AGO2

Summary

AGO2 (argonaute RISC catalytic component 2, HGNC:3263) is a protein-coding gene on chromosome 8q24.3, encoding Protein argonaute-2 (Q9UKV8). Required for RNA-mediated gene silencing (RNAi) by the RNA-induced silencing complex (RISC).

This gene encodes a member of the Argonaute family of proteins which play a role in RNA interference. The encoded protein is highly basic, and contains a PAZ domain and a PIWI domain. It may interact with dicer1 and play a role in short-interfering-RNA-mediated gene silencing. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 27161 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Lessel-Kreienkamp syndrome (Definitive, ClinGen)
• GWAS associations: 11
• Clinical variants (ClinVar): 215 total — 5 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 36
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_012154

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3263
Approved symbol	AGO2
Name	argonaute RISC catalytic component 2
Location	8q24.3
Locus type	gene with protein product
Status	Approved
Aliases	hAGO2, Q10, LINC00980
Ensembl gene	ENSG00000123908
Ensembl biotype	protein_coding
OMIM	606229
Entrez	27161

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 3 protein_coding, 3 protein_coding_CDS_not_defined, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000220592, ENST00000517293, ENST00000518019, ENST00000519347, ENST00000519980, ENST00000520412, ENST00000520628, ENST00000521325, ENST00000523609, ENST00000524328

RefSeq mRNA: 2 — MANE Select: NM_012154 NM_001164623, NM_012154

CCDS: CCDS55279, CCDS6380

Canonical transcript exons

ENST00000220592 — 19 exons

Exon	Start	End
ENSE00002115766	140635485	140635633
ENSE00002573500	140520156	140532152
ENSE00003465478	140572812	140572932
ENSE00003468648	140555896	140556018
ENSE00003476350	140532416	140532615
ENSE00003498594	140559395	140559529
ENSE00003499669	140556167	140556286
ENSE00003528791	140541164	140541358
ENSE00003544094	140562453	140562634
ENSE00003548954	140549114	140549298
ENSE00003569278	140557089	140557236
ENSE00003594655	140544213	140544303
ENSE00003598658	140551303	140551436
ENSE00003601006	140585119	140585311
ENSE00003641526	140539320	140539454
ENSE00003644665	140535468	140535569
ENSE00003660001	140558485	140558572
ENSE00003661900	140560374	140560510
ENSE00003679723	140547468	140547627

Expression profiles

Bgee: expression breadth ubiquitous, 279 present calls, max score 95.46.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.4114 / max 236.6233, expressed in 1799 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
95335	20.9811	1796
95326	0.4303	211

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
colonic epithelium	UBERON:0000397	95.46	gold quality
cartilage tissue	UBERON:0002418	94.78	gold quality
cauda epididymis	UBERON:0004360	94.45	gold quality
superficial temporal artery	UBERON:0001614	93.40	gold quality
trabecular bone tissue	UBERON:0002483	93.38	gold quality
corpus epididymis	UBERON:0004359	92.91	gold quality
mucosa of paranasal sinus	UBERON:0005030	92.73	gold quality
lower lobe of lung	UBERON:0008949	92.68	gold quality
tendon	UBERON:0000043	92.43	gold quality
calcaneal tendon	UBERON:0003701	92.31	gold quality
caput epididymis	UBERON:0004358	91.89	gold quality
corpus callosum	UBERON:0002336	91.69	gold quality
parietal pleura	UBERON:0002400	91.55	gold quality
blood	UBERON:0000178	91.41	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	91.30	gold quality
adrenal tissue	UBERON:0018303	91.26	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	91.10	gold quality
tendon of biceps brachii	UBERON:0008188	90.96	gold quality
visceral pleura	UBERON:0002401	90.74	gold quality
pleura	UBERON:0000977	90.71	gold quality
seminal vesicle	UBERON:0000998	90.08	gold quality
medial globus pallidus	UBERON:0002477	89.47	gold quality
oocyte	CL:0000023	89.46	gold quality
adult organism	UBERON:0007023	89.39	gold quality
biceps brachii	UBERON:0001507	89.34	gold quality
secondary oocyte	CL:0000655	89.06	gold quality
sural nerve	UBERON:0015488	89.03	gold quality
globus pallidus	UBERON:0001875	88.98	gold quality
synovial joint	UBERON:0002217	88.98	gold quality
tibia	UBERON:0000979	88.86	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
IL2	Activation

Upstream regulators (CollecTRI, top): ESR1, FOXC1

miRNA regulators (miRDB)

43 targeting AGO2, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-202-5P	99.78	67.65	991
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-4527	99.66	67.43	714
HSA-MIR-4502	99.65	66.99	1021
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-6503-5P	99.62	66.96	597
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-942-5P	99.41	68.40	1977
HSA-MIR-5580-5P	99.38	66.96	1139
HSA-MIR-92B-5P	99.36	63.29	110
HSA-MIR-376A-3P	99.06	69.17	1128
HSA-MIR-376B-3P	99.06	69.17	1128

Literature-anchored findings (GeneRIF, showing 40)

• responsible for messenger RNA cleavage activity; evidence supports a model in which Argonaute contributes “Slicer” activity to RISC, providing the catalytic engine for RNAi (PMID:15284456)
• Argonaute proteins catalyze mRNA cleavage within RNA-Induced Silencing Complex (PMID:15800637)
• Argonaute 2, a key component of RISC, is not randomly distributed but concentrates in mRNA decay centres that are known as cytoplasmic bodies. (PMID:15908945)
• Activity of siRNA duplexes containing full 2’-OMe substitutions in the sense strand is mediated by the RNA-induced silencing complex and that strand-specific loading to hAgo2 may be modulated through selective incorporation of these modifications. (PMID:16301602)
• miRNA loading complex (miRLC) is formed by Ago2 and Dicer prior to their encounter with pre-miRNA. (PMID:16357216)
• Here, we show that the human slicer Argonaute2 (HsAgo2), but not HsAgo1, functions in RNAi in the early divergent protozoan Trypanosoma brucei, thus mimicking the situation in mammalian cells (PMID:16611939)
• AGO1 and AGO2 associate with promoter DNA in cells treated with antigene RNAs (agRNAs), and inhibiting expression of AGO1 or AGO2 reverses transcriptional and post-transcriptional silencing. (PMID:16936728)
• give a quantitative account of the Argonaute protein localization and dynamics in living cells in different cellular states (PMID:17116888)
• A crosslinking-coupled affinity purification method was used to isolate TNF-alpha AU-rich element-associated proteins: two microRNP-related proteins, FXR1 and AGO2 were found that associate during translation activation. (PMID:17382880)
• Ago2 represses the initiation of mRNA translation by binding to the m(7)G cap of mRNA targets, thus likely precluding the recruitment of eIF4E (PMID:17524464)
• The action of RNA-induced silencing complex (RISC) requires the endonucleolytic slicer activity of Argonaute2 (Ago2) (PMID:17531811)
• Local widening of the duplex formed by the siRNA guide strand and the targeted region of mRNA is a possible reason for the intolerance of human Ago2, the RISC endonuclease, toward internal mismatch pairs involving native or chemically modified RNA. (PMID:17881374)
• Results describe a repetitive motif within Tas3, termed the ‘Argonaute hook’, that is conserved from yeast to humans and binds Ago1 and 2 through their PIWI domains in vitro and in vivo. (PMID:17891150)
• Data show that Argonaute1 and 2 reside in three complexes with distinct Dicer and RNA-induced silencing complex activities, and that the putative RNA-binding protein RBM4 is required for microRNA-guided gene regulation. (PMID:17932509)
• Ago2, Dicer, and TRBP comprise the RISC-loading complex (RLC) and assembles spontaneously in vitro from purified components (PMID:18178619)
• These present data demonstrate that siAgo2 inhibited indispensable events of angiogenesis in vitro. (PMID:18222171)
• The results suggest a potential regulatory mechanism for RNA silencing acting through Ago2 serine-387 phosphorylation mediated by the p38 MAPK pathway. (PMID:18476811)
• Ectopic expression of the Argonaute-2 (Ago2, eIF2C2) dramatically enhances RNA interference specifically for mRNA targets with perfectly matched binding sites. (PMID:18591665)
• findings identify hydroxylation as a post-translational modification important for Ago2 stability and effective RNA interference (PMID:18690212)
• The specificity of RNA interference depends on the concentration of Ago1, Ago3, and Ago4 relative to Ago2. (PMID:18771919)
• Ago2 is regulated at both the transcriptional and posttranslational level, and Ago2 and enhanced micro-RNA activity is seen in the tumorigenic progression of breast cancer cell lines. (PMID:18787018)
• Data show that siRNA transfection induces up-regulated expression of both GW182, a key P-body component, and Ago2, indicating that P-body localization and interaction with GW182 and Ago2 are important in siRNA-mediated RNAi. (PMID:18946079)
• plays a roll in processes of tumor angiogenesis. (PMID:18981691)
• Mutant Ago2 protein containing 6 point mutations (G32W, F128L, R196Q, P458S, T741A, S752G) failed to accumulate in P-bodies. (PMID:19061863)
• Data report that stable, long-term overexpression of Argonaute2, an Argonaute isoform, induces the production of a number of microRNAs, such as the let-7 family of microRNAs, in 293T cells. (PMID:19064005)
• Mapping of the MC sequence to the mid domain structure reveals Ago2 aromatics that are incompatible with eIF4E-like mRNA cap-binding, yet display some limited local structure similarities that cause the chance sequence match to eIF4E (PMID:19159466)
• Study demonstrates that Imp8 is required for the recruitment of Ago protein complexes to a large set of Ago2-associated target mRNAs, allowing for efficient and specific gene silencing. (PMID:19167051)
• Tethering the C-terminal half of Ago2 to the 3’-UTR of reporter mRNA recapitulated translational repression comparable to that of tethered Ago2, and this repression was greatly impaired upon GW182 knockdown. (PMID:19324964)
• EIF2C2 protein shows an opposite trend, with an expression in N-type cells that is lower than in I-type cells (PMID:19393748)
• Hsp90 is a critical modulator of Argonaute function. (PMID:19458189)
• The interaction of Argonaute2 with the 5’ uracil base plays a critical role in the recruitment of mRNA. (PMID:19508234)
• High-throughput sequencing of Ago bound RNAs isolated by crosslinking immunoprecipitation (HITS-CLIP) identifies functional protein-RNA interaction sites in brain; validated miR-124 sites are also identified in HeLa cells. (PMID:19536157)
• Ago2 immunoprecipitated from HeLa cells contained the double strand RNA-binding protein human immunodeficiency virus, type 1, trans-activating response RNA-binding protein (PMID:19625255)
• Data show that Ago1 and Ago2 (which encode argonautes, the key proteins forming the RNA-induced silencing complex (RISC)) had significantly higher expression levels in ER- than in ER+ breast cancer. (PMID:19723326)
• Ago2 immunoprecipitation identifies predicted microRNAs in human embryonic stem cells and neural precursors (PMID:19784364)
• Data show that RBM4 interacts directly with Ago2 during muscle cell differentiation and may recruit Ago2 to suppress translation of target mRNAs. (PMID:19801630)
• The RLC Dicer’s N-terminal DExH/D domain, located in a short ‘base branch’, interacts with TRBP, whereas its C-terminal catalytic domains in the main body are proximal to AGO2. (PMID:19820710)
• The authors demonstrate that AGO1 uses only miRNA duplexes when assembling translational repression-competent complexes, whereas AGO2 can use both miRNA and siRNA duplexes. (PMID:19946268)
• EIF2C2-4 and PIWIL4 appear increased in advanced tumors with distant metastasis, suggesting they may promote tumor invasion (PMID:20146808)
• Data show that fibroblast growth factor-2 is regulated by an endogenous antisense RNA and by argonaute-2. (PMID:20197313)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ago2	ENSDARG00000061268
mus_musculus	Ago2	ENSMUSG00000036698
rattus_norvegicus	Ago2	ENSRNOG00000008533
drosophila_melanogaster	AGO1	FBGN0262739
caenorhabditis_elegans		WBGENE00000105
caenorhabditis_elegans		WBGENE00000106

Paralogs (3): AGO1 (ENSG00000092847), AGO3 (ENSG00000126070), AGO4 (ENSG00000134698)

Protein

Protein identifiers

Protein argonaute-2 — Q9UKV8 (reviewed: Q9UKV8)

Alternative names: Argonaute RISC catalytic component 2, Eukaryotic translation initiation factor 2C 2, PAZ Piwi domain protein, Protein slicer

All UniProt accessions (3): E5RGG9, E5RJY2, Q9UKV8

UniProt curated annotations — full annotation on UniProt →

Function. Required for RNA-mediated gene silencing (RNAi) by the RNA-induced silencing complex (RISC). The ‘minimal RISC’ appears to include AGO2 bound to a short guide RNA such as a microRNA (miRNA) or short interfering RNA (siRNA). These guide RNAs direct RISC to complementary mRNAs that are targets for RISC-mediated gene silencing. The precise mechanism of gene silencing depends on the degree of complementarity between the miRNA or siRNA and its target. Binding of RISC to a perfectly complementary mRNA generally results in silencing due to endonucleolytic cleavage of the mRNA specifically by AGO2. Binding of RISC to a partially complementary mRNA results in silencing through inhibition of translation, and this is independent of endonuclease activity. May inhibit translation initiation by binding to the 7-methylguanosine cap, thereby preventing the recruitment of the translation initiation factor eIF4-E. May also inhibit translation initiation via interaction with EIF6, which itself binds to the 60S ribosomal subunit and prevents its association with the 40S ribosomal subunit. The inhibition of translational initiation leads to the accumulation of the affected mRNA in cytoplasmic processing bodies (P-bodies), where mRNA degradation may subsequently occur. In some cases RISC-mediated translational repression is also observed for miRNAs that perfectly match the 3’ untranslated region (3’-UTR). Can also up-regulate the translation of specific mRNAs under certain growth conditions. Binds to the AU element of the 3’-UTR of the TNF mRNA and up-regulates translation under conditions of serum starvation. Also required for transcriptional gene silencing (TGS), in which short RNAs known as antigene RNAs or agRNAs direct the transcriptional repression of complementary promoter regions. (Microbial infection) Upon Sars-CoV-2 infection, associates with viral miRNA-like small RNA, CoV2-miR-O7a, and may repress mRNAs, such as BATF2, to evade the IFN response.

Subunit / interactions. Interacts with DICER1 through its Piwi domain and with TARBP2 during assembly of the RNA-induced silencing complex (RISC). Together, DICER1, AGO2 and TARBP2 constitute the trimeric RISC loading complex (RLC), or micro-RNA (miRNA) loading complex (miRLC). Within the RLC/miRLC, DICER1 and TARBP2 are required to process precursor miRNAs (pre-miRNAs) to mature miRNAs and then load them onto AGO2. AGO2 bound to the mature miRNA constitutes the minimal RISC and may subsequently dissociate from DICER1 and TARBP2. Note however that the term RISC has also been used to describe the trimeric RLC/miRLC. The formation of RISC complexes containing siRNAs rather than miRNAs appears to occur independently of DICER1. Interacts with AGO1. Also interacts with DDB1, DDX5, DDX6, DDX20, DHX30, DHX36, DDX47, DHX9, ELAVL, FXR1, GEMIN4, HNRNPF, IGF2BP1, ILF3, IMP8, MATR3, PABPC1, PRMT5, P4HA1, P4HB, RBM4, SART3, TNRC6A, TNRC6B, UPF1 and YBX1. Interacts with the P-body components DCP1A and XRN1. Associates with polysomes and messenger ribonucleoproteins (mNRPs). Interacts with RBM4; the interaction is modulated under stress-induced conditions, occurs under both cell proliferation and differentiation conditions and in an RNA- and phosphorylation-independent manner. Interacts with LIMD1, WTIP and AJUBA. Interacts with TRIM71; the interaction increases in presence of RNA. Interacts with APOBEC3G in an RNA-dependent manner. Interacts with APOBEC3A, APOBEC3C, APOBEC3F and APOBEC3H. Interacts with DICER1, TARBP2, EIF6, MOV10 and RPL7A (60S ribosome subunit); they form a large RNA-induced silencing complex (RISC). Interacts with FMR1. Interacts with ZFP36. Found in a complex, composed of AGO2, CHD7 and ARB2A. Interacts with RC3H1; the interaction is RNA independent. Interacts with SND1. Interacts with SYT11. Interacts with CLNK. Interacts with GARRE1. Interacts with GRB2; this interaction is important for the formation of a ternary complex containing GRB2, AGO2 and DICER1. (Microbial infection) Interacts with Epstein-Barr virus (EBV) tegument protein BGLF2; this interaction participates in the regulation of cellular miRNA by the virus, leading to enhanced SUMOylation. (Microbial infection) Interacts with rotavirus A non-structural protein 5; this interaction probably plays a role in the sequestration of AGO2 in viral factories. (Microbial infection) Interacts with human herpesvirus 8 protein MTA/ORF57; this interaction inhibits P-body formation.

Subcellular location. Cytoplasm. P-body. Nucleus.

Post-translational modifications. Hydroxylated. 4-hydroxylation appears to enhance protein stability but is not required for miRNA-binding or endonuclease activity. 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 AGO2 when it is engaged with a TDMD target. Phosphorylated. A phosphorylation cycle of C-terminal serine cluster (Ser-824-Ser-834) regulates the release of target mRNAs. Target-binding leads to phosphorylation of these residues by CSNK1A1, which reduces the affinity of AGO2 for mRNA and enables target release. The ANKRD52-PPP6C phosphatase complex dephosphorylates the residues, which primes AGO2 for binding a new target. Phosphorylation at Ser-387 by AKT3; leads to up-regulate translational repression of microRNA target and down-regulate endonucleolytic cleavage.

Disease relevance. Lessel-Kreienkamp syndrome (LESKRES) [MIM:619149] An autosomal dominant disorder characterized by global developmental delay, intellectual disability of variable degree, and speech and language delay apparent from infancy or early childhood. Behavioral disorders are observed in most patients. Additional variable features include seizures, hypotonia, gait abnormalities, visual and cardiac defects, and non-specific facial dysmorphism. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by EDTA.

Domain organisation. The Piwi domain may perform RNA cleavage by a mechanism similar to that of RNase H. However, while RNase H utilizes a triad of Asp-Asp-Glu (DDE) for metal ion coordination, this protein appears to utilize a triad of Asp-Asp-His (DDH).

Similarity. Belongs to the argonaute family. Ago subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UKV8-1	1	yes
Q9UKV8-2	2

RefSeq proteins (2): NP_001158095, NP_036286* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003100	PAZ_dom	Domain
IPR003165	Piwi	Domain
IPR012337	RNaseH-like_sf	Homologous_superfamily
IPR014811	ArgoL1	Domain
IPR028602	AGO2	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 (144 total): strand 43, helix 29, mutagenesis site 23, turn 11, sequence variant 11, region of interest 8, modified residue 7, sequence conflict 4, binding site 3, domain 2, chain 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

67 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9BF2	X-RAY DIFFRACTION	1.59
4Z4D	X-RAY DIFFRACTION	1.6
3LUC	X-RAY DIFFRACTION	1.69
3LUK	X-RAY DIFFRACTION	1.7
7C6B	X-RAY DIFFRACTION	1.7
9LSN	X-RAY DIFFRACTION	1.75
9BF0	X-RAY DIFFRACTION	1.78
3LUJ	X-RAY DIFFRACTION	1.8
4Z4E	X-RAY DIFFRACTION	1.8
9LMZ	X-RAY DIFFRACTION	1.8
4W5O	X-RAY DIFFRACTION	1.8
3LUG	X-RAY DIFFRACTION	1.85
6RA4	X-RAY DIFFRACTION	1.9
9BEZ	X-RAY DIFFRACTION	1.9
3LUH	X-RAY DIFFRACTION	2
3QX9	X-RAY DIFFRACTION	2
7D7U	X-RAY DIFFRACTION	2
9OBD	X-RAY DIFFRACTION	2.02
3LUD	X-RAY DIFFRACTION	2.1
9LSO	X-RAY DIFFRACTION	2.13
5KI6	X-RAY DIFFRACTION	2.15
6CBD	X-RAY DIFFRACTION	2.2
4F3T	X-RAY DIFFRACTION	2.25
3QX8	X-RAY DIFFRACTION	2.3
4OLA	X-RAY DIFFRACTION	2.3
9OBE	X-RAY DIFFRACTION	2.3
4Z4C	X-RAY DIFFRACTION	2.3
8THQ	X-RAY DIFFRACTION	2.41
5JS1	X-RAY DIFFRACTION	2.5
4W5R	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UKV8-F1	92.82	0.86

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 (3): 597; 669; 807

Post-translational modifications (7): 2, 387, 700, 824, 828, 831, 834

Mutagenesis-validated functional residues (23):

Position	Phenotype
140	no effect.
470	no effect on mirna-binding or target mrna cleavage. abrogates binding to the 7-methylguanosine cap of mrna and prevents
470	no effect on binding to the 7-methylguanosine cap of mrna or inhibition of translation.
505	no effect on mirna-binding or target mrna cleavage. abrogates binding to the 7-methylguanosine cap of mrna and prevents
505	no effect on binding to the 7-methylguanosine cap of mrna or inhibition of translation.
533	impairs rna cleavage.
545	impairs rna cleavage.
570	impairs rna cleavage.
597	abrogates rna cleavage but does not affect binding to sirna or translational repression.
633	no effect.
633	abrogates rna cleavage. binds sirna.
634	abrogates rna cleavage. binds sirna.
669	abrogates rna cleavage but does not affect binding to sirna.
673	impairs rna cleavage.
673	no effect on rna cleavage.
676	impairs rna cleavage.
676	abrogates rna cleavage.
682	no effect.
683	no effect on rna cleavage.
700	reduced protein stability.
704	no effect.
744	no effect.
807	abrogates rna cleavage.

Function

Pathways and Gene Ontology

Reactome pathways

61 pathways

ID	Pathway
R-HSA-165159	MTOR signalling
R-HSA-1912408	Pre-NOTCH Transcription and Translation
R-HSA-203927	MicroRNA (miRNA) biogenesis
R-HSA-4086398	Ca2+ pathway
R-HSA-426486	Small interfering RNA (siRNA) biogenesis
R-HSA-426496	Post-transcriptional silencing by small RNAs
R-HSA-5578749	Transcriptional regulation by small RNAs
R-HSA-5628897	TP53 Regulates Metabolic Genes
R-HSA-5687128	MAPK6/MAPK4 signaling
R-HSA-8934593	Regulation of RUNX1 Expression and Activity
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-9820841	M-decay: degradation of maternal mRNAs by maternally stored factors
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
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease

MSigDB gene sets: 508 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, MODULE_97, REACTOME_SIGNALING_BY_NOTCH, GOBP_POSITIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, WANG_CLIM2_TARGETS_UP, GOBP_P_BODY_ASSEMBLY, PAX4_01, DACOSTA_UV_RESPONSE_VIA_ERCC3_XPCS_DN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOMF_NUCLEASE_ACTIVITY, STEARMAN_LUNG_CANCER_EARLY_VS_LATE_DN

GO Biological Process (28): translation (GO:0006412), post-embryonic development (GO:0009791), miRNA metabolic process (GO:0010586), siRNA processing (GO:0030422), regulatory ncRNA-mediated gene silencing (GO:0031047), pre-miRNA processing (GO:0031054), P-body assembly (GO:0033962), regulatory ncRNA-mediated post-transcriptional gene silencing (GO:0035194), miRNA processing (GO:0035196), miRNA-mediated gene silencing by inhibition of translation (GO:0035278), miRNA-mediated gene silencing by mRNA destabilization (GO:0035279), negative regulation of amyloid precursor protein biosynthetic process (GO:0042985), RNA stabilization (GO:0043489), positive regulation of translation (GO:0045727), positive regulation of angiogenesis (GO:0045766), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation of translational initiation (GO:0045947), positive regulation of nuclear-transcribed mRNA poly(A) tail shortening (GO:0060213), RISC complex assembly (GO:0070922), regulation of synapse maturation (GO:0090128), siRNA-mediated gene silencing by mRNA destabilization (GO:0090625), positive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay (GO:1900153), positive regulation of trophoblast cell migration (GO:1901165), regulation of DNA-templated transcription (GO:0006355), translational initiation (GO:0006413), regulation of translation (GO:0006417), gene expression (GO:0010467), positive regulation of gene expression (GO:0010628)

GO Molecular Function (22): RNA 7-methylguanosine cap binding (GO:0000340), RNA polymerase II complex binding (GO:0000993), core promoter sequence-specific DNA binding (GO:0001046), RNA binding (GO:0003723), double-stranded RNA binding (GO:0003725), single-stranded RNA binding (GO:0003727), translation initiation factor activity (GO:0003743), RNA endonuclease activity (GO:0004521), siRNA binding (GO:0035197), miRNA binding (GO:0035198), mRNA 3’-UTR AU-rich region binding (GO:0035925), metal ion binding (GO:0046872), endoribonuclease activity, cleaving siRNA-paired mRNA (GO:0070551), endoribonuclease activity, cleaving miRNA-paired mRNA (GO:0090624), mRNA cap binding (GO:0098808), nucleic acid binding (GO:0003676), mRNA binding (GO:0003729), nuclease activity (GO:0004518), endonuclease activity (GO:0004519), protein binding (GO:0005515), hydrolase activity (GO:0016787), RNA endonuclease activity producing 5’-phosphomonoesters, hydrolytic mechanism (GO:0016891)

GO Cellular Component (14): P-body (GO:0000932), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), RISC complex (GO:0016442), dendrite (GO:0030425), cytoplasmic ribonucleoprotein granule (GO:0036464), extracellular exosome (GO:0070062), RISC-loading complex (GO:0070578), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), ribonucleoprotein complex (GO:1990904)

Reactome top-level categories

Rollup of top-17 pathways:

Category	Pathways
Gene Silencing by RNA	4
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
Transcriptional regulation by RUNX1	1
PTEN Regulation	1
Regulation of PTEN mRNA translation	1
Generic Transcription Pathway	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
Regulation of CDH11 Expression and Function	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
translational initiation	3
RNA binding	3
regulatory ncRNA processing	2
regulatory ncRNA-mediated gene silencing	2
negative regulation of translation	2
miRNA-mediated post-transcriptional gene silencing	2
RNA cap binding	2
regulatory RNA binding	2
RNA endonuclease activity producing 5’-phosphomonoesters, hydrolytic mechanism	2
binding	2
cytoplasm	2
synapse	2
peptidyltransferase activity	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
multicellular organism development	1
multicellular organismal process	1
RNA metabolic process	1
negative regulation of gene expression	1
miRNA processing	1
membraneless organelle assembly	1
post-transcriptional gene silencing	1
mRNA destabilization	1
negative regulation of glycoprotein biosynthetic process	1
amyloid precursor protein biosynthetic process	1
regulation of amyloid precursor protein biosynthetic process	1
regulation of RNA stability	1
negative regulation of RNA catabolic process	1
translation	1
regulation of translation	1
positive regulation of gene expression	1
positive regulation of protein metabolic process	1
angiogenesis	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
regulation of transcription by RNA polymerase II	1

Protein interactions and networks

STRING

4432 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AGO2	DICER1	Q9UPY3	999
AGO2	TARBP2	Q15633	998
AGO2	TNRC6A	Q8NDV7	998
AGO2	DDX20	Q9UHI6	998
AGO2	GEMIN4	P57678	997
AGO2	FXR1	P51114	993
AGO2	FMR1	Q06787	993
AGO2	ELAVL1	Q15717	993
AGO2	MOV10	Q9HCE1	991
AGO2	HSP90AA1	P07900	990
AGO2	NPM1	P06748	989
AGO2	HSP90AB1	P08238	989
AGO2	DDX6	P26196	988
AGO2	AGO1	Q9UL18	982
AGO2	TNRC6B	Q9UPQ9	981

IntAct

279 interactions, top by confidence:

A	B	Type	Score
HDAC1	RB1	psi-mi:“MI:0914”(association)	0.960
TNRC6A	AGO2	psi-mi:“MI:0914”(association)	0.960
TNRC6A	AGO2	psi-mi:“MI:0915”(physical association)	0.960
TNRC6A	AGO2	psi-mi:“MI:0403”(colocalization)	0.960
TNRC6A	AGO2	psi-mi:“MI:2364”(proximity)	0.960
AGO2	TNRC6A	psi-mi:“MI:0403”(colocalization)	0.960
AGO2	TNRC6A	psi-mi:“MI:0915”(physical association)	0.960
DICER1	AGO2	psi-mi:“MI:0915”(physical association)	0.950
AGO2	TARBP2	psi-mi:“MI:0915”(physical association)	0.930
AGO2	TNRC6B	psi-mi:“MI:0915”(physical association)	0.930
AGO2	TARBP2	psi-mi:“MI:0914”(association)	0.930
DICER1	AGO2	psi-mi:“MI:0407”(direct interaction)	0.900
AGO2	DICER1	psi-mi:“MI:0915”(physical association)	0.900
AGO1	TNRC6A	psi-mi:“MI:0914”(association)	0.900
AGO2	DDX6	psi-mi:“MI:0914”(association)	0.810
AGO2	DDX6	psi-mi:“MI:0407”(direct interaction)	0.810
AGO2	DDX6	psi-mi:“MI:2364”(proximity)	0.810
AGO2	DDX6	psi-mi:“MI:0915”(physical association)	0.810

BioGRID (2397): AGO2 (Affinity Capture-MS), CNOT1 (Affinity Capture-Western), CNOT2 (Affinity Capture-Western), CNOT6 (Affinity Capture-Western), CNOT6L (Affinity Capture-Western), CNOT8 (Affinity Capture-Western), TNRC6C (Affinity Capture-Western), AGO2 (Affinity Capture-MS), AGO2 (Affinity Capture-MS), TARBP2 (Affinity Capture-MS), GMPS (Affinity Capture-MS), DICER1 (Affinity Capture-MS), AGO2 (Affinity Capture-MS), AGO2 (Affinity Capture-Western), CRBN (Affinity Capture-Western)

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

19 interactions.

A	Effect	B	Mechanism
AGO2	“form complex”	RISC(DICER1/AGO2/TARBP2)	binding
AGO2	“form complex”	DICER1/hAgo2/PRKRA	binding
MAPKAPK2	up-regulates	AGO2	phosphorylation
AKT3	up-regulates	AGO2	phosphorylation
CSNK1A1	“down-regulates activity”	AGO2	phosphorylation
PPP6C	“up-regulates activity”	AGO2	dephosphorylation
PTPN1	“down-regulates activity”	AGO2	dephosphorylation
EGFR	“up-regulates activity”	AGO2	phosphorylation
TNRC6B	“up-regulates activity”	AGO2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 117 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 MITF-M-dependent genes involved in apoptosis	8	64.2×	9e-11
Regulation of RUNX1 Expression and Activity	6	51.0×	6e-08
MicroRNA (miRNA) biogenesis	6	34.7×	5e-07
TGFBR3 expression	6	34.7×	5e-07
Regulation of MECP2 expression and activity	7	32.6×	7e-08
Oncogene Induced Senescence	7	29.8×	1e-07
Nuclear events stimulated by ALK signaling in cancer	7	28.9×	2e-07
Transcriptional Regulation by MECP2	7	28.1×	2e-07

GO biological processes:

GO term	Partners	Fold	FDR
miRNA-mediated gene silencing by inhibition of translation	9	79.8×	5e-13
pre-miRNA processing	6	67.4×	4e-08
positive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	5	56.2×	3e-06
miRNA processing	5	52.7×	4e-06
positive regulation of DNA repair	5	17.9×	6e-04
intrinsic apoptotic signaling pathway	5	17.9×	6e-04
mRNA transport	6	15.8×	2e-04
positive regulation of non-canonical NF-kappaB signal transduction	6	15.3×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	8
Uncertain significance	128
Likely benign	31
Benign	14

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
995791	NM_012154.5(AGO2):c.575T>C (p.Leu192Pro)	Pathogenic
995792	NM_012154.5(AGO2):c.1070C>T (p.Thr357Met)	Pathogenic
995793	NM_012154.5(AGO2):c.1091T>C (p.Met364Thr)	Pathogenic
995795	NM_012154.5(AGO2):c.541TTC[1] (p.Phe182del)	Pathogenic
995796	NM_012154.5(AGO2):c.2197G>C (p.Gly733Arg)	Pathogenic
1803264	NM_012154.5(AGO2):c.1619T>C (p.Leu540Pro)	Likely pathogenic
1992346	NM_012154.5(AGO2):c.2389G>A (p.Val797Met)	Likely pathogenic
2577022	NM_012154.5(AGO2):c.2479G>T (p.Gly827Ter)	Likely pathogenic
2577829	NM_012154.5(AGO2):c.1093A>G (p.Ile365Val)	Likely pathogenic
3064546	NM_012154.5(AGO2):c.1019C>A (p.Pro340His)	Likely pathogenic
3595287	NM_012154.5(AGO2):c.1082_1090dup (p.Thr363_Met364insThrSerThr)	Likely pathogenic
3602162	NM_012154.5(AGO2):c.1879G>A (p.Ala627Thr)	Likely pathogenic
4278604	NM_012154.5(AGO2):c.1517G>A (p.Arg506Gln)	Likely pathogenic

SpliceAI

4731 predictions. Top by Δscore:

Variant	Effect	Δscore
8:140532153:C:CC	acceptor_gain	1.0000
8:140532411:CTCA:C	donor_loss	1.0000
8:140532412:TCA:T	donor_loss	1.0000
8:140532413:CACCT:C	donor_loss	1.0000
8:140532414:A:AC	donor_gain	1.0000
8:140532414:A:T	donor_loss	1.0000
8:140532415:C:CC	donor_gain	1.0000
8:140532611:GTCCC:G	acceptor_gain	1.0000
8:140532612:TCCC:T	acceptor_gain	1.0000
8:140532613:CCC:C	acceptor_gain	1.0000
8:140532613:CCCC:C	acceptor_gain	1.0000
8:140532614:CC:C	acceptor_gain	1.0000
8:140532614:CCC:C	acceptor_gain	1.0000
8:140532615:CC:C	acceptor_gain	1.0000
8:140532616:C:CC	acceptor_gain	1.0000
8:140532616:C:T	acceptor_gain	1.0000
8:140532616:CTAAA:C	acceptor_loss	1.0000
8:140532617:T:G	acceptor_loss	1.0000
8:140532622:C:CT	acceptor_gain	1.0000
8:140539315:CTCA:C	donor_loss	1.0000
8:140539316:TCA:T	donor_loss	1.0000
8:140539317:CACCC:C	donor_loss	1.0000
8:140539318:A:AC	donor_gain	1.0000
8:140539318:AC:A	donor_gain	1.0000
8:140539318:ACC:A	donor_gain	1.0000
8:140539318:ACCCG:A	donor_gain	1.0000
8:140539319:C:CT	donor_gain	1.0000
8:140539319:CC:C	donor_gain	1.0000
8:140539319:CCC:C	donor_gain	1.0000
8:140539319:CCCG:C	donor_gain	1.0000

AlphaMissense

5668 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:140532050:A:C	F858L	1.000
8:140532050:A:T	F858L	1.000
8:140532052:A:G	F858L	1.000
8:140532446:C:A	R814M	1.000
8:140532464:A:G	L808P	1.000
8:140532488:G:T	P800Q	1.000
8:140532508:G:C	C793W	1.000
8:140532509:C:T	C793Y	1.000
8:140532510:A:G	C793R	1.000
8:140532526:A:C	C787W	1.000
8:140532527:C:T	C787Y	1.000
8:140532528:A:G	C787R	1.000
8:140532597:G:C	H764D	1.000
8:140532602:G:T	P762H	1.000
8:140532604:C:A	R761S	1.000
8:140532604:C:G	R761S	1.000
8:140532605:C:A	R761M	1.000
8:140532605:C:G	R761T	1.000
8:140532607:G:C	S760R	1.000
8:140532607:G:T	S760R	1.000
8:140532609:T:G	S760R	1.000
8:140532614:C:A	G758V	1.000
8:140532614:C:T	G758E	1.000
8:140532615:C:A	G758W	1.000
8:140532615:C:G	G758R	1.000
8:140532615:C:T	G758R	1.000
8:140535475:C:T	G755D	1.000
8:140535476:C:G	G755R	1.000
8:140535482:G:C	H753D	1.000
8:140535483:A:C	S752R	1.000

dbSNP variants (sampled 300 via entrez): RS1000003326 (8:140563853 C>T), RS1000010494 (8:140624471 C>T), RS1000026264 (8:140624227 C>T), RS1000061020 (8:140569289 G>A), RS1000091882 (8:140569563 G>A), RS1000115717 (8:140554284 G>A), RS1000123186 (8:140641349 A>G), RS1000124849 (8:140610054 G>A,T), RS1000203728 (8:140604082 G>A), RS1000266607 (8:140640155 C>T), RS1000366156 (8:140574479 G>A), RS1000385321 (8:140634444 G>A,C), RS1000416317 (8:140599232 C>T), RS1000422512 (8:140579408 C>T), RS1000437987 (8:140564044 G>A)

Disease associations

OMIM: gene MIM:606229 | disease phenotypes: MIM:619149, MIM:608996

GenCC curated gene-disease

Disease	Classification	Inheritance
Lessel-Kreienkamp syndrome	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Lessel-Kreienkamp syndrome	Definitive	AD

Mondo (3): neurodevelopmental disorder (MONDO:0700092), Lessel-Kreienkamp syndrome (MONDO:0030897), premature ovarian failure 3 (MONDO:0012169)

Orphanet (0):

HPO phenotypes

36 total (30 of 36 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000194	Open mouth
HP:0000219	Thin upper lip vermilion
HP:0000286	Epicanthus
HP:0000365	Hearing impairment
HP:0000396	Overfolded helix
HP:0000431	Wide nasal bridge
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000505	Visual impairment
HP:0000582	Upslanted palpebral fissure
HP:0000689	Dental malocclusion
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001270	Motor delay
HP:0001357	Plagiocephaly
HP:0001631	Atrial septal defect
HP:0001642	Pulmonic stenosis
HP:0001643	Patent ductus arteriosus
HP:0001647	Bicuspid aortic valve
HP:0001655	Patent foramen ovale
HP:0002007	Frontal bossing
HP:0002020	Gastroesophageal reflux
HP:0002793	Abnormal pattern of respiration
HP:0003593	Infantile onset
HP:0004209	Clinodactyly of the 5th finger

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST001859_52	Thiazide-induced adverse metabolic effects in hypertensive patients	8.000000e-06
GCST006940_75	Neurociticism	3.000000e-08
GCST007932_15	Medication use (thyroid preparations)	4.000000e-11
GCST010796_3346	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-09
GCST012332_20	Multisite chronic pain	3.000000e-08
GCST012442_44	Age-related hearing impairment	3.000000e-09
GCST90002390_616	Mean corpuscular hemoglobin	5.000000e-24
GCST90002392_523	Mean corpuscular volume	4.000000e-22
GCST90002396_445	Mean reticulocyte volume	4.000000e-10
GCST90002397_669	Mean spheric corpuscular volume	5.000000e-13
GCST90014023_27	Type 1 diabetes	3.000000e-08

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007660	neuroticism measurement
EFO:0009933	Thyroid preparation use measurement
EFO:0004327	electrocardiography
EFO:0010100	multisite chronic pain
EFO:0004527	mean corpuscular hemoglobin
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625
C563816	Premature Ovarian Failure 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4680043 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 199,316 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL21	SULFANILAMIDE	4	153,075
CHEMBL338802	SULFAGUANIDINE	4	4,956
CHEMBL485696	SULFISOMIDINE	4	4,437
CHEMBL265502	SURAMIN	3	36,848

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4961280	AGO2		0.00	0

ChEMBL bioactivities

4 potent at pChembl≥5 of 7 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.35	IC50	450	nM	CHEMBL4439201
6.16	IC50	690	nM	SURAMIN
5.79	IC50	1610	nM	OXIDOPAMINE HYDROCHLORIDE
5.37	Kd	4300	nM	SULFISOMIDINE

PubChem BioAssay actives

4 with measured affinity, of 21 total; 4 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
5-[(3-carboxy-4-hydroxyphenyl)-(3-carboxy-4-oxocyclohexa-2,5-dien-1-yl)methyl]-2-hydroxybenzoic acid	1930555: Inhibition of AGO2 (unknown origin)	ic50	0.4500	uM
8-[4-methyl-3-[(5Z)-5-[(Z)-[5-[[2-methyl-5-[(4,6,8-trisulfo-2H-naphthalen-1-ylidene)carbamoyl]cyclohexa-2,4-dien-1-ylidene]carbamoyl]cyclohexa-2,4-dien-1-ylidene]carbamoyl]iminocyclohexa-1,3-diene-1-carbonyl]iminocyclohexa-1,4-diene-1-carbonyl]imino-7H-naphthalene-1,3,5-trisulfonic acid	1930555: Inhibition of AGO2 (unknown origin)	ic50	0.6900	uM
5-(2-aminoethyl)benzene-1,2,4-triol;hydrochloride	1930555: Inhibition of AGO2 (unknown origin)	ic50	1.6100	uM
4-amino-N-(2,6-dimethylpyrimidin-4-yl)benzenesulfonamide	1682438: Binding affinity to human Argonaut protein 2 PAZ domain assessed as dissociation constant by using isothermal titration microcalorimetry	kd	4.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression, decreases reaction, increases localization, increases phosphorylation (+2 more)	6
Arsenic	affects methylation, increases expression, increases abundance	4
methylmercuric chloride	increases expression, affects cotreatment	3
bisphenol A	affects methylation, affects cotreatment, decreases expression	2
bisphenol S	decreases expression, decreases methylation, affects cotreatment	2
Arsenic Trioxide	affects binding, decreases reaction, decreases expression	2
Acetaminophen	affects binding, increases reaction, increases expression	2
Air Pollutants	decreases expression, increases abundance, affects expression, affects cotreatment	2
Cisplatin	affects cotreatment, decreases expression	2
Estradiol	increases expression	2
Ozone	affects cotreatment, decreases expression, increases abundance, affects expression	2
Tamoxifen	affects expression, affects cotreatment, decreases expression	2
Valproic Acid	decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cyclosporine	increases expression	2
Raloxifene Hydrochloride	affects expression, affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
FR900359	decreases phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
dicrotophos	increases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
sodium arsenate	increases abundance, increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
zinc chloride	affects cotreatment, decreases expression	1
benzo(e)pyrene	decreases methylation	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4677088	Binding	Binding affinity to human Argonaut protein 2 PAZ domain assessed as association constant by using isothermal titration microcalorimetry	Sulfonamide antibiotics inhibit RNAi by binding to human Argonaute protein 2 PAZ. — Bioorg Med Chem Lett

Cellosaurus cell lines

9 cell lines: 6 cancer cell line, 3 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A0DW	HeLa S3 AGO2KO	Cancer cell line	Female
CVCL_B8B3	Abcam HCT 116 AGO2 KO	Cancer cell line	Male
CVCL_B8S8	Abcam MCF-7 AGO2 KO	Cancer cell line	Female
CVCL_B9D5	Abcam A-549 AGO2 KO	Cancer cell line	Male
CVCL_D8YV	Ubigene HEK293 AGO2 KO	Transformed cell line	Female
CVCL_D9XD	Ubigene HeLa AGO2 KO	Cancer cell line	Female
CVCL_E1FM	Abcam HEK293 AGO2 KO	Transformed cell line	Female
CVCL_E8FP	HEK293T 3xFLAG-AGO2	Transformed cell line	Female
CVCL_KT32	HeLa SilenciX Argonaute 2	Cancer cell line	Female

Clinical trials (associated diseases)

204 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
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
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