AGO3

Summary

AGO3 (argonaute RISC catalytic component 3, HGNC:18421) is a protein-coding gene on chromosome 1p34.3, encoding Protein argonaute-3 (Q9H9G7). Required for RNA-mediated gene silencing (RNAi).

This gene encodes a member of the Argonaute family of proteins which play a role in RNA interference. The encoded protein is highly basic, contains a PAZ domain and a PIWI domain, and may play a role in short-interfering-RNA-mediated gene silencing. This gene is located on chromosome 1 in a tandem cluster of closely related family members including argonaute 4 and eukaryotic translation initiation factor 2C, 1. Two transcript variants encoding distinct isoforms have been identified for this gene.

Source: NCBI Gene 192669 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Limited, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 83 total
• MANE Select transcript: NM_024852

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18421
Approved symbol	AGO3
Name	argonaute RISC catalytic component 3
Location	1p34.3
Locus type	gene with protein product
Status	Approved
Aliases	hAGO3, FLJ12765
Ensembl gene	ENSG00000126070
Ensembl biotype	protein_coding
OMIM	607355
Entrez	192669

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 9 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000246314, ENST00000324350, ENST00000373191, ENST00000397828, ENST00000471099, ENST00000491443, ENST00000634486, ENST00000870913, ENST00000870914, ENST00000870915, ENST00000870916, ENST00000966283

RefSeq mRNA: 2 — MANE Select: NM_024852 NM_024852, NM_177422

CCDS: CCDS399, CCDS400

Canonical transcript exons

ENST00000373191 — 19 exons

Exon	Start	End
ENSE00000916726	36008690	36008777
ENSE00000916727	36008897	36009044
ENSE00000916729	36013630	36013752
ENSE00000916730	36013915	36014048
ENSE00000916731	36027114	36027298
ENSE00000916732	36034174	36034333
ENSE00000916733	36036177	36036267
ENSE00000916734	36039790	36039984
ENSE00000916735	36040307	36040441
ENSE00000916736	36043447	36043548
ENSE00001716136	35973375	35973511
ENSE00001743599	36054946	36055145
ENSE00001761593	35966955	35967075
ENSE00001777206	36009475	36009594
ENSE00001876121	35931105	35931445
ENSE00003600409	35945692	35945863
ENSE00003609381	35972024	35972232
ENSE00003642633	36004341	36004475
ENSE00003698562	36055637	36072500

Expression profiles

Bgee: expression breadth ubiquitous, 257 present calls, max score 96.55.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.5440 / max 699.1161, expressed in 1806 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
2140	6.7409	1601
2138	6.2011	1648
2136	2.1105	1130
2139	1.6937	928
2141	1.3886	659
2137	0.4093	162

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	96.55	gold quality
cauda epididymis	UBERON:0004360	92.65	gold quality
caput epididymis	UBERON:0004358	92.31	gold quality
corpus epididymis	UBERON:0004359	91.50	gold quality
cranial nerve II	UBERON:0000941	91.05	gold quality
sperm	CL:0000019	90.57	gold quality
endothelial cell	CL:0000115	90.17	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.49	gold quality
mammary duct	UBERON:0001765	87.43	gold quality
male germ cell	CL:0000015	87.08	gold quality
tendon of biceps brachii	UBERON:0008188	86.94	gold quality
corpus callosum	UBERON:0002336	86.84	gold quality
calcaneal tendon	UBERON:0003701	86.40	gold quality
adrenal tissue	UBERON:0018303	85.29	gold quality
medial globus pallidus	UBERON:0002477	85.26	gold quality
ventricular zone	UBERON:0003053	85.05	gold quality
colonic epithelium	UBERON:0000397	84.54	gold quality
inferior vagus X ganglion	UBERON:0005363	84.51	gold quality
epithelium of mammary gland	UBERON:0003244	83.70	gold quality
globus pallidus	UBERON:0001875	83.49	gold quality
cartilage tissue	UBERON:0002418	83.41	gold quality
tendon	UBERON:0000043	83.26	gold quality
parietal pleura	UBERON:0002400	82.83	gold quality
stromal cell of endometrium	CL:0002255	82.64	gold quality
visceral pleura	UBERON:0002401	82.52	gold quality
saphenous vein	UBERON:0007318	82.41	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.03	gold quality
sural nerve	UBERON:0015488	81.99	gold quality
germinal epithelium of ovary	UBERON:0001304	81.90	gold quality
substantia nigra pars reticulata	UBERON:0001966	81.55	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.39
E-CURD-135	no	576.37

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
RELA	Activation

Upstream regulators (CollecTRI, top): ESR1

miRNA regulators (miRDB)

126 targeting AGO3, 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-4776-3P	100.00	68.73	1340
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-30E-5P	100.00	76.32	3242
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-190A-3P	100.00	80.35	5520
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-4775	99.98	75.00	6394
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-4803	99.98	71.99	3117

Literature-anchored findings (GeneRIF, showing 11)

• The specificity of RNA interference depends on the concentration of Ago1, Ago3, and Ago4 relative to Ago2. (PMID:18771919)
• EIF@C3 protein is expressed in both Schwann and neuron-type differentiating cells. (PMID:19393748)
• reliable predictions of miRNA affinity to Ago2 AND Ago3 proteins were made. (PMID:21634124)
• Ago3 is able to load microRNAs efficiently in the absence of Ago1 and Ago2, despite a significant loss of global microRNA expression (PMID:22474261)
• DICER- and AGO3-dependent generation of retinoic acid-induced DR2 Alu RNAs regulates human stem cell proliferation. (PMID:23064648)
• The N-terminal domain of Ago3 inhibits cleavage activity. AAs 1-64 are largely unstructured & form a large loop surrounding an area containing two helices & another unstructured loop. (PMID:23665583)
• The Ago3 PIWI domain is slicing competent but our Ago3 model suggests multiple interactions between residues in the PIWI & N domains that may increase protein rigidity or invoke other properties that contribute to Ago3’s observed slicing deficiency. (PMID:23748378)
• Study uncovers a first example of a vertebrate protein factor, Argonaute-3, specifically affecting the guide-to-passenger-strand ratio of the miRNA let-7a. A multi-layered mechanism for the observed impact of Ago3 on the let-7a-3p passenger strand expression and activity is proposed. (PMID:24100239)
• Data show that recombinant AGO3 loaded with miR-20a cleaves complementary target RNAs. (PMID:29040713)
• Human Argonaute2 and Argonaute3 are catalytically activated by different lengths of guide RNA. (PMID:33122430)
• Argonaute 3 (AGO3) promotes malignancy potential of cervical cancer via regulation of Wnt/beta-catenin signaling pathway. (PMID:33444963)

Cross-species orthologs

14 orthologs

Organism	Symbol	Gene ID
danio_rerio	ago3a	ENSDARG00000059888
danio_rerio	ago3b	ENSDARG00000063079
mus_musculus	Ago3	ENSMUSG00000028842
rattus_norvegicus	Ago3	ENSRNOG00000034269
caenorhabditis_elegans	ppw-1	WBGENE00004093
caenorhabditis_elegans	ppw-2	WBGENE00004094
caenorhabditis_elegans		WBGENE00006449
caenorhabditis_elegans		WBGENE00007624
caenorhabditis_elegans		WBGENE00010263
caenorhabditis_elegans	wago-1	WBGENE00011061
caenorhabditis_elegans		WBGENE00011910
caenorhabditis_elegans	sago-2	WBGENE00018921
caenorhabditis_elegans		WBGENE00020707
caenorhabditis_elegans		WBGENE00022877

Paralogs (3): AGO1 (ENSG00000092847), AGO2 (ENSG00000123908), AGO4 (ENSG00000134698)

Protein

Protein identifiers

Protein argonaute-3 — Q9H9G7 (reviewed: Q9H9G7)

Alternative names: Argonaute RISC catalytic component 3, Eukaryotic translation initiation factor 2C 3

All UniProt accessions (3): Q9H9G7, A0A0U1RR19, Q5TA56

UniProt curated annotations — full annotation on UniProt →

Function. Required for RNA-mediated gene silencing (RNAi). Binds to short RNAs such as microRNAs (miRNAs) and represses the translation of mRNAs which are complementary to them. Proposed to be involved in stabilization of small RNA derivates (siRNA) derived from processed RNA polymerase III-transcribed Alu repeats containing a DR2 retinoic acid response element (RARE) in stem cells and in the subsequent siRNA-dependent degradation of a subset of RNA polymerase II-transcribed coding mRNAs by recruiting a mRNA decapping complex involving EDC4. Possesses RNA slicer activity but only on select RNAs bearing 5’- and 3’-flanking sequences to the region of guide-target complementarity.

Subunit / interactions. Interacts with EIF4B, IMP8, PRMT5 and TNRC6B. Interacts with APOBEC3F, APOBEC3G and APOBEC3H. Interacts with EDC4.

Subcellular location. Cytoplasm. P-body.

Post-translational modifications. Ubiquitinated on surface-exposed lysines by a SCF-like E3 ubiquitin-protein ligase complex containing ZSWIM8 during target-directed microRNA degradation (TDMD), a process that mediates degradation of microRNAs (miRNAs). Ubiquitination by the SCF-like E3 ubiquitin-protein ligase complex containing ZSWIM8 leads to its subsequent degradation, thereby exposing miRNAs for degradation. ZSWIM8 recognizes and binds AGO3 when it is engaged with a TDMD target.

Similarity. Belongs to the argonaute family. Ago subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H9G7-1	1	yes
Q9H9G7-2	2

RefSeq proteins (2): NP_079128, NP_803171 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003100	PAZ_dom	Domain
IPR003165	Piwi	Domain
IPR012337	RNaseH-like_sf	Homologous_superfamily
IPR014811	ArgoL1	Domain
IPR028603	AGO3	Family
IPR032472	ArgoL2	Domain
IPR032473	Argonaute_Mid_dom	Domain
IPR032474	Argonaute_N	Domain
IPR036085	PAZ_dom_sf	Homologous_superfamily
IPR036397	RNaseH_sf	Homologous_superfamily
IPR045246	Piwi_ago-like	Domain

Pfam: PF02170, PF02171, PF08699, PF16486, PF16487, PF16488

UniProt features (79 total): strand 33, helix 24, turn 8, binding site 4, domain 2, modified residue 2, region of interest 2, chain 1, splice variant 1, mutagenesis site 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
5VM9	X-RAY DIFFRACTION	3.28
8VAJ	X-RAY DIFFRACTION	3.45

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H9G7-F1	91.93	0.82

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 (4): 598; 638; 670; 808

Post-translational modifications (2): 825, 1

Mutagenesis-validated functional residues (1):

Position	Phenotype
638	loss of rna slicer activity.

Function

Pathways and Gene Ontology

Reactome pathways

65 pathways

ID	Pathway
R-HSA-165159	MTOR signalling
R-HSA-1912408	Pre-NOTCH Transcription and Translation
R-HSA-203927	MicroRNA (miRNA) biogenesis
R-HSA-2559580	Oxidative Stress Induced Senescence
R-HSA-2559585	Oncogene Induced Senescence
R-HSA-4086398	Ca2+ pathway
R-HSA-426486	Small interfering RNA (siRNA) biogenesis
R-HSA-426496	Post-transcriptional silencing by small RNAs
R-HSA-5628897	TP53 Regulates Metabolic Genes
R-HSA-5687128	MAPK6/MAPK4 signaling
R-HSA-8853884	Transcriptional Regulation by VENTX
R-HSA-8934593	Regulation of RUNX1 Expression and Activity
R-HSA-8936459	RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function
R-HSA-8943723	Regulation of PTEN mRNA translation
R-HSA-8948700	Competing endogenous RNAs (ceRNAs) regulate PTEN translation
R-HSA-8986944	Transcriptional Regulation by MECP2
R-HSA-9018519	Estrogen-dependent gene expression
R-HSA-9022692	Regulation of MECP2 expression and activity
R-HSA-9029569	NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux
R-HSA-9725371	Nuclear events stimulated by ALK signaling in cancer
R-HSA-9759811	Regulation of CDH11 mRNA translation by microRNAs
R-HSA-9764562	Regulation of CDH1 mRNA translation by microRNAs
R-HSA-9768778	Regulation of NPAS4 mRNA translation
R-HSA-9824594	Regulation of MITF-M-dependent genes involved in apoptosis
R-HSA-9839394	TGFBR3 expression
R-HSA-9909620	Regulation of PD-L1(CD274) translation
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-1266738	Developmental Biology
R-HSA-1500931	Cell-Cell communication
R-HSA-157118	Signaling by NOTCH

MSigDB gene sets: 243 (showing top): REACTOME_SIGNALING_BY_NOTCH, GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOMF_NUCLEASE_ACTIVITY, SP3_Q3, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_TRANSLATION, GOBP_STEM_CELL_PROLIFERATION, REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS, GOBP_TRANSLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOMF_RNA_ENDONUCLEASE_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_NON_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION

GO Biological Process (13): mRNA catabolic process (GO:0006402), positive regulation of gene expression (GO:0010628), pre-miRNA processing (GO:0031054), regulatory ncRNA-mediated post-transcriptional gene silencing (GO:0035194), miRNA processing (GO:0035196), miRNA-mediated gene silencing by inhibition of translation (GO:0035278), RISC complex assembly (GO:0070922), regulation of stem cell proliferation (GO:0072091), positive regulation of non-canonical NF-kappaB signal transduction (GO:1901224), translational initiation (GO:0006413), regulation of translation (GO:0006417), regulatory ncRNA-mediated gene silencing (GO:0031047), miRNA-mediated gene silencing by mRNA destabilization (GO:0035279)

GO Molecular Function (13): RNA binding (GO:0003723), double-stranded RNA binding (GO:0003725), single-stranded RNA binding (GO:0003727), RNA endonuclease activity (GO:0004521), miRNA binding (GO:0035198), metal ion binding (GO:0046872), endoribonuclease activity, cleaving miRNA-paired mRNA (GO:0090624), nucleic acid binding (GO:0003676), translation initiation factor activity (GO:0003743), nuclease activity (GO:0004518), endonuclease activity (GO:0004519), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (11): condensed nuclear chromosome (GO:0000794), P-body (GO:0000932), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), RISC complex (GO:0016442), cytoplasmic ribonucleoprotein granule (GO:0036464), RISC-loading complex (GO:0070578), ribonucleoprotein complex (GO:1990904)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Gene Silencing by RNA	3
Cellular Senescence	2
Generic Transcription Pathway	2
Transcriptional regulation by RUNX1	2
Signal Transduction	1
Pre-NOTCH Expression and Processing	1
Beta-catenin independent WNT signaling	1
Transcriptional Regulation by TP53	1
MAPK family signaling cascades	1
PTEN Regulation	1
Regulation of PTEN mRNA translation	1
ESR-mediated signaling	1
Transcriptional Regulation by MECP2	1
NR1H2 and NR1H3-mediated signaling	1
Signaling by ALK fusions and activated point mutants	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
negative regulation of gene expression	2
regulatory ncRNA-mediated gene silencing	2
miRNA-mediated post-transcriptional gene silencing	2
translation	2
RNA binding	2
binding	2
cytoplasm	2
RNA catabolic process	1
mRNA metabolic process	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
miRNA processing	1
post-transcriptional gene silencing	1
regulatory ncRNA processing	1
negative regulation of translation	1
protein-RNA complex assembly	1
regulation of cell population proliferation	1
stem cell proliferation	1
non-canonical NF-kappaB signal transduction	1
regulation of non-canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
formation of translation initiation ternary complex	1
metabolic process	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
mRNA destabilization	1
nucleic acid binding	1
endonuclease activity	1
RNA nuclease activity	1
regulatory RNA binding	1
cation binding	1
RNA endonuclease activity producing 5’-phosphomonoesters, hydrolytic mechanism	1
miRNA-mediated gene silencing by mRNA destabilization	1
translational initiation	1
translation factor activity	1
catalytic activity, acting on a nucleic acid	1
nuclease activity	1
catalytic activity	1

Protein interactions and networks

STRING

2008 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AGO3	AGO2	Q9UKV8	955
AGO3	AGO1	Q9UL18	858
AGO3	DICER1	Q9UPY3	786
AGO3	TNRC6A	Q8NDV7	745
AGO3	TARBP2	Q15633	740
AGO3	PLD6	Q8N2A8	715
AGO3	DROSHA	Q9NRR4	701
AGO3	AGO4	Q9HCK5	693
AGO3	TNRC6B	Q9UPQ9	685
AGO3	TBPL2	Q6SJ96	670
AGO3	DDX20	Q9UHI6	650
AGO3	HENMT1	Q5T8I9	649
AGO3	DGCR8	Q8WYQ5	619
AGO3	P4HA1	P13674	618
AGO3	PIR	O00625	618

IntAct

74 interactions, top by confidence:

A	B	Type	Score
AGO3	TNRC6A	psi-mi:“MI:0915”(physical association)	0.740
AGO3	TNRC6A	psi-mi:“MI:0403”(colocalization)	0.740
TNRC6A	AGO3	psi-mi:“MI:0915”(physical association)	0.740
TNRC6A	AGO3	psi-mi:“MI:0403”(colocalization)	0.740
AGO3	IPO8	psi-mi:“MI:0915”(physical association)	0.640
IPO8	AGO3	psi-mi:“MI:0915”(physical association)	0.640
IPO8	AGO3	psi-mi:“MI:0403”(colocalization)	0.640
PPP5C	IRS4	psi-mi:“MI:0914”(association)	0.570
AGO2	FKBP5	psi-mi:“MI:0914”(association)	0.530
AGO1	AIP	psi-mi:“MI:0914”(association)	0.530
AP3S1	AP3B1	psi-mi:“MI:0914”(association)	0.530
TNRC6B	AGO3	psi-mi:“MI:0914”(association)	0.530
AGO3	WTIP	psi-mi:“MI:0403”(colocalization)	0.520
AGO3	WTIP	psi-mi:“MI:2364”(proximity)	0.520
AGO3	WTIP	psi-mi:“MI:0915”(physical association)	0.520
PPP5C	AGO3	psi-mi:“MI:0915”(physical association)	0.500
AGO3	LIMD1	psi-mi:“MI:0915”(physical association)	0.460
AGO3	LIMD1	psi-mi:“MI:0403”(colocalization)	0.460
TNRC6B	AGO3	psi-mi:“MI:0915”(physical association)	0.460
TNRC6C	AGO3	psi-mi:“MI:0915”(physical association)	0.460
AGO3	TNRC6C	psi-mi:“MI:0403”(colocalization)	0.460
AGO3	TNRC6B	psi-mi:“MI:0403”(colocalization)	0.460
AGO3	EDC4	psi-mi:“MI:0915”(physical association)	0.400
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
AGO3	ATP4B	psi-mi:“MI:0915”(physical association)	0.370
AGO3	BDNF	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (217): HSP90AA1 (Affinity Capture-MS), HSP90AB4P (Affinity Capture-MS), HSP90AB3P (Affinity Capture-MS), HSP90AA5P (Affinity Capture-MS), AP3M1 (Affinity Capture-MS), AP3D1 (Affinity Capture-MS), FKBP5 (Affinity Capture-MS), AP3B1 (Affinity Capture-MS), AP3S1 (Affinity Capture-MS), ANKMY2 (Affinity Capture-MS), LONRF3 (Affinity Capture-MS), RANGRF (Affinity Capture-MS), AGO3 (Affinity Capture-MS), BAG5 (Affinity Capture-MS), CIR1 (Affinity Capture-MS)

ESM2 similar proteins: A2CEI6, A3KPK0, A6P7L8, A8D8P8, A8KBF3, A9ZSZ2, O04379, O48771, O76922, O77503, O89040, Q0JF58, Q4G033, Q4KLV6, Q5NBN9, Q5Z5B2, Q5ZLG4, Q5ZMW0, Q69VD5, Q6DCX2, Q6DJB9, Q6EU14, Q6K972, Q6QME8, Q6T5B7, Q6YSJ5, Q6Z4F1, Q7PLK0, Q7XSA2, Q7Y001, Q7Z3Z3, Q7Z3Z4, Q84VQ0, Q851R2, Q8CDG1, Q8CGT6, Q8CJF8, Q8CJF9, Q8CJG0, Q8CJG1

Diamond homologs: A3KPK0, O04379, O48771, O74957, O77503, P34681, Q0JF58, Q10F39, Q4KLV6, Q5NBN9, Q5Z5B2, Q5ZLG4, Q5ZMW0, Q69UP6, Q69VD5, Q6DCX2, Q6DJB9, Q6EU14, Q6H6C3, Q6K972, Q6QME8, Q6T5B7, Q6YSJ5, Q6Z4F1, Q75HC2, Q7XSA2, Q7XTS3, Q7XTS4, Q7Y001, Q84VQ0, Q851R2, Q852N2, Q8CJF8, Q8CJF9, Q8CJG0, Q8CJG1, Q9C793, Q9H9G7, Q9HCK5, Q9QZ81

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 70 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
Regulation of RUNX1 Expression and Activity	6	79.0×	3e-09
Regulation of MITF-M-dependent genes involved in apoptosis	6	74.6×	4e-09
TGFBR3 expression	6	53.7×	3e-08
Transcriptional Regulation by MECP2	7	43.5×	7e-09
Regulation of MECP2 expression and activity	6	43.3×	1e-07
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	6	36.3×	4e-07
Oncogene Induced Senescence	5	32.9×	8e-06
MTOR signalling	6	31.2×	9e-07

GO biological processes:

GO term	Partners	Fold	FDR
miRNA-mediated gene silencing by inhibition of translation	9	124.7×	4e-15

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	46
Likely benign	14
Benign	7

Top pathogenic / likely-pathogenic (0)

SpliceAI

3891 predictions. Top by Δscore:

Variant	Effect	Δscore
1:35945686:T:A	acceptor_gain	1.0000
1:35945687:G:A	acceptor_gain	1.0000
1:35945688:GCA:G	acceptor_loss	1.0000
1:35945689:CAGGA:C	acceptor_loss	1.0000
1:35945690:A:AG	acceptor_gain	1.0000
1:35945690:AG:A	acceptor_gain	1.0000
1:35945691:G:A	acceptor_loss	1.0000
1:35945691:G:GG	acceptor_gain	1.0000
1:35945691:GG:G	acceptor_gain	1.0000
1:35945691:GGA:G	acceptor_gain	1.0000
1:35945691:GGAC:G	acceptor_gain	1.0000
1:35945691:GGACC:G	acceptor_gain	1.0000
1:35945861:CAG:C	donor_loss	1.0000
1:35945862:AG:A	donor_loss	1.0000
1:35945863:GG:G	donor_loss	1.0000
1:35945864:G:GC	donor_loss	1.0000
1:35945864:G:GG	donor_gain	1.0000
1:35945865:T:A	donor_loss	1.0000
1:35966953:AG:A	acceptor_gain	1.0000
1:35966954:GG:G	acceptor_gain	1.0000
1:35967073:GGG:G	donor_gain	1.0000
1:35967074:GG:G	donor_gain	1.0000
1:35967074:GGG:G	donor_gain	1.0000
1:35967075:GG:G	donor_gain	1.0000
1:35972020:ACAG:A	acceptor_loss	1.0000
1:35972021:CA:C	acceptor_loss	1.0000
1:35972022:A:AT	acceptor_loss	1.0000
1:35972023:G:GA	acceptor_loss	1.0000
1:35972023:GGTA:G	acceptor_gain	1.0000
1:35972230:G:GT	donor_gain	1.0000

AlphaMissense

5619 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:35945777:C:A	N35K	1.000
1:35945777:C:G	N35K	1.000
1:35973389:G:A	G179E	1.000
1:35973400:T:C	F183L	1.000
1:35973402:C:A	F183L	1.000
1:35973402:C:G	F183L	1.000
1:35973457:G:A	G202R	1.000
1:35973457:G:C	G202R	1.000
1:35973458:G:A	G202E	1.000
1:35973458:G:T	G202V	1.000
1:35973500:T:C	L216P	1.000
1:35973508:G:C	D219H	1.000
1:35973509:A:T	D219V	1.000
1:36004347:C:A	A222D	1.000
1:36004353:C:A	A224D	1.000
1:36004355:T:C	F225L	1.000
1:36004357:C:A	F225L	1.000
1:36004357:C:G	F225L	1.000
1:36004470:T:A	I263K	1.000
1:36008699:T:A	V268D	1.000
1:36008741:T:A	V282D	1.000
1:36008765:C:A	A290D	1.000
1:36008898:T:C	F295L	1.000
1:36008899:T:C	F295S	1.000
1:36008900:T:A	F295L	1.000
1:36008900:T:G	F295L	1.000
1:36008952:T:C	F313L	1.000
1:36008953:T:C	F313S	1.000
1:36008954:C:A	F313L	1.000
1:36008954:C:G	F313L	1.000

dbSNP variants (sampled 300 via entrez): RS1000017230 (1:35985073 C>G), RS1000031916 (1:36027707 A>T), RS1000037733 (1:35943696 G>A), RS1000119444 (1:36026144 T>C), RS1000158127 (1:36033289 A>T), RS1000158292 (1:35964824 T>A,C), RS1000205525 (1:35981907 G>A,C), RS1000237441 (1:35958861 A>G), RS1000280959 (1:35930003 T>A,C,G), RS1000292259 (1:36071878 T>C), RS1000292843 (1:36051667 C>A,G), RS1000301709 (1:36016237 A>T), RS1000303103 (1:35974856 A>G), RS1000333320 (1:35995027 T>C), RS1000334083 (1:35975346 T>C)

Disease associations

OMIM: gene MIM:607355 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Limited	Autosomal dominant

Mondo (1): neurodevelopmental disorder (MONDO:0700092)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006529_1	Barrett’s esophagus x BMI interaction	4.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	decreases methylation, increases methylation	2
2,4,6-tribromophenol	decreases expression	1
testosterone enanthate	affects expression	1
bisphenol A	affects cotreatment, decreases expression	1
decabromobiphenyl ether	decreases expression	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
tetrabromobisphenol A	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol S	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects methylation	1
Carbamazepine	affects expression	1
Cisplatin	affects cotreatment, decreases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Diclofenac	affects expression	1
Indomethacin	affects cotreatment, decreases expression	1
Methyl Methanesulfonate	increases expression	1
Potassium Dichromate	decreases expression	1
Urethane	increases expression	1
Valproic Acid	increases expression	1
1-Methyl-3-isobutylxanthine	decreases expression, affects cotreatment	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Cyclosporine	increases expression	1

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1J8	Abcam HeLa AGO3 KO	Cancer cell line	Female
CVCL_C7ZL	HAP1 AGO3 (-) 1	Cancer cell line	Male
CVCL_C7ZM	HAP1 AGO3 (-) 2	Cancer cell line	Male
CVCL_D8YW	Ubigene HEK293 AGO3 KO	Transformed cell line	Female

Clinical trials (associated diseases)

202 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,
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
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
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
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
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice