# NM_000506.5(F2):c.730G>T (p.Ala244Ser)

https://sugi.bio/variant/f2-p-ala244ser

## Summary

**F2 p.Ala244Ser (c.730G>T)** is classified **Uncertain significance** in F2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely benign (0.0761); Very rare (popmax 0.000186%); Associated with thrombophilia due to thrombin defect.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs886048334 · 1 submitter · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.000186%)

## 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 thrombophilia due to thrombin defect.

*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 | 560 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010815/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.Ala244Ser |
| Coding change (HGVS c.) | c.730G>T |
| MANE Select transcript | [NM_000506](https://www.ncbi.nlm.nih.gov/nuccore/NM_000506) |
| dbSNP | [rs886048334](https://www.ncbi.nlm.nih.gov/snp/rs886048334/) |
| Variant type | single nucleotide variant |
| Location | chr11:46726029-46726029 (GRCh38) |
| ClinVar | [VCV304809](https://www.ncbi.nlm.nih.gov/clinvar/variation/304809/) |

**All HGVS expressions:** `LRG_551:g.11837G>T`, `NC_000011.10:g.46726029G>T`, `NC_000011.9:g.46747579G>T`, `NG_008953.1:g.11837G>T`, `NM_000506.5:c.730G>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0761)
- REVEL 0.054 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.797 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.926, GERP -1.92, phastCons 0.337 — weakly conserved position
- CADD: **PHRED 12.82**. 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): global (via dbSNP) **0.000186%** · 3/1,614,142 alleles overall — very rare (popmax 0.000186%).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,608 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,254 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **244** lies in an α-helix; the kringle 2 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.Ala244Ser falls in the kringle 2 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 2018-01-13.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2018); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |

## Associated conditions {#conditions}

[thrombophilia due to thrombin defect](https://sugi.bio/atlas/disease/thrombophilia-due-to-thrombin-defect/), [congenital prothrombin deficiency](https://sugi.bio/atlas/disease/congenital-prothrombin-deficiency/).

**Reported phenotype names (ClinVar):** Thrombophilia due to thrombin defect, Congenital prothrombin deficiency, Prothrombin Thrombophilia, Thrombosis susceptibility, THROMBOPHILIA DUE TO FACTOR 2 DEFECT, Prothrombin-Related Thrombophilia (Factor II), Factor II deficiency, Hereditary factor II deficiency disease, HYPOPROTHROMBINEMIA, Inherited hypoprothrombinemia.

## 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.Arg117Gln](/variant/f2-p-arg117gln).

### 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 2026-10-14); 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 304809). 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.*