# NM_005444.3(CNOT9):c.720del (p.Asp241fs)

https://sugi.bio/variant/cnot9-p-asp241fs

## Summary

**CNOT9 p.Asp241fs (c.720del)** is classified **Uncertain significance** in CNOT9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-15).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter

## For patients & families {#patients}

This is a change in the CNOT9 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [CNOT9](https://sugi.bio/atlas/gene/CNOT9/) |
| Protein change (HGVS p.) | p.Asp241fs |
| Coding change (HGVS c.) | c.720del |
| MANE Select transcript | [NM_005444](https://www.ncbi.nlm.nih.gov/nuccore/NM_005444) |
| Variant type | Deletion |
| Location | chr2:218592696-218592696 (GRCh38) |
| ClinVar | [VCV4281884](https://www.ncbi.nlm.nih.gov/clinvar/variation/4281884/) |

**All HGVS expressions:** `NC_000002.11:g.219457419del`, `NC_000002.12:g.218592696del`, `NM_001271634.2:c.816del`, `NM_001271635.2:c.720del`, `NM_005444.3:c.720del`, `NR_073390.2:n.726del`

## 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 7.632, GERP 1.97, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.523, pLI 0.96282), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **within the last 50 nt of the penultimate exon (7 of 8, 11 nt from its 3' end)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**CNOT9** population constraint: LOEUF 0.523, pLI 0.96282, missense-Z 3.6872. *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):

- **complex neurodevelopmental disorder** — Limited (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 92.83, 89% of residues very-high.

**14 experimental structure(s)** (PDB): [2FV2](https://www.rcsb.org/structure/2FV2), [4CRU](https://www.rcsb.org/structure/4CRU), [4CRV](https://www.rcsb.org/structure/4CRV), [4CT6](https://www.rcsb.org/structure/4CT6), [4CT7](https://www.rcsb.org/structure/4CT7), [5LSW](https://www.rcsb.org/structure/5LSW).

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

*Describes the biological roles of CNOT9 (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:** CNOT9's established molecular role includes transcription coactivator activity.


### Pathways affected {#pathways}

CNOT9 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Deadenylation of mRNA](https://reactome.org/content/detail/R-HSA-429947) | curated |
| [TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain](https://reactome.org/content/detail/R-HSA-6804115) | curated |
| [Activation of anterior HOX genes in hindbrain development during early embryogenesis](https://reactome.org/content/detail/R-HSA-5617472) | electronic |
| [M-decay: degradation of maternal mRNAs by maternally stored factors](https://reactome.org/content/detail/R-HSA-9820841) | electronic |

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

**Molecular function:** transcription coactivator activity, epidermal growth factor receptor binding, kinase binding, protein domain specific binding, protein homodimerization activity.

**Biological process:** positive regulation of peptidyl-serine phosphorylation, negative regulation of intracellular estrogen receptor signaling pathway, positive regulation of epidermal growth factor receptor signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-15.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-15 |

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

## Similar variants {#similar}

Related CNOT9 variant pages (same residue, condition, or type): [CNOT9 c.640-2_640-1del](/variant/cnot9-c-640-minus-2-640-minus-1del), [CNOT9 p.Tyr23fs](/variant/cnot9-p-tyr23fs).

### 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 4281884). 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.*