# NM_000506.5(F2):c.923_926del (p.Asp308fs)

https://sugi.bio/variant/f2-p-asp308fs

## Summary

**F2 p.Asp308fs (c.923_926del)** is classified **Pathogenic** in F2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-18). No gnomAD frequency available for this variant; Associated with congenital prothrombin deficiency.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2502830373 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the F2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to congenital prothrombin deficiency.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | All ages |
| Prevalence | <1 / 1 000 000 (Europe) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | F2 is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Congenital factor II deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Prolonged partial thromboplastin time — Very frequent (99-80%)
- Prolonged prothrombin time — Very frequent (99-80%)
- Reduced prothrombin antigen — Very frequent (99-80%)
- Epistaxis — Frequent (79-30%)
- Abnormal bleeding — Frequent (79-30%)
- Intracranial hemorrhage — Frequent (79-30%)
- Joint hemorrhage — Frequent (79-30%)
- Menorrhagia — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002926/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [F2](https://sugi.bio/atlas/gene/F2/) |
| Protein change (HGVS p.) | p.Asp308fs |
| Coding change (HGVS c.) | c.923_926del |
| MANE Select transcript | [NM_000506](https://www.ncbi.nlm.nih.gov/nuccore/NM_000506) |
| dbSNP | [rs2502830373](https://www.ncbi.nlm.nih.gov/snp/rs2502830373/) |
| Variant type | Deletion |
| Location | chr11:46726543-46726546 (GRCh38) |
| ClinVar | [VCV2872207](https://www.ncbi.nlm.nih.gov/clinvar/variation/2872207/) |

**All HGVS expressions:** `LRG_551:g.12354_12357del`, `LRG_551t1:c.923_926del`, `NC_000011.10:g.46726546_46726549del`, `NC_000011.9:g.46748096_46748099del`, `NG_008953.1:g.12354_12357del`, `NM_000506.5:c.923_926del`

## 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 -2.809, GERP -2.84 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.552, pLI 0.15426. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 8 of 14**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion 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}

**F2** population constraint: LOEUF 0.552, pLI 0.15426, missense-Z 2.7726. *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):

- **thrombophilia due to thrombin defect** — Definitive (AD)
- **congenital prothrombin deficiency** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 84.37, 56% of residues very-high.

**480 experimental structure(s)** (PDB): [13CM](https://www.rcsb.org/structure/13CM), [13ER](https://www.rcsb.org/structure/13ER), [1A2C](https://www.rcsb.org/structure/1A2C), [1A3B](https://www.rcsb.org/structure/1A3B), [1A3E](https://www.rcsb.org/structure/1A3E), [1A46](https://www.rcsb.org/structure/1A46) — incl. mutant structure 1B7X.

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

*Describes the biological roles of F2 (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:** F2's established molecular role includes lipopolysaccharide binding. In Reactome, F2 is annotated in disease pathway(s) including **Defective F8 cleavage by thrombin**, **Defective factor XII causes hereditary angioedema**.

**Disease mechanism (Reactome):** F2 loss or alteration is curated in [Defective F8 cleavage by thrombin](https://reactome.org/content/detail/R-HSA-9672391), [Defective factor XII causes hereditary angioedema](https://reactome.org/content/detail/R-HSA-9657688), [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481).

### Pathways affected {#pathways}

F2 participates in **19 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective F8 cleavage by thrombin](https://reactome.org/content/detail/R-HSA-9672391) | curated |
| ⚕ [Defective factor XII causes hereditary angioedema](https://reactome.org/content/detail/R-HSA-9657688) | curated |
| ⚕ [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481) | curated |
| [Amplification and propagation of coagulation cascade](https://reactome.org/content/detail/R-HSA-9769743) | curated |
| [Cell surface interactions at the vascular wall](https://reactome.org/content/detail/R-HSA-202733) | curated |
| [Fibrin formation](https://reactome.org/content/detail/R-HSA-9769733) | curated |
| [G alpha (q) signalling events](https://reactome.org/content/detail/R-HSA-416476) | curated |
| [Gamma-carboxylation of protein precursors](https://reactome.org/content/detail/R-HSA-159740) | curated |
| [Initiation of coagulation cascade](https://reactome.org/content/detail/R-HSA-9769735) | curated |
| [Peptide ligand-binding receptors](https://reactome.org/content/detail/R-HSA-375276) | curated |
| [Platelet Aggregation (Plug Formation)](https://reactome.org/content/detail/R-HSA-76009) | curated |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |
| [Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)](https://reactome.org/content/detail/R-HSA-381426) | curated |
| [Regulation of clotting cascade](https://reactome.org/content/detail/R-HSA-9769739) | curated |
| [Removal of aminoterminal propeptides from gamma-carboxylated proteins](https://reactome.org/content/detail/R-HSA-159782) | curated |
| [Thrombin signalling through proteinase activated receptors (PARs)](https://reactome.org/content/detail/R-HSA-456926) | curated |
| [Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus](https://reactome.org/content/detail/R-HSA-159763) | curated |
| [None](https://reactome.org/content/detail/R-HSA-140837) | other |
| [None](https://reactome.org/content/detail/R-HSA-140875) | other |

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

**Molecular function:** lipopolysaccharide binding, serine-type endopeptidase activity, signaling receptor binding, heparin binding, receptor ligand activity, thrombospondin receptor activity.

**Biological process:** cell surface receptor signaling pathway, response to wounding, platelet activation, positive regulation of blood coagulation, negative regulation of blood coagulation, positive regulation of collagen biosynthetic process.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-09-18.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-09-18 |

## Associated conditions {#conditions}

[congenital prothrombin deficiency](https://sugi.bio/atlas/disease/congenital-prothrombin-deficiency/).

**Reported phenotype names (ClinVar):** Congenital prothrombin deficiency, Factor II deficiency, Hereditary factor II deficiency disease, HYPOPROTHROMBINEMIA, Inherited hypoprothrombinemia, Congenital factor II deficiency, Inherited prothrombin deficiency.

## Similar variants {#similar}

Related F2 variant pages (same residue, condition, or type): [F2 p.Val185fs](/variant/f2-p-val185fs), [F2 p.His605fs](/variant/f2-p-his605fs), [F2 c.1131-18_1131-15del](/variant/f2-c-1131-minus-18-1131-minus-15del), [F2 c.80-13del](/variant/f2-c-80-minus-13del), [F2 p.Arg461Trp](/variant/f2-p-arg461trp), [F2 p.Arg500Gln](/variant/f2-p-arg500gln), [F2 p.Arg581Cys](/variant/f2-p-arg581cys), [F2 p.Arg596Gln](/variant/f2-p-arg596gln).

### 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 2872207). 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.*