# NM_014516.4(CNOT3):c.1116C>G (p.Ala372=)

https://sugi.bio/variant/cnot3-p-ala372

## Summary

**CNOT3 p.Ala372= (c.1116C>G)** is classified **Uncertain significance** in CNOT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-08). Very rare (popmax 0.0036%, amr); Associated with intellectual developmental disorder with speech delay, autism, and dysmorphic facies.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs767822171 · 1 submitter · 1 linked condition · very rare (popmax 0.0036%, amr)

## For patients & families {#patients}

This is a change in the CNOT3 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 speech delay, autism, and dysmorphic facies.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0027947/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CNOT3](https://sugi.bio/atlas/gene/CNOT3/) |
| Protein change (HGVS p.) | p.Ala372= |
| Coding change (HGVS c.) | c.1116C>G |
| MANE Select transcript | [NM_014516](https://www.ncbi.nlm.nih.gov/nuccore/NM_014516) |
| dbSNP | [rs767822171](https://www.ncbi.nlm.nih.gov/snp/rs767822171/) |
| Variant type | single nucleotide variant |
| Location | chr19:54148369-54148369 (GRCh38) |
| ClinVar | [VCV3237487](https://www.ncbi.nlm.nih.gov/clinvar/variation/3237487/) |

**All HGVS expressions:** `NC_000019.10:g.54148369C>G`, `NC_000019.9:g.54652104C>G`, `NM_014516.4:c.1116C>G`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.23) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -1.174, GERP -1.71, phastCons 0.001 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 13.76**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.23**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.23**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0036%** (amr) · FAF95 0.000597% · FAF99 0.000223% · 2/55,598 in the highest group · 2/1,419,384 alleles overall — very rare (popmax 0.0036%, amr).

*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}

**CNOT3** population constraint: LOEUF 0.057, pLI 1, missense-Z 3.7821; ClinGen dosage — haploinsufficiency 0, 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)

## Protein context {#protein}

Residue **372** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 68.53, 42% of residues very-high.

**6 experimental structure(s)** (PDB): [4C0D](https://www.rcsb.org/structure/4C0D), [4C0G](https://www.rcsb.org/structure/4C0G), [5FU6](https://www.rcsb.org/structure/5FU6), [5FU7](https://www.rcsb.org/structure/5FU7), [9C3H](https://www.rcsb.org/structure/9C3H), [9C3I](https://www.rcsb.org/structure/9C3I) — incl. mutant structure 5FU6.

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

*Describes the biological roles of CNOT3 (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.*


### Pathways affected {#pathways}

CNOT3 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}

**Biological process:** regulation of stem cell population maintenance.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-08.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-08 |

## Associated conditions {#conditions}

[intellectual developmental disorder with speech delay, autism, and dysmorphic facies](https://sugi.bio/atlas/disease/intellectual-developmental-disorder-with-speech-delay-autism-and-dysmorphic-facies/).

**Reported phenotype names (ClinVar):** Intellectual developmental disorder with speech delay, autism, and dysmorphic facies.

## Similar variants {#similar}

Related CNOT3 variant pages (same residue, condition, or type): [CNOT3 c.1904+2T>C](/variant/cnot3-c-1904-plus-2t-c), [CNOT3 p.Arg697Ter](/variant/cnot3-p-arg697ter), [CNOT3 p.Arg81Ser](/variant/cnot3-p-arg81ser), [CNOT3 p.Arg96Ter](/variant/cnot3-p-arg96ter), [CNOT3 p.Thr86=](/variant/cnot3-p-thr86), [CNOT3 c.483+6T>G](/variant/cnot3-c-483-plus-6t-g), [CNOT3 p.Arg665His](/variant/cnot3-p-arg665his), [CNOT3 p.Gln453Leu](/variant/cnot3-p-gln453leu).

### 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 3237487). 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.*