# NM_000506.3(F2):c.1273C>T (p.Arg425Cys)

https://sugi.bio/variant/f2-p-arg425cys

## Summary

**F2 p.Arg425Cys (c.1273C>T)** is classified **Likely pathogenic** in F2 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-08-26). AlphaMissense: likely pathogenic (0.8904); Very rare (popmax 8.48e-05%, nfe); Associated with congenital prothrombin deficiency.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs121918479 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the F2 gene that is considered likely disease-causing, submitted by 2 submitters, 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.Arg425Cys |
| Coding change (HGVS c.) | c.1273C>T |
| MANE Select transcript | [NM_000506](https://www.ncbi.nlm.nih.gov/nuccore/NM_000506) |
| dbSNP | [rs121918479](https://www.ncbi.nlm.nih.gov/snp/rs121918479/) |
| Variant type | single nucleotide variant |
| Location | chr11:46728138-46728138 (GRCh38) |
| ClinVar | [VCV13305](https://www.ncbi.nlm.nih.gov/clinvar/variation/13305/) |

**All HGVS expressions:** `LRG_551:g.13946C>T`, `NC_000011.10:g.46728138C>T`, `NC_000011.9:g.46749688C>T`, `NG_008953.1:g.13946C>T`, `NM_000506.5:c.1273C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8904) — concordant with the pathogenic call
- REVEL 0.93 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -8.199 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- Conservation: phyloP 7.568, GERP 1.65, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 34.0**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.80 donor 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 (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,178,784 in the highest group · 1/1,458,220 alleles overall — very rare (popmax 8.48e-05%, 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 **425** lies in the peptidase s1 domain; a β-strand; a disulfide bond; a UniProt-annotated variant site (in fa2d; quick-1).

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.Arg425Cys 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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-08-26.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Likely pathogenic).

**Submission history:** 2 submissions (1992–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1992-04-01 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-08-26 |

## 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, Hereditary factor II deficiency disease, Factor II deficiency, HYPOPROTHROMBINEMIA.

## Same-residue context {#hotspot}

Residue **425** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [F2 p.Arg425His](/variant/f2-p-arg425his). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related F2 variant pages (same residue, condition, or type): [F2 p.Arg425His](/variant/f2-p-arg425his), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 13305). 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.*