AGO1
protein-codingargonaute RISC component 1, the group of Argonaute RISC component family
Gene summary
This gene encodes a member of the argonaute family of proteins, which associate with small RNAs and have important roles in RNA interference (RNAi) and RNA silencing. This protein binds to microRNAs (miRNAs) or small interfering RNAs (siRNAs) and represses translation of mRNAs that are complementary to them. It is also involved in transcriptional gene silencing (TGS) of promoter regions that are complementary to bound short antigene RNAs (agRNAs), as well as in the degradation of miRNA-bound mRNA targets. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. A recent study showed this gene to be an authentic stop codon readthrough target, and that its mRNA could give rise to an additional C-terminally extended isoform by use of an alternative in-frame translation termination codon. [provided by RefSeq, Nov 2015]
- EIF2C1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~60.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0859531
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: ClinGen
The *AGO1* gene is located on chromosome 1 at 1p34.3 and encodes the argonaute RISC catalytic component 1, which is associated with RNA-mediated gene silencing as part of the RNA-induced silencing complex (RISC). Although *de novo* missense variants in *AGO1* had been observed in large cohort studies of individuals with autism and/or intellectual disability as early as 2012 (PMIDs: 22495306, 23020937, 25356899, 27620904), the first report focusing on variants in *AGO1* as a cause of autosomal dominant complex neurodevelopmental disorder was published in 2022 (Schalk et al., PMID: 34930816). The reported phenotypes include global developmental delay, intellectual disability of varying severity, significant speech delay, autism or autistic behavior, sleep disturbances, seizures, hypotonia, feeding difficulties, brain MRI abnormalities, and subtle facial dysmorphism. Ten unique variants (missense and in-frame deletions) that have been reported in 27 probands in four publications (PMIDs: 23020937, 30213762, 34930816, 35060114) are included in this curation. Variants were *de novo* in all instances in which parental DNA was available. Several variants are recurrent, including p.Phe180del (in 5 patients) and p.Gly199Ser (in 8 patients). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. *AGO1* is significantly constrained for loss-of-function variants (pLI = 1, LOEUF = 0.16, gnomAD v4.1.0) and missense variants (Z = 6.44). The mechanism of pathogenicity appears to be dominant negative. *AGO1* variants in *C. elegans* disrupt microRNA processing, microRNA-induced silencing complex (miRISC) formation, and/or target repression (PMID: 41237208). Heterozygous truncating variants (*de novo* or inherited) and multigene 1p34.3 deletions encompassing *AGO1* have been reported in individuals with neurodevelopmental disorders (PMIDs: 25271087, 28191890, 28965761, 37589173), but were not scored in this curation due to the unclear contribution of these variants to the neurodevelopmental phenotype. This gene-disease relationship is also supported by experimental evidence, including biochemical function and protein interaction. AGO2, which belongs to the same Argonaute family of proteins, is implicated in Lessel-Kreienkamp syndrome, which exhibits a neurodevelopmental phenotype similar to that of *AGO1* (PMID: 35736234). *AGO1* is implicated in the function of the *FMR1* gene associated with fragile X syndrome (PMID: 14703574). In summary, there is definitive evidence supporting the relationship between *AGO1* and autosomal dominant complex neurodevelopment disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Disorders Gene Curation Expert Panel on November 19, 2025 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0859531
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0859531
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0859531
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to AGO1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_012199.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 3 | 25 | 4 | 32 | ||
| missense | 1 | 15 | 126 | 3 | 145 | |
| nonsense | 4 | 4 | ||||
| start loss | 0 | |||||
| frameshift | 10 | 10 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | 9 | 11 | ||
| Total | 2 | 16 | 152 | 28 | 4 | 202 |
Highest pathogenic variant AF is 0.000003420286
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_036331.1 | 19 | MANE Select | |
| Ensembl | ENSP00000362300.4 | 19 | MANE Select | |
| RefSeq | NP_001304051.1 | 19 | Standard | |
| RefSeq | NP_001304052.1 | 17 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Competing endogenous RNAs (ceRNAs) regulate PTEN translation
- Signal Transduction
- Gene expression (Transcription)
- Generic Transcription Pathway
- Oncogene Induced Senescence
Biological Process
- nuclear-transcribed mRNA catabolic process
- Wnt signaling pathway, calcium modulating pathway
- RNA secondary structure unwinding
- miRNA metabolic process
- positive regulation of gene expression
Molecular Function
- RNA polymerase II proximal promoter sequence-specific DNA binding
- RNA polymerase II complex binding
- core promoter binding
- RNA binding
- double-stranded RNA binding
Cellular Component
- P-body
- nucleus
- nucleoplasm
- cytoplasm
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000373204
- Coding exons
- 19
- Length
- 59803
- Individuals with no LoFs
- 125745
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 3
- Defined
- 125748
- p
- 0.0000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 5.68 | 171 | 543 | 0.315 | 0.0000337 | 5599 |
| Missense (PolyPhen) | 73 | 285.11 | 0.25605 | 2867 | ||
| Synonymous | -0.0111 | 200 | 200 | 1.00 | 0.0000117 | 1688 |
| Loss of Function | 6.71 | 0 | 52.4 | 0.00 | 0.00000317 | 517 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000027 | 0.000026 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Required for RNA-mediated gene silencing (RNAi). Binds to short RNAs such as microRNAs (miRNAs) or short interfering RNAs (siRNAs), and represses the translation of mRNAs which are complementary to them. Lacks endonuclease activity and does not appear to cleave target mRNAs. Also required for transcriptional gene silencing (TGS) of promoter regions which are complementary to bound short antigene RNAs (agRNAs). {ECO:0000269|PubMed:16289642, ECO:0000269|PubMed:16936728, ECO:0000269|PubMed:18771919}.;
Recessive Scores
- pRec
- 0.161
Intolerance Scores
- RVIS EVS
- -0.8
- RVIS percentile EVS
- 12.24
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |