# NM_000128.4(F11):c.727dup (p.Ser243fs)

https://sugi.bio/variant/f11-p-ser243fs

## Summary

**F11 p.Ser243fs (c.727dup)** is classified **Pathogenic** in F11 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-19). Very rare (popmax 0.00223%, eas).

**At a glance:** Pathogenic · review: Single submitter · rsID rs2477280027 · 1 submitter · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the F11 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [F11](https://sugi.bio/atlas/gene/F11/) |
| Protein change (HGVS p.) | p.Ser243fs |
| Coding change (HGVS c.) | c.727dup |
| MANE Select transcript | [NM_000128](https://www.ncbi.nlm.nih.gov/nuccore/NM_000128) |
| dbSNP | [rs2477280027](https://www.ncbi.nlm.nih.gov/snp/rs2477280027/) |
| Variant type | Duplication |
| Location | chr4:186276358-186276359 (GRCh38) |
| ClinVar | [VCV2580632](https://www.ncbi.nlm.nih.gov/clinvar/variation/2580632/) |

**All HGVS expressions:** `LRG_583:g.15399dup`, `LRG_583t1:c.727dup`, `NC_000004.11:g.187197516dup`, `NC_000004.12:g.186276362dup`, `NG_008051.1:g.15399dup`, `NM_000128.4:c.727dup`

## 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 1.67, GERP 2.36, phastCons 1 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.145, pLI 4.4437e-22. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 of 15**, 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 (gnomAD v4.1): grpmax **0.00223%** (eas) · 1/44,870 in the highest group · 1/1,614,078 alleles overall — very rare (popmax 0.00223%, eas).

*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}

**F11** population constraint: LOEUF 1.145, pLI 4.4437e-22, missense-Z 0.84839. *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):

- **congenital factor XI deficiency** — Definitive (SD)

## Protein context {#protein}

Residue **243** lies in the apple 3 domain.

AlphaFold model confidence (whole protein): pLDDT 86.94, 65% of residues very-high.

**117 experimental structure(s)** (PDB): [1XX9](https://www.rcsb.org/structure/1XX9), [1XXD](https://www.rcsb.org/structure/1XXD), [1XXF](https://www.rcsb.org/structure/1XXF), [1ZHM](https://www.rcsb.org/structure/1ZHM), [1ZHP](https://www.rcsb.org/structure/1ZHP), [1ZHR](https://www.rcsb.org/structure/1ZHR) — incl. mutant structure 1XXF.

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

*Describes the biological roles of F11 (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:** F11's established molecular role includes identical protein binding. p.Ser243fs falls in the apple 3 domain. In Reactome, F11 is annotated in disease pathway(s) including **Defective F9 activation**.

**Disease mechanism (Reactome):** F11 loss or alteration is curated in [Defective F9 activation](https://reactome.org/content/detail/R-HSA-9673221).

### Pathways affected {#pathways}

F11 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective F9 activation](https://reactome.org/content/detail/R-HSA-9673221) | curated |
| [Amplification and propagation of coagulation cascade](https://reactome.org/content/detail/R-HSA-9769743) | curated |
| [FXIIa, PKa-dependent activation of coagulation pathway](https://reactome.org/content/detail/R-HSA-9935598) | curated |
| [Regulation of clotting cascade](https://reactome.org/content/detail/R-HSA-9769739) | curated |
| [None](https://reactome.org/content/detail/R-HSA-140837) | other |

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

**Molecular function:** identical protein binding.

**Biological process:** blood coagulation, plasminogen activation, positive regulation of fibrinolysis.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-12-19.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2024-12-19 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Same-residue context {#hotspot}

Residue **243** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [F11 p.Ser243Phe](/variant/f11-p-ser243phe). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related F11 variant pages (same residue, condition, or type): [F11 p.Ser243Phe](/variant/f11-p-ser243phe), [F11 p.Cys103Ter](/variant/f11-p-cys103ter), [F11 p.Thr428fs](/variant/f11-p-thr428fs), [F11 p.Tyr52Ter](/variant/f11-p-tyr52ter), [F11 p.Asp457fs](/variant/f11-p-asp457fs), [F11 p.Ile164fs](/variant/f11-p-ile164fs), [F11 p.Thr240fs](/variant/f11-p-thr240fs), [F11 p.Trp73fs](/variant/f11-p-trp73fs).

### 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 2580632). 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.*