# NM_005225.3(E2F1):c.875C>G (p.Pro292Arg)

https://sugi.bio/variant/e2f1-p-pro292arg

## Summary

**E2F1 p.Pro292Arg (c.875C>G)** is classified **Uncertain significance** in E2F1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-08). AlphaMissense: ambiguous (0.4682); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense ambiguous · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the E2F1 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 | [E2F1](https://sugi.bio/atlas/gene/E2F1/) |
| Protein change (HGVS p.) | p.Pro292Arg |
| Coding change (HGVS c.) | c.875C>G |
| MANE Select transcript | [NM_005225](https://www.ncbi.nlm.nih.gov/nuccore/NM_005225) |
| Variant type | single nucleotide variant |
| Location | chr20:33677296-33677296 (GRCh38) |
| ClinVar | [VCV4015804](https://www.ncbi.nlm.nih.gov/clinvar/variation/4015804/) |

**All HGVS expressions:** `NC_000020.10:g.32265102G>C`, `NC_000020.11:g.33677296G>C`, `NG_046988.1:g.14109C>G`, `NM_005225.3:c.875C>G`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this damaging; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.4682) — no call either way
- REVEL 0.933 (strongly pathogenic-leaning)
- SaProt LLR -11.708 (damaging)
- → **In-silico consensus:** REVEL and SaProt both call this damaging; AlphaMissense makes no call
- Conservation: phyloP 11.854, GERP 6.47, phastCons 1 — highly conserved
- CADD: **PHRED 28.4**. 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 0.65** across the covering region of the MANE Select transcript (33,677,269–33,678,347), spanning 1,078 bp. Chi-square p 2.6e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>A, Δ0.26 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- 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}

**E2F1** population constraint: LOEUF 0.399, pLI 0.99923, missense-Z 1.8728; ClinGen dosage — haploinsufficiency 30, 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.*

## Protein context {#protein}

Residue **292** lies in the 'required for interaction with trim28' region.

AlphaFold model confidence (whole protein): pLDDT 63.40, 24% of residues very-high.

**8 experimental structure(s)** (PDB): [1H24](https://www.rcsb.org/structure/1H24), [1O9K](https://www.rcsb.org/structure/1O9K), [2AZE](https://www.rcsb.org/structure/2AZE), [5M9N](https://www.rcsb.org/structure/5M9N), [5M9O](https://www.rcsb.org/structure/5M9O), [6G0P](https://www.rcsb.org/structure/6G0P).

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

*Describes the biological roles of E2F1 (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:** E2F1's established molecular role includes DNA-binding transcription factor activity, RNA polymerase II-specific. p.Pro292Arg falls in the required for interaction with trim28 region. In Reactome, E2F1 is annotated in disease pathway(s) including **Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)**.

**Disease mechanism (Reactome):** E2F1 loss or alteration is curated in [Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)](https://reactome.org/content/detail/R-HSA-9661069).

### Pathways affected {#pathways}

E2F1 participates in **17 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)](https://reactome.org/content/detail/R-HSA-9661069) | curated |
| [Activation of NOXA and translocation to mitochondria](https://reactome.org/content/detail/R-HSA-111448) | curated |
| [Activation of PUMA and translocation to mitochondria](https://reactome.org/content/detail/R-HSA-139915) | curated |
| [Cyclin A:Cdk2-associated events at S phase entry](https://reactome.org/content/detail/R-HSA-69656) | curated |
| [Cyclin D associated events in G1](https://reactome.org/content/detail/R-HSA-69231) | curated |
| [Cyclin E associated events during G1/S transition ](https://reactome.org/content/detail/R-HSA-69202) | curated |
| [G2 Phase](https://reactome.org/content/detail/R-HSA-68911) | 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 |
| [TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest](https://reactome.org/content/detail/R-HSA-6804116) | curated |
| [Transcriptional Regulation by E2F6](https://reactome.org/content/detail/R-HSA-8953750) | curated |
| [G1/S-Specific Transcription](https://reactome.org/content/detail/R-HSA-69205) | electronic |
| [Inhibition of replication initiation of damaged DNA by RB1/E2F1](https://reactome.org/content/detail/R-HSA-113501) | electronic |
| [Pre-NOTCH Transcription and Translation](https://reactome.org/content/detail/R-HSA-1912408) | electronic |
| [Transcription of E2F targets under negative control by DREAM complex](https://reactome.org/content/detail/R-HSA-1362277) | electronic |
| [Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1](https://reactome.org/content/detail/R-HSA-1362300) | electronic |
| [Transcriptional regulation of granulopoiesis](https://reactome.org/content/detail/R-HSA-9616222) | electronic |

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

**Molecular function:** DNA-binding transcription factor activity, RNA polymerase II-specific, cis-regulatory region sequence-specific DNA binding, DNA-binding transcription activator activity, DNA-binding transcription activator activity, RNA polymerase II-specific, DNA binding, DNA-binding transcription factor activity.

**Biological process:** DNA damage checkpoint signaling, negative regulation of transcription by RNA polymerase II, regulation of DNA-templated transcription, intrinsic apoptotic signaling pathway in response to DNA damage, positive regulation of gene expression, positive regulation of apoptotic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-08.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-08 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related E2F1 variant pages (same residue, condition, or type): [RBP3 p.Arg388Ter](/variant/rbp3-p-arg388ter), [RBP3 p.Gln141Ter](/variant/rbp3-p-gln141ter), [RBP3 p.Gln54Ter](/variant/rbp3-p-gln54ter), [RBP3 p.Glu149Ter](/variant/rbp3-p-glu149ter), [RBP3 p.Glu692Ter](/variant/rbp3-p-glu692ter), [RBP3 p.Tyr784Ter](/variant/rbp3-p-tyr784ter), [RBP3 p.Tyr841Ter](/variant/rbp3-p-tyr841ter), [RBP3 c.3388+4C>G](/variant/rbp3-c-3388-plus-4c-g).

### 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 4015804). 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.*