# NM_000505.4(F12):c.923C>T (p.Ser308Phe)

https://sugi.bio/variant/f12-p-ser308phe

## Summary

**F12 p.Ser308Phe (c.923C>T)** is classified **Uncertain significance** in F12 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-27). AlphaMissense: likely benign (0.1056); Very rare (popmax 0.00512%, amr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs139263608 · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00512%, amr)

## 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 2 submitters, and is linked to Inborn genetic diseases.

*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.Ser308Phe |
| Coding change (HGVS c.) | c.923C>T |
| MANE Select transcript | [NM_000505](https://www.ncbi.nlm.nih.gov/nuccore/NM_000505) |
| dbSNP | [rs139263608](https://www.ncbi.nlm.nih.gov/snp/rs139263608/) |
| Variant type | single nucleotide variant |
| Location | chr5:177404291-177404291 (GRCh38) |
| ClinVar | [VCV2158503](https://www.ncbi.nlm.nih.gov/clinvar/variation/2158503/) |

**All HGVS expressions:** `LRG_145:g.10286C>T`, `LRG_145t1:c.923C>T`, `NC_000005.10:g.177404291G>A`, `NC_000005.9:g.176831292G>A`, `NG_007568.1:g.10286C>T`, `NG_016223.2:g.24859G>A`, `NG_106810.1:g.708G>A`, `NM_000505.4:c.923C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1056)
- REVEL 0.112 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.667 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -0.738, GERP -2.75 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 8.423**. 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.*
- Regional missense constraint: **o/e 0.97** across the covering region of the MANE Select transcript (177,402,295–177,409,527), spanning 7,232 bp. Chi-square p 0.39. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.52 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00512%** (amr) · FAF95 0.0036% · FAF99 0.00323% · 3/58,602 in the highest group · 61/1,601,492 alleles overall — very rare (popmax 0.00512%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00512% | 19,534 |
| European (non-Finnish) | 0.0046% | 21,736 |
| Remaining individuals (not grpmax-eligible) | 0.00162% | 61,850 |
| Finnish (not grpmax-eligible) | 0.0016% | 62,466 |
| African / African-American | 0.00134% | 74,592 |
| South Asian | 0.00111% | 89,800 |

*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 **308** lies in the 'disordered' region.

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.Ser308Phe falls in the disordered region. 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-05-27.

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

**Submission history:** 2 submissions (2023–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-07 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-05-27 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

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

## Similar variants {#similar}

Related F12 variant pages (same residue, condition, or type): [F12 p.Ser308Tyr](/variant/f12-p-ser308tyr), [F12 p.Ser308Thr](/variant/f12-p-ser308thr), [F12 p.Ala452Thr](/variant/f12-p-ala452thr), [F12 p.Arg55Trp](/variant/f12-p-arg55trp), [F12 p.Glu288Lys](/variant/f12-p-glu288lys), [F12 p.Gly360Val](/variant/f12-p-gly360val), [F12 p.Leu120His](/variant/f12-p-leu120his), [F12 p.Phe518Ser](/variant/f12-p-phe518ser).

### 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 2158503). 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.*