# NM_000505.4(F12):c.303_304del (p.His101fs)

https://sugi.bio/variant/f12-p-his101fs

## Summary

**F12 p.His101fs (c.303_304del)** is classified **Pathogenic** in F12 (ClinVar, Single submitter, 1 submitter). Very rare (popmax 0.00668%, eas); Associated with congenital factor XII deficiency.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.00668%, eas)

## For patients & families {#patients}

This is a change in the F12 gene that is reported as disease-causing, but on limited review, 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.His101fs |
| Coding change (HGVS c.) | c.303_304del |
| MANE Select transcript | [NM_000505](https://www.ncbi.nlm.nih.gov/nuccore/NM_000505) |
| Variant type | Microsatellite |
| Location | chr5:177405416-177405417 (GRCh38) |
| ClinVar | [VCV3381898](https://www.ncbi.nlm.nih.gov/clinvar/variation/3381898/) |

**All HGVS expressions:** `LRG_145:g.9158CA[1]`, `LRG_145t1:c.300_301AC[1]`, `NC_000005.10:g.177405417GT[1]`, `NC_000005.9:g.176832418GT[1]`, `NG_007568.1:g.9158CA[1]`, `NG_016223.2:g.25985GT[1]`, `NM_000505.4:c.303_304del`

## 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 -1.198, GERP -3.07 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.286, pLI 2.9444e-26. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 5 of 14**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite 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 **0.00668%** (eas) · FAF95 0.00177% · FAF99 0.000891% · 3/44,878 in the highest group · 4/1,461,328 alleles overall — very rare (popmax 0.00668%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00668% | 14,959 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,498 |

*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 **101** lies in a disulfide bond; the egf-like 1 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.His101fs falls in the egf-like 1 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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Juno Genomics, Hangzhou Juno Genomics, Inc | Pathogenic | criteria provided, single submitter | clinical testing |  |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Factor XII deficiency disease, Reduced factor XII activity, F12 DEFICIENCY, HAF DEFICIENCY, Congenital factor XII deficiency.

## Similar variants {#similar}

Related F12 variant pages (same residue, condition, or type): [F12 c.971_1018+24del](/variant/f12-c-971-1018-plus-24del), [F12 p.Gly506fs](/variant/f12-p-gly506fs), [F12 p.Thr328Lys](/variant/f12-p-thr328lys), [F12 p.Gly360Val](/variant/f12-p-gly360val), [F12 p.Leu120His](/variant/f12-p-leu120his), [F12 c.398-12C>T](/variant/f12-c-398-minus-12c-t), [F12 c.-4T>C](/variant/f12-c-minus-4t-c), [F12 c.-8C>T](/variant/f12-c-minus-8c-t).

### 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 3381898). 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.*