# NM_022845.3(CBFB):c.295_296dup (p.Pro100fs)

https://sugi.bio/variant/cbfb-p-pro100fs

## Summary

**CBFB p.Pro100fs (c.295_296dup)** is classified **Uncertain significance** in CBFB (ClinVar, Single submitter, 2 submitters; last evaluated 2019-07-26). No gnomAD frequency available for this variant; Associated with acute myeloid leukemia.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1961069899 · 2 submitters · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CBFB gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to acute myeloid leukemia.

*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 | 2278 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012757/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CBFB](https://sugi.bio/atlas/gene/CBFB/) |
| Protein change (HGVS p.) | p.Pro100fs |
| Coding change (HGVS c.) | c.295_296dup |
| MANE Select transcript | [NM_022845](https://www.ncbi.nlm.nih.gov/nuccore/NM_022845) |
| dbSNP | [rs1961069899](https://www.ncbi.nlm.nih.gov/snp/rs1961069899/) |
| Variant type | Duplication |
| Location | chr16:67066693-67066694 (GRCh38) |
| ClinVar | [VCV930504](https://www.ncbi.nlm.nih.gov/clinvar/variation/930504/) |

**All HGVS expressions:** `LRG_1364:g.42548_42549dup`, `LRG_1364t1:c.295_296dup`, `LRG_1364t2:c.295_296dup`, `NC_000016.10:g.67066694_67066695dup`, `NC_000016.9:g.67100597_67100598dup`, `NG_009281.1:g.42548_42549dup`, `NM_001368707.1:c.178_179dup`, `NM_001368708.1:c.283-15519_283-15518dup`, `NM_001368709.1:c.178_179dup`, `NM_001368710.1:c.283-15519_283-15518dup`, `NM_001755.3:c.295_296dup`, `NM_022845.3:c.295_296dup`

## 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 2.95, GERP 0.829, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.065, pLI 0.19912. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 6**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication 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}

**CBFB** population constraint: LOEUF 1.065, pLI 0.19912, missense-Z 0.50011; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *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):

- **cleidocranial dysplasia 2** — Definitive (AD)

## Protein context {#protein}

Residue **100** lies in a β-strand; a UniProt-annotated variant site (in clcd2); a UniProt-annotated variant site (in a breast cancer sample; somatic mutation).

AlphaFold model confidence (whole protein): pLDDT 85.81, 56% of residues very-high.

**22 experimental structure(s)** (PDB): [1CL3](https://www.rcsb.org/structure/1CL3), [1E50](https://www.rcsb.org/structure/1E50), [1H9D](https://www.rcsb.org/structure/1H9D), [4N9F](https://www.rcsb.org/structure/4N9F), [6NIL](https://www.rcsb.org/structure/6NIL), [6P59](https://www.rcsb.org/structure/6P59).

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

*Describes the biological roles of CBFB (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.*


### Pathways affected {#pathways}

CBFB participates in **25 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Estrogen-dependent gene expression](https://reactome.org/content/detail/R-HSA-9018519) | curated |
| [RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)](https://reactome.org/content/detail/R-HSA-8877330) | curated |
| [RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known](https://reactome.org/content/detail/R-HSA-8939243) | curated |
| [RUNX1 regulates estrogen receptor mediated transcription](https://reactome.org/content/detail/R-HSA-8931987) | curated |
| [RUNX1 regulates expression of components of tight junctions](https://reactome.org/content/detail/R-HSA-8935964) | curated |
| [RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function](https://reactome.org/content/detail/R-HSA-8936459) | curated |
| [RUNX1 regulates transcription of genes involved in BCR signaling](https://reactome.org/content/detail/R-HSA-8939245) | curated |
| [RUNX1 regulates transcription of genes involved in WNT signaling](https://reactome.org/content/detail/R-HSA-8939256) | curated |
| [RUNX1 regulates transcription of genes involved in differentiation of myeloid cells](https://reactome.org/content/detail/R-HSA-8939246) | curated |
| [RUNX1 regulates transcription of genes involved in interleukin signaling](https://reactome.org/content/detail/R-HSA-8939247) | curated |
| [RUNX2 regulates bone development](https://reactome.org/content/detail/R-HSA-8941326) | curated |
| [RUNX2 regulates genes involved in differentiation of myeloid cells](https://reactome.org/content/detail/R-HSA-8941333) | curated |
| [RUNX3 regulates RUNX1-mediated transcription](https://reactome.org/content/detail/R-HSA-8951911) | curated |
| [RUNX3 regulates p14-ARF](https://reactome.org/content/detail/R-HSA-8951936) | curated |
| [Regulation of RUNX1 Expression and Activity](https://reactome.org/content/detail/R-HSA-8934593) | curated |
| [Regulation of RUNX3 expression and activity](https://reactome.org/content/detail/R-HSA-8941858) | curated |
| [RUNX1 regulates transcription of genes involved in differentiation of HSCs](https://reactome.org/content/detail/R-HSA-8939236) | electronic |
| [RUNX1 regulates transcription of genes involved in differentiation of keratinocytes](https://reactome.org/content/detail/R-HSA-8939242) | electronic |
| [RUNX2 regulates chondrocyte maturation](https://reactome.org/content/detail/R-HSA-8941284) | electronic |
| [RUNX2 regulates genes involved in cell migration](https://reactome.org/content/detail/R-HSA-8941332) | electronic |
| [RUNX2 regulates osteoblast differentiation](https://reactome.org/content/detail/R-HSA-8940973) | electronic |
| [RUNX3 Regulates Immune Response and Cell Migration](https://reactome.org/content/detail/R-HSA-8949275) | electronic |
| [Regulation of RUNX2 expression and activity](https://reactome.org/content/detail/R-HSA-8939902) | electronic |
| [Transcriptional regulation by RUNX2](https://reactome.org/content/detail/R-HSA-8878166) | electronic |
| [Transcriptional regulation of granulopoiesis](https://reactome.org/content/detail/R-HSA-9616222) | electronic |

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

**Biological process:** protein polyubiquitination, regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-07-26.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Pathogenic).

**Submission history:** 2 submissions (2019–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Centre for Mendelian Genomics, University Medical Centre Ljubljana | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-07-26 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2023-04-25 |

## Associated conditions {#conditions}

[acute myeloid leukemia](https://sugi.bio/atlas/disease/acute-myeloid-leukemia/), [cleidocranial dysplasia 2](https://sugi.bio/atlas/disease/cleidocranial-dysplasia-2/).

**Reported phenotype names (ClinVar):** Acute myeloid leukemia, Cleidocranial dysplasia 2, Leukemia, acute myeloid, somatic, Leukemia, acute myelogenous, somatic, CEBPA-Associated Familial Acute Myeloid Leukemia (AML), Acute myeloid leukemia, adult, AML adult, Acute non-lymphocytic leukemia, Acute granulocytic leukemia.

## Similar variants {#similar}

Related CBFB variant pages (same residue, condition, or type): [CBFB c.283-2A>G](/variant/cbfb-c-283-minus-2a-g), [CBFB p.Arg83Ter](/variant/cbfb-p-arg83ter), [CBFB c.283-1039_400-7568del](/variant/cbfb-c-283-minus-1039-400-minus-7568del), [CBFB c.78+1G>T](/variant/cbfb-c-78-plus-1g-t), [CBFB c.*2dup](/variant/cbfb-c-star-2dup).

### 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 930504). 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.*