPase involved both in DNA repair and rescue of stalled ribosomes. 3’-5’ DNA helicase involved in repair of alkylated DNA: promotes DNA unwinding to generate single-stranded substrate needed for ALKBH3, enabling ALKBH3 to process alkylated N3-methylcytosine (3mC) within double-stranded regions. Also involved in activation of the ribosome quality control (RQC) pathway, a pathway that degrades nascent peptide chains during problematic translation. Drives the splitting of stalled ribosomes that are ubiquitinated in a ZNF598-dependent manner, as part of the ribosome quality control trigger (RQT) complex. Part of the ASC-1 complex that enhances NF-kappa-B, SRF and AP1 transactivation.

Subunit / interactions. Identified in the ASCC complex that contains ASCC1, ASCC2 and ASCC3. Functions as scaffolding subunit that interacts directly with both ASCC1 and ASCC2. Interacts directly with ALKBH3, and thereby recruits ALKBH3 to the ASCC complex. Part of the ASC-1/TRIP4 complex, that contains TRIP4, ASCC1, ASCC2 and ASCC3. Part of the RQT (ribosome quality control trigger) complex, that contains ASCC2, ASCC3 and TRIP4. Associates with ribosomes; recruited to collided ribosomes. Interacts with ZCCHC4. Interacts with ZNF598. Interacts with RPS3.

Subcellular location. Nucleus. Nucleus speckle. Cytoplasm. Cytosol.

Tissue specificity. Ubiquitous.

Disease relevance. Intellectual developmental disorder, autosomal recessive 81 (MRT81) [MIM:620700] An autosomal recessive disorder characterized by variable features including mild to severe developmental delay, hypotonia, feeding difficulties, extreme fatigue, and neurobehavioral abnormalities. The disease may be caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the helicase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8N3C0-1	1	yes
Q8N3C0-3	2
Q8N3C0-4	3

RefSeq proteins (3): NP_001271200, NP_006819, NP_071374 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001650	Helicase_C-like	Domain
IPR003593	AAA+_ATPase	Domain
IPR004179	Sec63-dom	Domain
IPR011545	DEAD/DEAH_box_helicase_dom	Domain
IPR014001	Helicase_ATP-bd	Domain
IPR014756	Ig_E-set	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR035892	C2_domain_sf	Homologous_superfamily
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR050474	Hel308_SKI2-like	Family
IPR057842	WH_MER3	Domain
IPR058856	ASCC3_N	Domain

Pfam: PF00270, PF00271, PF02889, PF23445, PF26582

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (225 total): helix 91, strand 63, turn 22, sequence variant 20, domain 6, sequence conflict 6, splice variant 4, modified residue 3, short sequence motif 2, binding site 2, mutagenesis site 2, coiled-coil region 2, chain 1, region of interest 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6YXQ	X-RAY DIFFRACTION	2.7
8ALZ	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N3C0-F1	79.93	0.28

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (2): 499–506; 1349–1356

Post-translational modifications (3): 12, 572, 2195

Mutagenesis-validated functional residues (2):

Position	Phenotype
505	defective activation of the ribosome quality control (rqc) pathway. impairs its association with ribosomes.
1354	abolishes 3’-5’ dna helicase activity and ability to promote dna repair.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-112126	ALKBH3 mediated reversal of alkylation damage
R-HSA-9954716	ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA
R-HSA-73894	DNA Repair
R-HSA-73942	DNA Damage Reversal
R-HSA-73943	Reversal of alkylation damage by DNA dioxygenases

MSigDB gene sets: 298 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_TRANSLATION, WEI_MYCN_TARGETS_WITH_E_BOX, DACOSTA_UV_RESPONSE_VIA_ERCC3_COMMON_DN, GOBP_DNA_DAMAGE_RESPONSE, TGACATY_UNKNOWN, GARY_CD5_TARGETS_DN, GOBP_TRANSLATIONAL_ELONGATION, DODD_NASOPHARYNGEAL_CARCINOMA_UP, TGTTTAC_MIR30A5P_MIR30C_MIR30D_MIR30B_MIR30E5P, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, REACTOME_DNA_REPAIR

GO Biological Process (10): DNA replication (GO:0006260), DNA alkylation repair (GO:0006307), ribosome disassembly (GO:0032790), rescue of stalled cytosolic ribosome (GO:0072344), ribosome-associated ubiquitin-dependent protein catabolic process (GO:1990116), DNA repair (GO:0006281), protein monoubiquitination (GO:0006513), DNA damage response (GO:0006974), protein ufmylation (GO:0071569), CAT tailing (GO:0140708)

GO Molecular Function (10): RNA binding (GO:0003723), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), 3’-5’ DNA helicase activity (GO:0043138), nucleotide binding (GO:0000166), nucleic acid binding (GO:0003676), helicase activity (GO:0004386), protein binding (GO:0005515), hydrolase activity (GO:0016787), isomerase activity (GO:0016853)

GO Cellular Component (9): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), membrane (GO:0016020), nuclear speck (GO:0016607), cytosolic ribosome (GO:0022626), RQC-trigger complex (GO:0180022), DNA repair complex (GO:1990391), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Reversal of alkylation damage by DNA dioxygenases	1
Ribosome-associated quality control	1
DNA Repair	1
DNA Damage Reversal	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
DNA metabolic process	2
cytoplasmic translational elongation	2
ATP-dependent activity	2
binding	2
catalytic activity	2
DNA biosynthetic process	1
DNA repair	1
organelle disassembly	1
ribosome disassembly	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
DNA damage response	1
protein ubiquitination	1
cellular response to stress	1
protein modification by small protein conjugation	1
rescue of stalled cytosolic ribosome	1
ribosome-associated ubiquitin-dependent protein catabolic process	1
nucleic acid binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
DNA helicase activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
nucleic acid conformation isomerase activity	1
catalytic activity, acting on a nucleic acid	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
nuclear ribonucleoprotein granule	1
cytosol	1
ribosome	1
protein-containing complex	1
catalytic complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2457 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ASCC3	ASCC2	Q9H1I8	986
ASCC3	ASCC1	Q8N9N2	973
ASCC3	TRIP4	Q15650	969
ASCC3	ZNF598	Q86UK7	812
ASCC3	ALKBH3	Q96Q83	748
ASCC3	NEMF	O60524	640
ASCC3	ALKBH2	Q6NS38	582
ASCC3	ARCN1	P48444	538
ASCC3	PELO	Q9BRX2	533
ASCC3	PRPF3	O43395	522
ASCC3	DHX29	Q7Z478	521
ASCC3	GCN1	Q92616	521
ASCC3	GIGYF2	Q6Y7W6	512
ASCC3	RPS20	P17075	502
ASCC3	SPAG17	Q6Q759	500

IntAct

169 interactions, top by confidence:

A	B	Type	Score
ARPC5	ARPC1B	psi-mi:“MI:0914”(association)	0.890
ASCC2	ASCC3	psi-mi:“MI:0915”(physical association)	0.790
ASCC2	ASCC3	psi-mi:“MI:0407”(direct interaction)	0.790
ASCC2	ASCC3	psi-mi:“MI:0403”(colocalization)	0.790
ASCC3	ASCC2	psi-mi:“MI:0915”(physical association)	0.790
ASCC1	ASCC3	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ASCC1	ASCC3	psi-mi:“MI:0915”(physical association)	0.690
ASCC1	ASCC3	psi-mi:“MI:0407”(direct interaction)	0.690
ASCC1	ASCC3	psi-mi:“MI:0914”(association)	0.690
CEP170	KIF2A	psi-mi:“MI:2364”(proximity)	0.650
ASCC2	TRIP4	psi-mi:“MI:0914”(association)	0.640
DNAJC7	PLD2	psi-mi:“MI:0914”(association)	0.640
RACK1	RIOK3	psi-mi:“MI:0914”(association)	0.640
ASCC3	HCCS	psi-mi:“MI:0915”(physical association)	0.560
ASCC3	rep	psi-mi:“MI:0915”(physical association)	0.550
ALKBH3	INPPL1	psi-mi:“MI:0914”(association)	0.530
RPS3	ZNF316	psi-mi:“MI:0914”(association)	0.530
TRIP4	ASCC3	psi-mi:“MI:0914”(association)	0.530
HSPB8	VWA8	psi-mi:“MI:0914”(association)	0.530
RPS2	MPHOSPH10	psi-mi:“MI:0914”(association)	0.530
ALKBH3	TRIP4	psi-mi:“MI:0914”(association)	0.530
ASCC1	TRIP4	psi-mi:“MI:0914”(association)	0.530

BioGRID (272): ASCC3 (Affinity Capture-RNA), ASCC3 (Affinity Capture-RNA), ASCC3 (Affinity Capture-RNA), ASCC3 (Affinity Capture-MS), ASCC3 (Affinity Capture-MS), ASCC3 (Affinity Capture-MS), ASCC3 (Affinity Capture-MS), ASCC3 (Affinity Capture-MS), ASCC3 (Co-fractionation), ASCC3 (Affinity Capture-MS), ASCC3 (Affinity Capture-MS), ASCC3 (Proximity Label-MS), ASCC3 (Proximity Label-MS), ASCC3 (Proximity Label-MS), ASCC3 (Affinity Capture-MS)

ESM2 similar proteins: A0A8J1M587, A0FLQ6, A8WS58, A8WZU5, B2RR83, B3M383, B4GEU5, B4PRJ9, D4A2Z8, F1LPQ2, F4IDQ6, F4ILR7, F4IM84, F4INY4, F4JMJ3, F4KGU4, H2KY86, O13799, O18017, O22243, O42643, O60072, O94536, P0CE10, P20095, P24384, P34305, P34668, P36009, P51979, P53327, P53695, P90740, Q04149, Q10752, Q19546, Q1EHT7, Q296Q5, Q5D892, Q5R746

Diamond homologs: A2PYH4, A2RUV5, A8MB76, B0R7Q2, B6DMK2, D3Z4R1, E1BNG3, E7F8F4, E9PZJ8, F1LNJ2, F1LPQ2, F1NTD6, F4JAA5, O48534, O59025, O60072, O75643, P32639, P51979, P53327, Q09475, Q54G57, Q54XN7, Q55CI8, Q5D892, Q5H9U9, Q5JGV6, Q5UYM9, Q6P4T2, Q8N3C0, Q974S1, Q9FNQ1, Q9HMV6, Q9P7T8, Q9SYP1, Q9UT24, Q9V0A9, Q9VUV9, A7IB61, D0KN27

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 194 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
Formation of the ternary complex, and subsequently, the 43S complex	12	20.7×	1e-10
Translation initiation complex formation	13	19.8×	4e-11
Eukaryotic Translation Initiation	8	19.8×	4e-07
Cap-dependent Translation Initiation	8	19.8×	4e-07
SARS-CoV-1 modulates host translation machinery	8	19.8×	4e-07
Ribosomal scanning and start codon recognition	12	18.3×	4e-10
Eukaryotic Translation Elongation	8	17.8×	8e-07
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S	8	17.4×	9e-07

GO biological processes:

GO term	Partners	Fold	FDR
formation of cytoplasmic translation initiation complex	5	33.4×	2e-04
translational initiation	7	14.9×	2e-04
cytoplasmic translation	11	12.1×	2e-06
ribosomal small subunit biogenesis	7	9.5×	2e-03
negative regulation of translation	8	9.3×	7e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	4
Uncertain significance	291
Likely benign	27
Benign	9

Top pathogenic / likely-pathogenic (18)

Variant ID	HGVS	Classification
1527267	GRCh37/hg19 6q15-16.3(chr6:92576950-104658245)	Pathogenic
1807814	GRCh37/hg19 6q16.1-21(chr6:96946110-106497526)x1	Pathogenic
1807838	GRCh37/hg19 6q16.1-21(chr6:96596732-105554568)x1	Pathogenic
2691800	NM_006828.4(ASCC3):c.4690T>C (p.Ser1564Pro)	Pathogenic
2691801	NM_006828.4(ASCC3):c.4553G>A (p.Arg1518His)	Pathogenic
2691804	NM_006828.4(ASCC3):c.4415G>A (p.Arg1472Gln)	Pathogenic
2691806	NM_006828.4(ASCC3):c.3631C>T (p.Gln1211Ter)	Pathogenic
2691808	NM_006828.4(ASCC3):c.5281C>T (p.Arg1761Ter)	Pathogenic
2691809	NM_006828.4(ASCC3):c.4955G>A (p.Gly1652Asp)	Pathogenic
2691810	NM_006828.4(ASCC3):c.4984A>T (p.Ile1662Phe)	Pathogenic
2691811	NM_006828.4(ASCC3):c.3522dup (p.Cys1175fs)	Pathogenic
3233652	NM_006828.4(ASCC3):c.5769_5770del (p.Cys1924fs)	Pathogenic
58439	GRCh38/hg38 6q16.1-16.3(chr6:97853776-102580597)x1	Pathogenic
58440	GRCh38/hg38 6q16.1-16.3(chr6:98668529-101266950)x1	Pathogenic
2582588	NM_006828.4(ASCC3):c.3101T>A (p.Leu1034Ter)	Likely pathogenic
2691852	NM_006828.4(ASCC3):c.1597-2A>G	Likely pathogenic
3629890	NM_006828.4(ASCC3):c.802-2A>C	Likely pathogenic
931384	NM_006828.4(ASCC3):c.801+1G>T	Likely pathogenic

SpliceAI

7986 predictions. Top by Δscore:

Variant	Effect	Δscore
6:100509995:A:AC	donor_gain	1.0000
6:100509996:C:CC	donor_gain	1.0000
6:100509996:CT:C	donor_gain	1.0000
6:100512704:TATA:T	donor_loss	1.0000
6:100512707:ACC:A	donor_loss	1.0000
6:100512708:C:CG	donor_loss	1.0000
6:100516174:TCTTA:T	donor_loss	1.0000
6:100516175:CTTA:C	donor_loss	1.0000
6:100516176:TTAC:T	donor_loss	1.0000
6:100516177:TACCT:T	donor_loss	1.0000
6:100516179:C:CT	donor_loss	1.0000
6:100517986:ATTAC:A	donor_loss	1.0000
6:100517989:A:AC	donor_gain	1.0000
6:100517989:A:T	donor_loss	1.0000
6:100517990:C:CT	donor_gain	1.0000
6:100518045:T:TA	donor_gain	1.0000
6:100518139:TTGC:T	acceptor_gain	1.0000
6:100518140:TGC:T	acceptor_gain	1.0000
6:100518141:GC:G	acceptor_gain	1.0000
6:100518141:GCC:G	acceptor_loss	1.0000
6:100518142:CC:C	acceptor_gain	1.0000
6:100518142:CCTGA:C	acceptor_loss	1.0000
6:100518143:C:CC	acceptor_gain	1.0000
6:100518143:C:G	acceptor_loss	1.0000
6:100518144:T:C	acceptor_loss	1.0000
6:100540158:CATA:C	donor_loss	1.0000
6:100540159:ATAC:A	donor_loss	1.0000
6:100540160:TACCT:T	donor_loss	1.0000
6:100540161:A:T	donor_loss	1.0000
6:100540162:C:CG	donor_loss	1.0000

AlphaMissense

14575 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:100540268:T:A	K1890N	1.000
6:100540268:T:G	K1890N	1.000
6:100601828:C:G	R1762P	1.000
6:100601829:G:T	R1762S	1.000
6:100605597:A:C	F1716L	1.000
6:100605597:A:T	F1716L	1.000
6:100605598:A:G	F1716S	1.000
6:100605599:A:G	F1716L	1.000
6:100605643:G:T	A1701D	1.000
6:100605649:C:T	G1699D	1.000
6:100605650:C:G	G1699R	1.000
6:100605673:C:T	G1691E	1.000
6:100605674:C:A	G1691W	1.000
6:100605676:G:T	A1690D	1.000
6:100605679:C:G	R1689P	1.000
6:100605680:G:T	R1689S	1.000
6:100605682:C:T	G1688E	1.000
6:100605683:C:A	G1688W	1.000
6:100605683:C:G	G1688R	1.000
6:100605683:C:T	G1688R	1.000
6:100605694:A:G	L1684P	1.000
6:100606794:C:G	G1664R	1.000
6:100606794:C:T	G1664R	1.000
6:100606814:G:T	A1657D	1.000
6:100606829:C:T	G1652D	1.000
6:100606830:C:G	G1652R	1.000
6:100606831:C:A	W1651C	1.000
6:100606831:C:G	W1651C	1.000
6:100606832:C:G	W1651S	1.000
6:100606833:A:G	W1651R	1.000

dbSNP variants (sampled 300 via entrez): RS1000003555 (6:100659498 T>C), RS1000007000 (6:100797192 G>A), RS1000021169 (6:100735077 C>T), RS1000026412 (6:100637984 G>A), RS1000032507 (6:100863981 C>T), RS1000039812 (6:100852073 G>C), RS1000043276 (6:100747641 G>A), RS1000059174 (6:100508547 ATAAT>A), RS1000067074 (6:100724533 T>A,C), RS1000071410 (6:100814810 T>G), RS1000071964 (6:100610761 G>A), RS1000077703 (6:100616721 C>A), RS1000079306 (6:100789800 G>A), RS1000080241 (6:100731160 G>T), RS1000088429 (6:100528652 A>G)

Disease associations

OMIM: gene MIM:614217 | disease phenotypes: MIM:620700, MIM:117000

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual developmental disorder, autosomal recessive 81	Strong	Autosomal recessive
intellectual disability	Limited	Autosomal recessive

Mondo (3): intellectual developmental disorder, autosomal recessive 81 (MONDO:0958204), congenital myopathy (MONDO:0019952), intellectual disability (MONDO:0001071)

Orphanet (1): Congenital myopathy (Orphanet:97245)

HPO phenotypes

55 total (30 of 55 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000175	Cleft palate
HP:0000189	Narrow palate
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000303	Mandibular prognathia
HP:0000307	Pointed chin
HP:0000316	Hypertelorism
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000527	Long eyelashes
HP:0000545	Myopia
HP:0000574	Thick eyebrow
HP:0000717	Autism
HP:0000739	Anxiety
HP:0000750	Delayed speech and language development
HP:0000938	Osteopenia
HP:0001238	Slender finger
HP:0001250	Seizure
HP:0001256	Mild intellectual disability
HP:0001258	Spastic paraplegia
HP:0001263	Global developmental delay
HP:0001511	Intrauterine growth retardation
HP:0001572	Macrodontia
HP:0001761	Pes cavus
HP:0001763	Pes planus

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST001515_11	Economic and political preferences (immigration/crime)	2.000000e-06
GCST002541_53	Menarche (age at onset)	3.000000e-08
GCST003783_4	Multiple system atrophy (pathologically confirmed)	4.000000e-06
GCST005083_1	Putamen volume	8.000000e-06
GCST005232_142	Neuroticism	2.000000e-08
GCST006940_40	Neurociticism	5.000000e-09
GCST007326_33	Number of sexual partners	1.000000e-10
GCST007327_18	Smoking status (ever vs never smokers)	2.000000e-08
GCST007387_48	Insomnia symptoms (never/rarely vs. sometimes/usually)	7.000000e-06
GCST007388_36	Insomnia symptoms (never/rarely vs. usually)	9.000000e-09
GCST008810_61	Smoking initiation (ever regular vs never regular)	2.000000e-08
GCST009201_8	Sub-cortical grey matter volume	2.000000e-06
GCST009391_1669	Metabolite levels	6.000000e-06
GCST011346_46	Total cholesterol levels	3.000000e-08
GCST011703_77	Smoking initiation	3.000000e-08
GCST012354_24	Anxiety	1.000000e-09
GCST012355_37	Depression	2.000000e-15
GCST90000047_125	Age at first sexual intercourse	7.000000e-09

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004827	economic and social preference
EFO:0004703	age at menarche
EFO:0007660	neuroticism measurement
EFO:0004318	smoking behavior
EFO:0007876	insomnia measurement
EFO:0005670	smoking initiation
EFO:0005420	grey matter volume measurement
EFO:0010470	carnosine measurement
EFO:0004574	total cholesterol measurement
EFO:0009863	anxiety measurement
EFO:0009749	age at first sexual intercourse measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, decreases expression	2
sodium arsenite	affects cotreatment, decreases expression	2
mercuric bromide	increases expression, affects cotreatment	2
Acetaminophen	decreases expression, increases expression	2
Benzo(a)pyrene	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
deoxynivalenol	increases expression	1
lead acetate	affects cotreatment, decreases expression	1
pyrogallol 1,3-dimethyl ether	affects localization, decreases expression, affects cotreatment	1
decabromobiphenyl ether	decreases expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
cobaltous chloride	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
deguelin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol S	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9XY	Ubigene HeLa ASCC3 KO	Cancer cell line	Female

Clinical trials (associated diseases)

210 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