# NM_000505.4(F12):c.1704G>A (p.Val568=)

https://sugi.bio/variant/f12-p-val568

## Summary

**F12 p.Val568= (c.1704G>A)** is classified **Conflicting classifications of pathogenicity** in F12 (ClinVar, Conflicting submitters, 1 submitter; last evaluated 2018-01-13). Ultra-rare (popmax 0.0851%, sas); Associated with congenital factor XII deficiency.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs536390950 · 1 submitter · 2 linked conditions · ultra-rare (popmax 0.0851%, sas)

## For patients & families {#patients}

This is a change in the F12 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 1 submitter, and is linked to congenital factor XII 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 recessive |
| Age of onset (of this condition) | All ages |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | F12 is a diagnostic-grade gene on 5 Genomics England panels |

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

- Prolonged partial thromboplastin time — Very frequent (99-80%)
- Reduced factor XII activity — Very frequent (99-80%)
- Thromboembolism — Occasional (29-5%)
- Abnormal thrombosis — Occasional (29-5%)
- Retinal arteriolar occlusion — Occasional (29-5%)
- Retinal vein occlusion — Occasional (29-5%)
- Recurrent spontaneous abortion — Occasional (29-5%)
- Penetrating foot ulcers — Very rare (<4-1%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006558/index) · [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.Val568= |
| Coding change (HGVS c.) | c.1704G>A |
| MANE Select transcript | [NM_000505](https://www.ncbi.nlm.nih.gov/nuccore/NM_000505) |
| dbSNP | [rs536390950](https://www.ncbi.nlm.nih.gov/snp/rs536390950/) |
| Variant type | single nucleotide variant |
| Location | chr5:177402436-177402436 (GRCh38) |
| ClinVar | [VCV904430](https://www.ncbi.nlm.nih.gov/clinvar/variation/904430/) |

**All HGVS expressions:** `LRG_145:g.12141G>A`, `LRG_145t1:c.1704G>A`, `NC_000005.10:g.177402436C>T`, `NC_000005.9:g.176829437C>T`, `NG_007568.1:g.12141G>A`, `NM_000505.4:c.1704G>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 (below), not from a missing predictor score.
- Conservation: phyloP -0.796, GERP -4.58, phastCons 0.006 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 9.634**. 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: **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): grpmax **0.0851%** (sas) · FAF95 0.0698% · FAF99 0.0641% · 77/90,478 in the highest group · 89/1,610,082 alleles overall — ultra-rare (popmax 0.0851%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0851% | 1,175 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00677% | 14,764 |
| Remaining individuals (not grpmax-eligible) | 0.00642% | 15,575 |
| Admixed American | 0.00336% | 29,802 |
| European (non-Finnish) | 0.000339% | 294,640 |

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

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.Val568= 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2018-01-13.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Benign).

**Submission history:** 2 submissions (2018); classifications have differed over time.

### Submitter classifications {#submitters}

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

## Associated conditions {#conditions}

[congenital factor XII deficiency](https://sugi.bio/atlas/disease/congenital-factor-xii-deficiency/), [hereditary angioedema type 3](https://sugi.bio/atlas/disease/hereditary-angioedema-type-3/).

**Reported phenotype names (ClinVar):** Factor XII deficiency disease, Hereditary angioedema type 3, Reduced factor XII activity, Congenital factor XII deficiency, F12 DEFICIENCY, HAF DEFICIENCY, ANGIONEUROTIC EDEMA, HEREDITARY, WITH NORMAL C1 INHIBITOR CONCENTRATION AND FUNCTION, ESTROGEN-RELATED HAE, ESTROGEN-SENSITIVE HAE, HAE WITH NORMAL C1 INHIBITOR CONCENTRATION AND FUNCTION.

## Similar variants {#similar}

Related F12 variant pages (same residue, condition, or type): [F12 p.Thr328Lys](/variant/f12-p-thr328lys), [F12 p.Gly360Val](/variant/f12-p-gly360val), [F12 p.Leu120His](/variant/f12-p-leu120his), [F12 c.1019-28T>C](/variant/f12-c-1019-minus-28t-c), [F12 c.1251-9C>T](/variant/f12-c-1251-minus-9c-t), [F12 c.1681-7G>A](/variant/f12-c-1681-minus-7g-a), [F12 c.398-12C>T](/variant/f12-c-398-minus-12c-t), [F12 c.-4T>C](/variant/f12-c-minus-4t-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 904430). 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.*