# NM_004958.4(MTOR):c.7400C>T (p.Ala2467Val)

https://sugi.bio/variant/mtor-p-ala2467val

## Summary

**MTOR p.Ala2467Val (c.7400C>T)** is classified **Uncertain significance** in MTOR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-26). AlphaMissense: likely benign (0.0744); Very rare (popmax 0.00329%, sas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00329%, sas)

## For patients & families {#patients}

This is a change in the MTOR 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 | [MTOR](https://sugi.bio/atlas/gene/MTOR/) |
| Protein change (HGVS p.) | p.Ala2467Val |
| Coding change (HGVS c.) | c.7400C>T |
| MANE Select transcript | [NM_004958](https://www.ncbi.nlm.nih.gov/nuccore/NM_004958) |
| Variant type | single nucleotide variant |
| Location | chr1:11109696-11109696 (GRCh38) |
| ClinVar | [VCV3633467](https://www.ncbi.nlm.nih.gov/clinvar/variation/3633467/) |

**All HGVS expressions:** `LRG_734:g.157856C>T`, `LRG_734t1:c.7400C>T`, `NC_000001.10:g.11169753G>A`, `NC_000001.11:g.11109696G>A`, `NG_033239.1:g.157856C>T`, `NM_001386500.1:c.7400C>T`, `NM_001386501.1:c.6152C>T`, `NM_004958.4:c.7400C>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** (0.0744)
- REVEL 0.08 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.531 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 11.655, GERP 1.73, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.6**. 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 0.72** across the covering region of the MANE Select transcript (11,109,649–11,114,330), spanning 4,681 bp. Chi-square p 0.024. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.00329%** (sas) · FAF95 0.000875% · FAF99 0.000443% · 3/91,084 in the highest group · 3/1,461,858 alleles overall — very rare (popmax 0.00329%, sas).

*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}

**MTOR** population constraint: LOEUF 0.268, pLI 1, missense-Z 9.505; 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):

- **overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes** — Definitive (AD)

## Protein context {#protein}

Residue **2467** lies in the pi3k/pi4k catalytic domain.

AlphaFold model confidence (whole protein): pLDDT 78.57, 11% of residues very-high.

**73 experimental structure(s)** (PDB): [1AUE](https://www.rcsb.org/structure/1AUE), [1FAP](https://www.rcsb.org/structure/1FAP), [1NSG](https://www.rcsb.org/structure/1NSG), [2FAP](https://www.rcsb.org/structure/2FAP), [2GAQ](https://www.rcsb.org/structure/2GAQ), [2NPU](https://www.rcsb.org/structure/2NPU) — incl. mutant structure 6M4U.

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

*Describes the biological roles of MTOR (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:** MTOR's established molecular role includes inositol hexakisphosphate binding. p.Ala2467Val falls in the pi3k/pi4k catalytic domain. In Reactome, MTOR is annotated in disease pathway(s) including **Constitutive Signaling by AKT1 E17K in Cancer**, **Dengue virus modulates apoptosis**.

**Disease mechanism (Reactome):** MTOR loss or alteration is curated in [Constitutive Signaling by AKT1 E17K in Cancer](https://reactome.org/content/detail/R-HSA-5674400), [Dengue virus modulates apoptosis](https://reactome.org/content/detail/R-HSA-9920951).

### Pathways affected {#pathways}

MTOR participates in **15 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by AKT1 E17K in Cancer](https://reactome.org/content/detail/R-HSA-5674400) | curated |
| ⚕ [Dengue virus modulates apoptosis](https://reactome.org/content/detail/R-HSA-9920951) | curated |
| [Amino acids regulate mTORC1](https://reactome.org/content/detail/R-HSA-9639288) | curated |
| [CD28 dependent PI3K/Akt signaling](https://reactome.org/content/detail/R-HSA-389357) | curated |
| [Energy dependent regulation of mTOR by LKB1-AMPK](https://reactome.org/content/detail/R-HSA-380972) | curated |
| [HSF1-dependent transactivation](https://reactome.org/content/detail/R-HSA-3371571) | curated |
| [High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells](https://reactome.org/content/detail/R-HSA-9856530) | curated |
| [MTOR signalling](https://reactome.org/content/detail/R-HSA-165159) | curated |
| [Macroautophagy](https://reactome.org/content/detail/R-HSA-1632852) | curated |
| [PIP3 activates AKT signaling](https://reactome.org/content/detail/R-HSA-1257604) | curated |
| [Regulation of PTEN gene transcription](https://reactome.org/content/detail/R-HSA-8943724) | curated |
| [Regulation of TP53 Degradation](https://reactome.org/content/detail/R-HSA-6804757) | curated |
| [TP53 Regulates Metabolic Genes](https://reactome.org/content/detail/R-HSA-5628897) | curated |
| [VEGFR2 mediated vascular permeability](https://reactome.org/content/detail/R-HSA-5218920) | curated |
| [mTORC1-mediated signalling](https://reactome.org/content/detail/R-HSA-166208) | curated |

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

**Molecular function:** inositol hexakisphosphate binding, RNA polymerase III type 1 promoter sequence-specific DNA binding, RNA polymerase III type 2 promoter sequence-specific DNA binding, RNA polymerase III type 3 promoter sequence-specific DNA binding, TFIIIC-class transcription factor complex binding, protein kinase activity.

**Biological process:** regulation of cell growth, protein phosphorylation, regulation of cell size, cellular response to starvation, negative regulation of autophagy, positive regulation of epithelial to mesenchymal transition.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-09-26.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-26 |

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

## Similar variants {#similar}

Related MTOR variant pages (same residue, condition, or type): [MTOR p.Ala2467=](/variant/mtor-p-ala2467), [MTOR p.Ala1669Ser](/variant/mtor-p-ala1669ser), [MTOR p.Cys1483Arg](/variant/mtor-p-cys1483arg), [MTOR p.Cys1483Tyr](/variant/mtor-p-cys1483tyr), [MTOR p.Leu1460Pro](/variant/mtor-p-leu1460pro), [MTOR p.Leu2427Pro](/variant/mtor-p-leu2427pro), [MTOR p.Ser2215Phe](/variant/mtor-p-ser2215phe), [MTOR p.Ser2215Tyr](/variant/mtor-p-ser2215tyr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 3633467). 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.*