# NM_002392.6(MDM2):c.631A>G (p.Ile211Val)

https://sugi.bio/variant/mdm2-p-ile211val

## Summary

**MDM2 p.Ile211Val (c.631A>G)** is classified **Uncertain significance** in MDM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-27). AlphaMissense: likely benign (0.1172); Absent from gnomAD v4.1; Associated with Accelerated tumor formation, susceptibility to.

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

## For patients & families {#patients}

This is a change in the MDM2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Accelerated tumor formation, susceptibility to.

*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 | [MDM2](https://sugi.bio/atlas/gene/MDM2/) |
| Protein change (HGVS p.) | p.Ile211Val |
| Coding change (HGVS c.) | c.631A>G |
| MANE Select transcript | [NM_002392](https://www.ncbi.nlm.nih.gov/nuccore/NM_002392) |
| Variant type | single nucleotide variant |
| Location | chr12:68828878-68828878 (GRCh38) |
| ClinVar | [VCV3704730](https://www.ncbi.nlm.nih.gov/clinvar/variation/3704730/) |

**All HGVS expressions:** `NC_000012.11:g.69222658A>G`, `NC_000012.12:g.68828878A>G`, `NG_016708.1:g.25688A>G`, `NG_016708.2:g.25708A>G`, `NM_001145337.3:c.613A>G`, `NM_001145339.2:c.466A>G`, `NM_001145340.3:c.157-6951A>G`, `NM_001278462.2:c.157-6951A>G`, `NM_001367990.1:c.613A>G`, `NM_002392.6:c.631A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1172)
- REVEL 0.009 (strongly benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.016 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 1.422, GERP -1.88, phastCons 0.999 — weakly conserved position
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **I205V** vs ClinVar **I211V**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 19.4**. 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 0.71** across the covering region of the MANE Select transcript (68,820,357–68,839,309), spanning 18,952 bp. Chi-square p 8.3e-06. 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: **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}

**MDM2** population constraint: LOEUF 0.325, pLI 1, missense-Z 2.585. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **211** lies in the 'arf-binding' region; the 'disordered' region; the 'interaction with pyhin1 and necessary for interaction with rffl and rnf34' region; the 'interaction with mtbp' region; the 'mediates interaction with rad54b' region.

AlphaFold model confidence (whole protein): pLDDT 63.24, 30% of residues very-high.

**148 experimental structure(s)** (PDB): [1RV1](https://www.rcsb.org/structure/1RV1), [1T4E](https://www.rcsb.org/structure/1T4E), [1T4F](https://www.rcsb.org/structure/1T4F), [1YCR](https://www.rcsb.org/structure/1YCR), [1Z1M](https://www.rcsb.org/structure/1Z1M), [22IZ](https://www.rcsb.org/structure/22IZ) — incl. mutant structure 3LNZ.

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

*Describes the biological roles of MDM2 (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:** MDM2's established molecular role includes p53 binding. p.Ile211Val falls in the arf-binding region. In Reactome, MDM2 is annotated in disease pathway(s) including **Constitutive Signaling by AKT1 E17K in Cancer**, **Signaling by ALK fusions and activated point mutants**.

**Disease mechanism (Reactome):** MDM2 loss or alteration is curated in [Constitutive Signaling by AKT1 E17K in Cancer](https://reactome.org/content/detail/R-HSA-5674400), [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370).

### Pathways affected {#pathways}

MDM2 participates in **16 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by AKT1 E17K in Cancer](https://reactome.org/content/detail/R-HSA-5674400) | curated |
| ⚕ [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370) | curated |
| [AKT phosphorylates targets in the cytosol](https://reactome.org/content/detail/R-HSA-198323) | curated |
| [Degradation of CDH1](https://reactome.org/content/detail/R-HSA-9766229) | curated |
| [Oncogene Induced Senescence](https://reactome.org/content/detail/R-HSA-2559585) | curated |
| [Oxidative Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559580) | curated |
| [Regulation of RUNX3 expression and activity](https://reactome.org/content/detail/R-HSA-8941858) | curated |
| [Regulation of TP53 Activity through Methylation](https://reactome.org/content/detail/R-HSA-6804760) | curated |
| [Regulation of TP53 Activity through Phosphorylation](https://reactome.org/content/detail/R-HSA-6804756) | curated |
| [Regulation of TP53 Degradation](https://reactome.org/content/detail/R-HSA-6804757) | curated |
| [SUMOylation of transcription factors](https://reactome.org/content/detail/R-HSA-3232118) | curated |
| [SUMOylation of ubiquitinylation proteins](https://reactome.org/content/detail/R-HSA-3232142) | curated |
| [Stabilization of p53](https://reactome.org/content/detail/R-HSA-69541) | curated |
| [Trafficking of AMPA receptors](https://reactome.org/content/detail/R-HSA-399719) | curated |
| [Ub-specific processing proteases](https://reactome.org/content/detail/R-HSA-5689880) | curated |
| [NPAS4 regulates expression of target genes](https://reactome.org/content/detail/R-HSA-9768919) | electronic |

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

**Molecular function:** p53 binding, ubiquitin-protein transferase activity, 5S rRNA binding, zinc ion binding, ligase activity, SUMO transferase activity.

**Biological process:** negative regulation of transcription by RNA polymerase II, ubiquitin-dependent protein catabolic process, apoptotic process, protein ubiquitination, DNA damage response, signal transduction by p53 class mediator, protein destabilization.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-07-27.

**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 | 2024-07-27 |

## Associated conditions {#conditions}

[Accelerated tumor formation, susceptibility to](https://sugi.bio/atlas/disease/accelerated-tumor-formation-susceptibility-to/).

**Reported phenotype names (ClinVar):** Accelerated tumor formation, susceptibility to.

## Similar variants {#similar}

Related MDM2 variant pages (same residue, condition, or type): [MDM2 p.Ile211Leu](/variant/mdm2-p-ile211leu), [MDM2 c.523+5A>G](/variant/mdm2-c-523-plus-5a-g), [MDM2 p.Arg332His](/variant/mdm2-p-arg332his), [MDM2 p.Asn117Ser](/variant/mdm2-p-asn117ser), [MDM2 p.Asn374Ser](/variant/mdm2-p-asn374ser), [MDM2 p.Gln414Leu](/variant/mdm2-p-gln414leu), [MDM2 p.Glu273Ala](/variant/mdm2-p-glu273ala), [MDM2 p.Gly341Glu](/variant/mdm2-p-gly341glu).

### 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 3704730). 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.*