# NM_000506.5(F2):c.1351C>A (p.Pro451Thr)

https://sugi.bio/variant/f2-p-pro451thr

## Summary

**F2 p.Pro451Thr (c.1351C>A)** is classified **Uncertain significance** in F2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-20). AlphaMissense: ambiguous (0.4521); Very rare (popmax 0.000593%, nfe); Associated with congenital prothrombin deficiency.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs763016866 · 1 submitter · 1 linked condition · AlphaMissense ambiguous · very rare (popmax 0.000593%, nfe)

## For patients & families {#patients}

This is a change in the F2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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.Pro451Thr |
| Coding change (HGVS c.) | c.1351C>A |
| MANE Select transcript | [NM_000506](https://www.ncbi.nlm.nih.gov/nuccore/NM_000506) |
| dbSNP | [rs763016866](https://www.ncbi.nlm.nih.gov/snp/rs763016866/) |
| Variant type | single nucleotide variant |
| Location | chr11:46728716-46728716 (GRCh38) |
| ClinVar | [VCV2906676](https://www.ncbi.nlm.nih.gov/clinvar/variation/2906676/) |

**All HGVS expressions:** `LRG_551:g.14524C>A`, `LRG_551t1:c.1351C>A`, `NC_000011.10:g.46728716C>A`, `NC_000011.9:g.46750266C>A`, `NG_008953.1:g.14524C>A`, `NM_000506.5:c.1351C>A`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate — descriptive only.

- AlphaMissense **ambiguous** (0.4521) — no call either way
- REVEL 0.868 (moderately pathogenic-leaning)
- SaProt LLR -7.759 (tolerated)
- → **In-silico consensus:** REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate
- Conservation: phyloP 7.524, GERP 1.99, phastCons 1 — highly conserved
- CADD: **PHRED 27.2**. 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 0.76** across the covering region of the MANE Select transcript (46,719,236–46,739,405), spanning 20,169 bp. Chi-square p 1.8e-12. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000593%** (nfe) · FAF95 0.000247% · FAF99 0.000159% · 7/1,180,040 in the highest group · 7/1,614,240 alleles overall — very rare (popmax 0.000593%, nfe).

*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}

Residue **451** lies in the peptidase s1 domain.

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. p.Pro451Thr falls in the peptidase s1 domain. 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-05-20.

**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 | 2023-05-20 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related F2 variant pages (same residue, condition, or type): [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), [F2 p.Gln387Ter](/variant/f2-p-gln387ter), [F2 c.559+5G>A](/variant/f2-c-559-plus-5g-a), [F2 p.Ala17Ser](/variant/f2-p-ala17ser), [F2 p.Arg124Gln](/variant/f2-p-arg124gln).

### 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 2906676). 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.*