# NM_002392.6(MDM2):c.1248T>C (p.Asp416=)

https://sugi.bio/variant/mdm2-p-asp416

## Summary

**MDM2 p.Asp416= (c.1248T>C)** is classified **Likely benign** in MDM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-03). Very rare (popmax 0.00475%, nfe); Associated with Accelerated tumor formation, susceptibility to.

**At a glance:** Likely benign · review: Single submitter · rsID rs368366429 · 1 submitter · 1 linked condition · very rare (popmax 0.00475%, nfe)

## For patients & families {#patients}

This is a change in the MDM2 gene that is classified as likely benign — not considered disease-causing, 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.Asp416= |
| Coding change (HGVS c.) | c.1248T>C |
| MANE Select transcript | [NM_002392](https://www.ncbi.nlm.nih.gov/nuccore/NM_002392) |
| dbSNP | [rs368366429](https://www.ncbi.nlm.nih.gov/snp/rs368366429/) |
| Variant type | single nucleotide variant |
| Location | chr12:68839603-68839603 (GRCh38) |
| ClinVar | [VCV2156229](https://www.ncbi.nlm.nih.gov/clinvar/variation/2156229/) |

**All HGVS expressions:** `NC_000012.11:g.69233383T>C`, `NC_000012.12:g.68839603T>C`, `NG_016708.1:g.36413T>C`, `NG_016708.2:g.36433T>C`, `NM_001145337.3:c.1089T>C`, `NM_001145339.2:c.1083T>C`, `NM_001145340.3:c.642T>C`, `NM_001278462.2:c.720T>C`, `NM_001367990.1:c.1230T>C`, `NM_002392.6:c.1248T>C`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP -1.296, GERP -1.92 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 5.179**. 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: **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 **0.00475%** (nfe) · FAF95 0.00375% · FAF99 0.00337% · 56/1,179,980 in the highest group · 60/1,613,352 alleles overall — very rare (popmax 0.00475%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,618 |
| European (non-Finnish) (grpmax) | 0.00475% | 21,071 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **416** lies in the 'necessary for interaction with usp2' region; the 'disordered' 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.Asp416= falls in the necessary for interaction with usp2 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-06-03.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-06-03 |

## 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 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), [MDM2 p.Ser122Leu](/variant/mdm2-p-ser122leu).

### 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 2156229). 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.*