# NM_012154.5(AGO2):c.135C>T (p.Phe45=)

https://sugi.bio/variant/ago2-p-phe45

## Summary

**AGO2 p.Phe45= (c.135C>T)** is classified **Likely benign** in AGO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-01). Ultra-rare (popmax 0.0115%, nfe).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · ultra-rare (popmax 0.0115%, nfe)

## For patients & families {#patients}

This is a change in the AGO2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AGO2](https://sugi.bio/atlas/gene/AGO2/) |
| Protein change (HGVS p.) | p.Phe45= |
| Coding change (HGVS c.) | c.135C>T |
| MANE Select transcript | [NM_012154](https://www.ncbi.nlm.nih.gov/nuccore/NM_012154) |
| Variant type | single nucleotide variant |
| Location | chr8:140585199-140585199 (GRCh38) |
| ClinVar | [VCV3770965](https://www.ncbi.nlm.nih.gov/clinvar/variation/3770965/) |

**All HGVS expressions:** `NC_000008.10:g.141595298G>A`, `NC_000008.11:g.140585199G>A`, `NM_001164623.3:c.135C>T`, `NM_012154.5:c.135C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.554, GERP -0.28, phastCons 0.914 — weakly conserved position
- CADD: **PHRED 11.61**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0115%** (nfe) · FAF95 0.00994% · FAF99 0.00931% · 136/1,180,018 in the highest group · 286/1,614,022 alleles overall — ultra-rare (popmax 0.0115%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.211% | 474 |
| Remaining individuals (not grpmax-eligible) | 0.0128% | 7,811 |
| European (non-Finnish) (grpmax) | 0.0115% | 8,677 |
| South Asian | 0.00439% | 22,771 |
| African / African-American | 0.00267% | 37,451 |
| Admixed American | 0.00167% | 60,002 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**AGO2** population constraint: LOEUF 0.102, pLI 1, missense-Z 6.9835. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Lessel-Kreienkamp syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **45** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 92.82, 86% of residues very-high.

**71 experimental structure(s)** (PDB): [10BE](https://www.rcsb.org/structure/10BE), [11GI](https://www.rcsb.org/structure/11GI), [11GJ](https://www.rcsb.org/structure/11GJ), [11GK](https://www.rcsb.org/structure/11GK), [3LUC](https://www.rcsb.org/structure/3LUC), [3LUD](https://www.rcsb.org/structure/3LUD) — incl. mutant structure 4Z4H.

## What this gene does {#gene-function}

*Describes the biological roles of AGO2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** AGO2's established molecular role includes RNA 7-methylguanosine cap binding. In Reactome, AGO2 is annotated in disease pathway(s) including **Nuclear events stimulated by ALK signaling in cancer**.

**Disease mechanism (Reactome):** AGO2 loss or alteration is curated in [Nuclear events stimulated by ALK signaling in cancer](https://reactome.org/content/detail/R-HSA-9725371).

### Pathways affected {#pathways}

AGO2 participates in **25 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Nuclear events stimulated by ALK signaling in cancer](https://reactome.org/content/detail/R-HSA-9725371) | curated |
| [Ca2+ pathway](https://reactome.org/content/detail/R-HSA-4086398) | curated |
| [Competing endogenous RNAs (ceRNAs) regulate PTEN translation](https://reactome.org/content/detail/R-HSA-8948700) | curated |
| [Estrogen-dependent gene expression](https://reactome.org/content/detail/R-HSA-9018519) | curated |
| [MAPK6/MAPK4 signaling](https://reactome.org/content/detail/R-HSA-5687128) | curated |
| [MTOR signalling](https://reactome.org/content/detail/R-HSA-165159) | curated |
| [MicroRNA (miRNA) biogenesis](https://reactome.org/content/detail/R-HSA-203927) | curated |
| [NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux](https://reactome.org/content/detail/R-HSA-9029569) | curated |
| [Post-transcriptional silencing by small RNAs](https://reactome.org/content/detail/R-HSA-426496) | curated |
| [Pre-NOTCH Transcription and Translation](https://reactome.org/content/detail/R-HSA-1912408) | curated |
| [Regulation of CDH1 mRNA translation by microRNAs](https://reactome.org/content/detail/R-HSA-9764562) | curated |
| [Regulation of MITF-M-dependent genes involved in apoptosis](https://reactome.org/content/detail/R-HSA-9824594) | curated |
| [Regulation of NPAS4 mRNA translation](https://reactome.org/content/detail/R-HSA-9768778) | curated |
| [Regulation of PD-L1(CD274) translation](https://reactome.org/content/detail/R-HSA-9909620) | curated |
| [Regulation of PTEN mRNA translation](https://reactome.org/content/detail/R-HSA-8943723) | curated |
| [Regulation of RUNX1 Expression and Activity](https://reactome.org/content/detail/R-HSA-8934593) | curated |
| [Small interfering RNA (siRNA) biogenesis](https://reactome.org/content/detail/R-HSA-426486) | curated |
| [TGFBR3 expression](https://reactome.org/content/detail/R-HSA-9839394) | curated |
| [TP53 Regulates Metabolic Genes](https://reactome.org/content/detail/R-HSA-5628897) | curated |
| [Transcriptional regulation by small RNAs](https://reactome.org/content/detail/R-HSA-5578749) | curated |
| [Transcriptional regulation of multiciliogenesis](https://reactome.org/content/detail/R-HSA-9945556) | curated |
| [M-decay: degradation of maternal mRNAs by maternally stored factors](https://reactome.org/content/detail/R-HSA-9820841) | electronic |
| [Regulation of CDH11 mRNA translation by microRNAs](https://reactome.org/content/detail/R-HSA-9759811) | electronic |
| [Regulation of MECP2 expression and activity](https://reactome.org/content/detail/R-HSA-9022692) | electronic |
| [Transcriptional Regulation by MECP2](https://reactome.org/content/detail/R-HSA-8986944) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** RNA 7-methylguanosine cap binding, RNA polymerase II complex binding, core promoter sequence-specific DNA binding, RNA binding, double-stranded RNA binding, single-stranded RNA binding.

**Biological process:** pre-miRNA processing, P-body assembly, miRNA processing, miRNA-mediated gene silencing by inhibition of translation, miRNA-mediated gene silencing by mRNA destabilization, positive regulation of translation.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-07-01.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-01 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related AGO2 variant pages (same residue, condition, or type): [AGO2 p.Arg714Trp](/variant/ago2-p-arg714trp), [AGO2 p.Cys751Tyr](/variant/ago2-p-cys751tyr), [AGO2 p.Gly201Val](/variant/ago2-p-gly201val), [AGO2 p.Gly604Arg](/variant/ago2-p-gly604arg), [AGO2 p.Thr357Met](/variant/ago2-p-thr357met), [AGO2 p.Ala142Thr](/variant/ago2-p-ala142thr), [AGO2 p.Ala372Val](/variant/ago2-p-ala372val), [AGO2 p.Arg630His](/variant/ago2-p-arg630his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 3770965). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*