# NM_014515.7(CNOT2):c.406C>T (p.Pro136Ser)

https://sugi.bio/variant/cnot2-p-pro136ser

## Summary

**CNOT2 p.Pro136Ser (c.406C>T)** is classified **Uncertain significance** in CNOT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-15). AlphaMissense: likely benign (0.0506); Absent from gnomAD v4.1; Associated with intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2499107829 · 1 submitter · 1 linked condition · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CNOT2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies.

*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 | [CNOT2](https://sugi.bio/atlas/gene/CNOT2/) |
| Protein change (HGVS p.) | p.Pro136Ser |
| Coding change (HGVS c.) | c.406C>T |
| MANE Select transcript | [NM_014515](https://www.ncbi.nlm.nih.gov/nuccore/NM_014515) |
| dbSNP | [rs2499107829](https://www.ncbi.nlm.nih.gov/snp/rs2499107829/) |
| Variant type | single nucleotide variant |
| Location | chr12:70330306-70330306 (GRCh38) |
| ClinVar | [VCV2440168](https://www.ncbi.nlm.nih.gov/clinvar/variation/2440168/) |

**All HGVS expressions:** `NC_000012.11:g.70724086C>T`, `NC_000012.12:g.70330306C>T`, `NM_001199302.2:c.406C>T`, `NM_001199303.2:c.406C>T`, `NM_001414651.1:c.406C>T`, `NM_001414652.1:c.406C>T`, `NM_001414653.1:c.379C>T`, `NM_001414654.1:c.379C>T`, `NM_001414655.1:c.379C>T`, `NM_001414656.1:c.364C>T`, `NM_001414657.1:c.346C>T`, `NM_001414658.1:c.346C>T`, `NM_001414659.1:c.346C>T`, `NM_001414660.1:c.346C>T`, `NM_001414661.1:c.283C>T`, `NM_001414662.1:c.386+736C>T`, `NM_014515.7:c.406C>T`, `NR_037615.2:n.1307C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0506)
- REVEL 0.102 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.231 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 7.645, GERP 1.81, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 20.5**. 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 0.67** across the covering region of the MANE Select transcript (70,278,227–70,330,453), spanning 52,226 bp. Chi-square p 3.3e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.22 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- 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}

**CNOT2** population constraint: LOEUF 0.211, pLI 0.99999, missense-Z 3.2082; ClinGen dosage — haploinsufficiency 1/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 60.35, 26% of residues very-high.

**4 experimental structure(s)** (PDB): [4C0D](https://www.rcsb.org/structure/4C0D), [4C0F](https://www.rcsb.org/structure/4C0F), [5FU6](https://www.rcsb.org/structure/5FU6), [5FU7](https://www.rcsb.org/structure/5FU7) — incl. mutant structure 5FU6.

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

*Describes the biological roles of CNOT2 (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:** CNOT2's established molecular role includes transcription corepressor binding.


### Pathways affected {#pathways}

CNOT2 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:** transcription corepressor binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, positive regulation of cytoplasmic mRNA processing body assembly, negative regulation of intracellular estrogen receptor signaling pathway, regulation of stem cell population maintenance.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-11-15.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-11-15 |

## Associated conditions {#conditions}

[intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies](https://sugi.bio/atlas/disease/intellectual-developmental-disorder-with-nasal-speech-dysmorphic-facies-and-variable-skeletal-anomalies/).

**Reported phenotype names (ClinVar):** Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies.

## Similar variants {#similar}

Related CNOT2 variant pages (same residue, condition, or type): [CNOT2 p.Tyr494Cys](/variant/cnot2-p-tyr494cys), [CNOT2 p.Gln411Arg](/variant/cnot2-p-gln411arg), [CNOT2 p.Lys316Ter](/variant/cnot2-p-lys316ter), [CNOT2 p.Gln457fs](/variant/cnot2-p-gln457fs), [CNOT2 p.His526fs](/variant/cnot2-p-his526fs), [CNOT2 p.Leu376fs](/variant/cnot2-p-leu376fs), [CNOT2 p.Arg183Gln](/variant/cnot2-p-arg183gln), [CNOT2 p.Gly32Glu](/variant/cnot2-p-gly32glu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 2440168). 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.*