AGO2

Chr 8

argonaute RISC catalytic component 2

Also known as: CASC7, EIF2C2, LESKRES, LINC00980, PPD, Q10

NCBI Gene: 27161 ENSG00000123908 UniProt: Q9UKV8

This protein is essential for RNA-mediated gene silencing, functioning as the catalytic component of the RNA-induced silencing complex (RISC) that uses microRNAs and small interfering RNAs to regulate gene expression through mRNA cleavage or translational repression. Mutations cause Lessel-Kreienkamp syndrome, an autosomal dominant neurodevelopmental disorder. The gene is highly constrained against loss-of-function mutations (pLI >0.99, LOEUF 0.106), indicating that complete protein loss is likely incompatible with normal development.

ResearchSummary from RefSeq, OMIM, UniProt

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. [provided by RefSeq, Sep 2009]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.11

Clinical Summary— AGO2

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Gene-Disease Validity (ClinGen)

Lessel-Kreienkamp syndrome · 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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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.11LOEUF

pLI 1.000

Z-score 6.07

OE 0.02 (0.01–0.11)

Highly constrained

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

Missense Constraint?

6.06Z-score

OE missense 0.29 (0.25–0.33)

162 obs / 568.4 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.02 (0.01–0.11)

0≤0.351.4

Missense OE?0.29 (0.25–0.33)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 1 / 44.9Missense obs/exp: 162 / 568.4Syn Z: 0.90

This gene — mechanism propensity

0.2997th %ile

GOF

0.2696th %ile

LOF

0.76top 10%

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

LOFprediction above median · 1 literature citation · LOEUF 0.11

Literature Evidence

LOFThere was no evidence for a dominant-negative effect, indicating that the mutations most likely result in a loss of function.1

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

References