# NM_002392.6(MDM2):c.309G>A (p.Arg103=)

https://sugi.bio/variant/mdm2-p-arg103

## Summary

**MDM2 p.Arg103= (c.309G>A)** is classified **Uncertain significance** in MDM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-10-23). Very rare (popmax 0.00591%, nfe); Associated with Accelerated tumor formation, susceptibility to.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs766553126 · 1 submitter · 1 linked condition · very rare (popmax 0.00591%, nfe)

## 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.Arg103= |
| Coding change (HGVS c.) | c.309G>A |
| MANE Select transcript | [NM_002392](https://www.ncbi.nlm.nih.gov/nuccore/NM_002392) |
| dbSNP | [rs766553126](https://www.ncbi.nlm.nih.gov/snp/rs766553126/) |
| Variant type | single nucleotide variant |
| Location | chr12:68820325-68820325 (GRCh38) |
| ClinVar | [VCV971609](https://www.ncbi.nlm.nih.gov/clinvar/variation/971609/) |

**All HGVS expressions:** `NC_000012.11:g.69214105G>A`, `NC_000012.12:g.68820325G>A`, `NG_016708.1:g.17135G>A`, `NM_001145337.3:c.291G>A`, `NM_001145339.2:c.309G>A`, `NM_001145340.3:c.156+6697G>A`, `NM_001278462.2:c.156+6697G>A`, `NM_001367990.1:c.291G>A`, `NM_002392.6:c.309G>A`

## 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 **donor loss** (Δ 0.26) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.356, GERP 0.762, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 21.1**. 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 **0.25**, donor loss **0.26**, acceptor gain **0.08**, donor gain **0.00**. Largest is donor loss, 49 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.08**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.00591%** (nfe) · FAF95 0.00475% · FAF99 0.00435% · 69/1,168,338 in the highest group · 72/1,587,952 alleles overall — very rare (popmax 0.00591%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00591% | 16,932 |
| Remaining individuals (not grpmax-eligible) | 0.00489% | 20,471 |

*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 **103** lies in the swib/mdm2 domain; the 'necessary for interaction with usp2' region; an α-helix.

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.Arg103= falls in the swib/mdm2 domain. 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 2019-10-23.

**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 | 2019-10-23 |

## 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 2026-10-14); 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 971609). 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.*