# NM_000505.4(F12):c.1221G>A (p.Val407=)

https://sugi.bio/variant/f12-p-val407

## Summary

**F12 p.Val407= (c.1221G>A)** is classified **Uncertain significance** in F12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-01). Very rare (popmax 0.000258%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · very rare (popmax 0.000258%, nfe)

## For patients & families {#patients}

This is a change in the F12 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 | [F12](https://sugi.bio/atlas/gene/F12/) |
| Protein change (HGVS p.) | p.Val407= |
| Coding change (HGVS c.) | c.1221G>A |
| MANE Select transcript | [NM_000505](https://www.ncbi.nlm.nih.gov/nuccore/NM_000505) |
| Variant type | single nucleotide variant |
| Location | chr5:177403888-177403888 (GRCh38) |
| ClinVar | [VCV4280924](https://www.ncbi.nlm.nih.gov/clinvar/variation/4280924/) |

**All HGVS expressions:** `LRG_145:g.10689G>A`, `LRG_145t1:c.1221G>A`, `NC_000005.10:g.177403888C>T`, `NC_000005.9:g.176830889C>T`, `NG_007568.1:g.10689G>A`, `NG_016223.2:g.24456C>T`, `NG_106810.1:g.305C>T`, `NG_106810.2:g.305C>T`, `NM_000505.4:c.1221G>A`

## 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 gain** (Δ 0.49) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 3.27, GERP 2.13, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 20.4**. 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 **0.00**, donor loss **0.08**, acceptor gain **0.01**, donor gain **0.49**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.01**, donor gain **0.49**.
- Population frequency (gnomAD v4.1): grpmax **0.000258%** (nfe) · FAF95 6.9e-05% · FAF99 1.9e-05% · 3/1,161,816 in the highest group · 4/1,570,898 alleles overall — very rare (popmax 0.000258%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00165% | 60,756 |
| European (non-Finnish) (grpmax) | 0.000258% | 387,273 |

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}

**F12** population constraint: LOEUF 1.286, pLI 2.9444e-26, missense-Z -0.22747. *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 XII deficiency** — Definitive (AR)
- **hereditary angioedema type 3** — Definitive (AD)

## Protein context {#protein}

Residue **407** lies in a disulfide bond; the peptidase s1 domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 76.47, 41% of residues very-high.

**17 experimental structure(s)** (PDB): [4BDW](https://www.rcsb.org/structure/4BDW), [4BDX](https://www.rcsb.org/structure/4BDX), [4XDE](https://www.rcsb.org/structure/4XDE), [4XE4](https://www.rcsb.org/structure/4XE4), [6B74](https://www.rcsb.org/structure/6B74), [6B77](https://www.rcsb.org/structure/6B77).

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

*Describes the biological roles of F12 (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:** F12's established molecular role includes serine-type endopeptidase activity. p.Val407= falls in the peptidase s1 domain. In Reactome, F12 is annotated in disease pathway(s) including **Aggregated β-amyloid induces FXII autocatalysis**, **Defective SERPING1 causes hereditary angioedema**.

**Disease mechanism (Reactome):** F12 loss or alteration is curated in [Aggregated β-amyloid induces FXII autocatalysis](https://reactome.org/content/detail/R-HSA-9936900), [Defective SERPING1 causes hereditary angioedema](https://reactome.org/content/detail/R-HSA-9657689), [Defective factor XII causes hereditary angioedema](https://reactome.org/content/detail/R-HSA-9657688).

### Pathways affected {#pathways}

F12 participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Aggregated β-amyloid induces FXII autocatalysis](https://reactome.org/content/detail/R-HSA-9936900) | curated |
| ⚕ [Defective SERPING1 causes hereditary angioedema](https://reactome.org/content/detail/R-HSA-9657689) | curated |
| ⚕ [Defective factor XII causes hereditary angioedema](https://reactome.org/content/detail/R-HSA-9657688) | curated |
| [FXIIa activates plasma kallikrein-kinin system](https://reactome.org/content/detail/R-HSA-9970672) | curated |
| [FXIIa, PKa-dependent activation of coagulation pathway](https://reactome.org/content/detail/R-HSA-9935598) | curated |
| [Regulation of FXIIa and plasma kallikrein activity](https://reactome.org/content/detail/R-HSA-9855719) | curated |
| [None](https://reactome.org/content/detail/R-HSA-140837) | other |

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

**Molecular function:** serine-type endopeptidase activity.

**Biological process:** plasma kallikrein-kinin cascade, Factor XII activation, positive regulation of plasminogen activation, protein processing, protein autoprocessing, positive regulation of blood coagulation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-01 |

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

## Similar variants {#similar}

Related F12 variant pages (same residue, condition, or type): [F12 p.Glu193Ter](/variant/f12-p-glu193ter), [F12 p.Thr328Lys](/variant/f12-p-thr328lys), [F12 c.57+4A>G](/variant/f12-c-57-plus-4a-g), [F12 p.Ala452Thr](/variant/f12-p-ala452thr), [F12 p.Arg55Trp](/variant/f12-p-arg55trp), [F12 p.Asp283=](/variant/f12-p-asp283), [F12 p.Glu288Lys](/variant/f12-p-glu288lys), [F12 p.Gly360Val](/variant/f12-p-gly360val).

### 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 4280924). 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.*