# NM_004364.5(CEBPA):c.342_343insATGA (p.Pro115fs)

https://sugi.bio/variant/cebpa-p-pro115fs

## Summary

**CEBPA p.Pro115fs (c.342_343insATGA)** is classified **Likely pathogenic** in CEBPA (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-22). No gnomAD frequency available for this variant; Associated with hereditary neoplastic syndrome.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2145262824 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CEBPA gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to hereditary neoplastic syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 31 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019921/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CEBPA](https://sugi.bio/atlas/gene/CEBPA/) |
| Protein change (HGVS p.) | p.Pro115fs |
| Coding change (HGVS c.) | c.342_343insATGA |
| MANE Select transcript | [NM_004364](https://www.ncbi.nlm.nih.gov/nuccore/NM_004364) |
| dbSNP | [rs2145262824](https://www.ncbi.nlm.nih.gov/snp/rs2145262824/) |
| Variant type | Insertion |
| Location | chr19:33302072-33302073 (GRCh38) |
| ClinVar | [VCV1692807](https://www.ncbi.nlm.nih.gov/clinvar/variation/1692807/) |

**All HGVS expressions:** `LRG_456:g.5452_5453insATGA`, `LRG_456t1:c.342_343insATGA`, `NC_000019.10:g.33302072_33302073insTCAT`, `NC_000019.9:g.33792978_33792979insTCAT`, `NG_012022.1:g.5452_5453insATGA`, `NM_001285829.2:c.-16_-15insATGA`, `NM_001287424.2:c.447_448insATGA`, `NM_001287435.2:c.300_301insATGA`, `NM_004364.5:c.342_343insATGA`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 6.174, GERP -2.46, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.372, pLI 0.26038. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (1 of 1)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no insertion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**CEBPA** population constraint: LOEUF 1.372, pLI 0.26038, missense-Z -1.2385; 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):

- **acute myeloid leukemia** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 63.67, 21% of residues very-high.

**2 experimental structure(s)** (PDB): [6DC0](https://www.rcsb.org/structure/6DC0), [8K8C](https://www.rcsb.org/structure/8K8C).

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

*Describes the biological roles of CEBPA (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:** CEBPA's established molecular role includes transcription cis-regulatory region binding.


### Pathways affected {#pathways}

CEBPA participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis](https://reactome.org/content/detail/R-HSA-9841922) | electronic |
| [Somatic hypermutation of immunoglobulin genes](https://reactome.org/content/detail/R-HSA-9938024) | electronic |
| [Transcriptional regulation of granulopoiesis](https://reactome.org/content/detail/R-HSA-9616222) | electronic |
| [Transcriptional regulation of white adipocyte differentiation](https://reactome.org/content/detail/R-HSA-381340) | electronic |

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

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

**Biological process:** regulation of DNA-templated transcription, transcription by RNA polymerase I, negative regulation of cell population proliferation, positive regulation of transcription by RNA polymerase II, interleukin-6-mediated signaling pathway, positive regulation of DNA-templated transcription initiation.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-11-22.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Sema4, Sema4 | Likely pathogenic | criteria provided, single submitter | curation | 2021-11-22 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Hereditary neoplastic syndrome, Tumor predisposition, Neoplastic Syndromes, Hereditary, Hereditary Cancer Syndrome.

## Similar variants {#similar}

Related CEBPA variant pages (same residue, condition, or type): [CEBPA p.Pro115Leu](/variant/cebpa-p-pro115leu), [CEBPA p.Pro115Ser](/variant/cebpa-p-pro115ser), [CEBPA p.Pro115=](/variant/cebpa-p-pro115), [CEBPA p.191HP[2]](/variant/cebpa-p-191hp-2), [CEBPA p.191HP[5]](/variant/cebpa-p-191hp-5), [CEBPA p.Gln88Arg](/variant/cebpa-p-gln88arg), [CEBPA p.Gly122Ala](/variant/cebpa-p-gly122ala), [CEBPA p.His18Tyr](/variant/cebpa-p-his18tyr).

### 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 1692807). 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.*