# NM_000128.4(F11):c.756A>T (p.Arg252Ser)

https://sugi.bio/variant/f11-p-arg252ser

## Summary

**F11 p.Arg252Ser (c.756A>T)** is classified **Uncertain significance** in F11 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-03-24). AlphaMissense: likely pathogenic (0.6929); Very rare (popmax 0.0011%, sas); Associated with congenital factor XI deficiency.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1441160252 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the F11 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to congenital factor XI 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 dominant, Autosomal recessive |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |

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

- Abnormal bleeding — Very frequent (99-80%)
- Reduced factor XI activity — Very frequent (99-80%)
- Prolonged partial thromboplastin time — Very frequent (99-80%)
- Prolonged bleeding after dental extraction — Very frequent (99-80%)
- Abnormality of the intrinsic pathway — Very frequent (99-80%)
- Menorrhagia — Frequent (79-30%)
- Epistaxis — Frequent (79-30%)
- Gastrointestinal hemorrhage — Very rare (<4-1%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009670/index) · [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.Arg252Ser |
| Coding change (HGVS c.) | c.756A>T |
| MANE Select transcript | [NM_001322131](https://www.ncbi.nlm.nih.gov/nuccore/NM_001322131) (variant reported on NM_000128) |
| dbSNP | [rs1441160252](https://www.ncbi.nlm.nih.gov/snp/rs1441160252/) |
| Variant type | single nucleotide variant |
| Location | chr4:186280012-186280012 (GRCh38) |
| ClinVar | [VCV555730](https://www.ncbi.nlm.nih.gov/clinvar/variation/555730/) |

**All HGVS expressions:** `LRG_583:g.19049A>T`, `LRG_583t1:c.756A>T`, `NC_000004.11:g.187201166A>T`, `NC_000004.12:g.186280012A>T`, `NG_008051.1:g.19049A>T`, `NM_000128.4:c.756A>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.6929)
- REVEL 0.686 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.725 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **acceptor loss** (Δ 0.37) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 5.15, GERP 2.36, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 24.3**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.37**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.37** (loss), gain 0.01 / loss 0.37. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (sas) · FAF95 0.000292% · FAF99 0.000211% · 1/91,006 in the highest group · 10/1,458,904 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,404 |
| South Asian (grpmax) | 0.0011% | 91,006 |
| European (non-Finnish) | 0.000679% | 147,173 |

Remaining individuals 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}


Curated gene–disease validity (ClinGen):

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

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 68.98, 3% of residues very-high.

## 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.*


### Pathways affected {#pathways}

F11 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Generic Transcription Pathway](https://reactome.org/content/detail/R-HSA-212436) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-24.

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

**Submission history:** 2 submissions (2017–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Counsyl | Uncertain significance | no assertion criteria provided | clinical testing | 2017-12-28 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-03-24 |

## Associated conditions {#conditions}

[congenital factor XI deficiency](https://sugi.bio/atlas/disease/congenital-factor-xi-deficiency/).

**Reported phenotype names (ClinVar):** Hereditary factor XI deficiency disease, not provided, Congenital factor XI deficiency, PLASMA THROMBOPLASTIN ANTECEDENT DEFICIENCY, PTA DEFICIENCY, ROSENTHAL SYNDROME, none provided.

## Similar variants {#similar}

Related F11 variant pages (same residue, condition, or type): [F11 c.1481-1G>T](/variant/f11-c-1481-minus-1g-t), [F11 c.1716+1G>A](/variant/f11-c-1716-plus-1g-a), [F11 c.325+1G>A](/variant/f11-c-325-plus-1g-a), [F11 c.326-1G>A](/variant/f11-c-326-minus-1g-a), [F11 c.755+2T>C](/variant/f11-c-755-plus-2t-c), [F11 c.865+2T>C](/variant/f11-c-865-plus-2t-c), [F11 p.Ala109Thr](/variant/f11-p-ala109thr), [F11 p.Ala430Thr](/variant/f11-p-ala430thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 555730). 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.*