# NM_000128.4(F11):c.1575A>G (p.Arg525=)

https://sugi.bio/variant/f11-p-arg525

## Summary

**F11 p.Arg525= (c.1575A>G)** is classified **Uncertain significance** in F11 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-27). Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · absent from gnomAD v4.1

## 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 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.Arg525= |
| Coding change (HGVS c.) | c.1575A>G |
| MANE Select transcript | [NM_001322131](https://www.ncbi.nlm.nih.gov/nuccore/NM_001322131) (variant reported on NM_000128) |
| Variant type | single nucleotide variant |
| Location | chr4:186286509-186286509 (GRCh38) |
| ClinVar | [VCV4687739](https://www.ncbi.nlm.nih.gov/clinvar/variation/4687739/) |

**All HGVS expressions:** `LRG_583:g.25546A>G`, `LRG_583t1:c.1575A>G`, `NC_000004.11:g.187207663A>G`, `NC_000004.12:g.186286509A>G`, `NG_008051.1:g.25546A>G`, `NM_000128.4:c.1575A>G`, `NM_001440590.1:c.1527A>G`, `NM_001440593.1:c.1480+696A>G`, `NM_001440596.1:c.1432+696A>G`, `NM_001440605.1:c.1305A>G`, `NM_001440606.1:c.1257A>G`, `NM_001440607.1:c.1210+696A>G`, `NM_001440608.1:c.1162+696A>G`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.44) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 6.387, GERP 1.19, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 19.06**. 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 **0.04**, donor loss **0.44**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.44**, acceptor gain **0.00**, donor gain **0.00**.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 2025-10-27.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-10-27 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related F11 variant pages (same residue, condition, or type): [F11 c.1136-1G>C](/variant/f11-c-1136-minus-1g-c), [F11 c.1480+1G>T](/variant/f11-c-1480-plus-1g-t), [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.595+3A>G](/variant/f11-c-595-plus-3a-g), [F11 c.755+2T>C](/variant/f11-c-755-plus-2t-c).

### 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 4687739). 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.*