AGO1

Chr 1AD

argonaute RISC component 1

Also known as: EIF2C, EIF2C1, GERP95, NEDLBAS, Q99, hAgo1

NCBI Gene: 26523 ENSG00000092847 UniProt: Q9UL18 OMIM: 606228

The protein binds to microRNAs and small interfering RNAs to repress translation of complementary mRNAs and mediate transcriptional gene silencing, functioning as a key component of the RNA interference pathway. Mutations cause autosomal dominant neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures. This gene is highly constrained against loss-of-function variants, indicating that such variants are likely pathogenic when they occur.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.061 OMIM phenotype

Clinical Summary— AGO1

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

16 unique Pathogenic / Likely Pathogenic· 123 VUS of 190 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.06LOEUF

pLI 1.000

Z-score 6.71

OE 0.00 (0.00–0.06)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

5.68Z-score

OE missense 0.31 (0.28–0.36)

171 obs / 543.3 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.06)

0≤0.351.4

Missense OE?0.31 (0.28–0.36)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 0 / 52.4Missense obs/exp: 171 / 543.3Syn Z: -0.01

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongAGO1-related developmental disorderOTHERAD

This gene — mechanism propensity

0.2499th %ile

GOF

0.2796th %ile

LOF

0.76top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.06

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

190 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic15

VUS123

Likely Benign21

Benign7

Conflicting4

Pathogenic

Likely Pathogenic

123

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	0	0	1
Likely Pathogenic	1	14	0	0	15
VUS	14	104	3	2	123
Likely Benign	0	1	0	20	21
Benign	0	0	2	5	7
Conflicting	—				4
Total	16	119	5	27	171

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

9 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap AGO1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →