# NM_016284.5(CNOT1):c.2489C>T (p.Ser830Phe)

https://sugi.bio/variant/cnot1-p-ser830phe

## Summary

**CNOT1 p.Ser830Phe (c.2489C>T)** is classified **Uncertain significance** in CNOT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-03). AlphaMissense: likely pathogenic (0.6223); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CNOT1 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 | [CNOT1](https://sugi.bio/atlas/gene/CNOT1/) |
| Protein change (HGVS p.) | p.Ser830Phe |
| Coding change (HGVS c.) | c.2489C>T |
| MANE Select transcript | [NM_016284](https://www.ncbi.nlm.nih.gov/nuccore/NM_016284) |
| Variant type | single nucleotide variant |
| Location | chr16:58555899-58555899 (GRCh38) |
| ClinVar | [VCV4930345](https://www.ncbi.nlm.nih.gov/clinvar/variation/4930345/) |

**All HGVS expressions:** `NC_000016.10:g.58555899G>A`, `NC_000016.9:g.58589803G>A`, `NM_001265612.2:c.2474C>T`, `NM_016284.5:c.2489C>T`, `NM_206999.3:c.2489C>T`, `NR_049763.2:n.2747C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.6223)
- REVEL 0.423 (indeterminate)
- SaProt LLR -7.953 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- SpliceAI predicts **acceptor gain** (Δ 0.43) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.785, GERP 2.45, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 34.0**. 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.*
- Regional missense constraint: **o/e 0.40** across the covering region of the MANE Select transcript (58,553,810–58,555,900), spanning 2,090 bp. Chi-square p 3.9e-16. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.43**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.43**, donor gain **0.00**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**CNOT1** population constraint: LOEUF 0.064, pLI 1, missense-Z 9.1629; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *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** — Definitive (AD)
- **holoprosencephaly 12 with or without pancreatic agenesis** — Limited (AD)

## Protein context {#protein}

Residue **830** lies in a turn; the 'interaction with zfp36' region; a UniProt-annotated variant site (in vibos).

AlphaFold model confidence (whole protein): pLDDT 75.22, 19% of residues very-high.

**21 experimental structure(s)** (PDB): [4C0D](https://www.rcsb.org/structure/4C0D), [4CQO](https://www.rcsb.org/structure/4CQO), [4CRU](https://www.rcsb.org/structure/4CRU), [4CRV](https://www.rcsb.org/structure/4CRV), [4CRW](https://www.rcsb.org/structure/4CRW), [4CT4](https://www.rcsb.org/structure/4CT4) — incl. mutant structure 5FU6.

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

*Describes the biological roles of CNOT1 (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:** CNOT1's established molecular role includes RNA binding. p.Ser830Phe falls in the interaction with zfp36 region.


### Pathways affected {#pathways}

CNOT1 participates in **3 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 |
| [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:** RNA binding, protein domain specific binding, nuclear estrogen receptor binding, nuclear retinoic acid receptor binding, molecular adaptor activity, armadillo repeat domain binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, positive regulation of cytoplasmic mRNA processing body assembly, negative regulation of translation, negative regulation of intracellular estrogen receptor signaling pathway, miRNA-mediated post-transcriptional gene silencing, negative regulation of retinoic acid receptor signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-03.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-03 |

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

## Similar variants {#similar}

Related CNOT1 variant pages (same residue, condition, or type): [CNOT1 p.Ser830=](/variant/cnot1-p-ser830), [CNOT1 c.434-2A>G](/variant/cnot1-c-434-minus-2a-g), [CNOT1 p.Arg26Ter](/variant/cnot1-p-arg26ter), [CNOT1 p.Arg535Cys](/variant/cnot1-p-arg535cys), [CNOT1 c.310-3C>G](/variant/cnot1-c-310-minus-3c-g), [CNOT1 c.5895+4T>C](/variant/cnot1-c-5895-plus-4t-c), [CNOT1 p.Ala1368Val](/variant/cnot1-p-ala1368val), [CNOT1 p.Ala1503Thr](/variant/cnot1-p-ala1503thr).

### 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 4930345). 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.*