# NM_000130.5(F5):c.552G>T (p.Ser184=)

https://sugi.bio/variant/f5-p-ser184

## Summary

**F5 p.Ser184= (c.552G>T)** is classified **Benign/Likely benign** in F5 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Common (popmax 60.6%, eas) — too common for a highly-penetrant pathogenic allele; Associated with thrombophilia due to thrombin defect.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs6022 · 5 submitters · 4 linked conditions · common (popmax 60.6%, eas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the F5 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 5 submitters, and is linked to thrombophilia due to thrombin defect.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 560 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010815/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [F5](https://sugi.bio/atlas/gene/F5/) |
| Protein change (HGVS p.) | p.Ser184= |
| Coding change (HGVS c.) | c.552G>T |
| MANE Select transcript | [NM_000130](https://www.ncbi.nlm.nih.gov/nuccore/NM_000130) |
| dbSNP | [rs6022](https://www.ncbi.nlm.nih.gov/snp/rs6022/) |
| Variant type | single nucleotide variant |
| Location | chr1:169560588-169560588 (GRCh38) |
| ClinVar | [VCV255212](https://www.ncbi.nlm.nih.gov/clinvar/variation/255212/) |

**All HGVS expressions:** `LRG_553:g.30944G>T`, `LRG_553t1:c.552G>T`, `NC_000001.10:g.169529826C>A`, `NC_000001.11:g.169560588C>A`, `NG_011806.1:g.30944G>T`, `NM_000130.5:c.552G>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 60.6%, eas) — too common for a highly-penetrant pathogenic allele.

- **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 -4.26, GERP -3.83 — fast-evolving / accelerated position
- CADD: **PHRED 0.096**. 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 **60.6%** (eas) · FAF95 60% · FAF99 59.8% · 27,164/44,816 in the highest group · 343,919/1,613,178 alleles overall — common (popmax 60.6%, eas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 60.6% | 2 |
| African / African-American | 58.7% | 2 |
| Admixed American | 27.8% | 4 |
| Finnish (not grpmax-eligible) | 25.7% | 4 |
| Remaining individuals (not grpmax-eligible) | 24.8% | 4 |
| Middle Eastern | 21.2% | 5 |
| Ashkenazi Jewish (not grpmax-eligible) | 20.9% | 5 |
| South Asian | 17.6% | 6 |
| European (non-Finnish) | 17% | 6 |
| Amish (not grpmax-eligible) | 8.77% | 11 |

*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}

**F5** population constraint: LOEUF 0.704, pLI 5.2212e-24, missense-Z 2.7865. *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):

- **thrombophilia due to activated protein C resistance** — Definitive (AD)
- **congenital factor V deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **184** lies in an α-helix; the f5/8 type a 1 domain; the plastocyanin-like 1 domain.

AlphaFold model confidence (whole protein): pLDDT 62.57, 22% of residues very-high.

**23 experimental structure(s)** (PDB): [1CZS](https://www.rcsb.org/structure/1CZS), [1CZT](https://www.rcsb.org/structure/1CZT), [1CZV](https://www.rcsb.org/structure/1CZV), [36JA](https://www.rcsb.org/structure/36JA), [36JB](https://www.rcsb.org/structure/36JB), [3P6Z](https://www.rcsb.org/structure/3P6Z).

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

*Describes the biological roles of F5 (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:** p.Ser184= falls in the f5/8 type a 1 domain. In Reactome, F5 is annotated in disease pathway(s) including **Defective cleavage of FV variant at R334**, **Defective cleavage of FV variant at a.a.534 **.

**Disease mechanism (Reactome):** F5 loss or alteration is curated in [Defective cleavage of FV variant at R334](https://reactome.org/content/detail/R-HSA-9930479), [Defective cleavage of FV variant at a.a.534 ](https://reactome.org/content/detail/R-HSA-9930449).

### Pathways affected {#pathways}

F5 participates in **11 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective cleavage of FV variant at R334](https://reactome.org/content/detail/R-HSA-9930479) | curated |
| ⚕ [Defective cleavage of FV variant at a.a.534 ](https://reactome.org/content/detail/R-HSA-9930449) | curated |
| [Amplification and propagation of coagulation cascade](https://reactome.org/content/detail/R-HSA-9769743) | curated |
| [COPII-mediated vesicle transport](https://reactome.org/content/detail/R-HSA-204005) | curated |
| [Cargo concentration in the ER](https://reactome.org/content/detail/R-HSA-5694530) | curated |
| [Initiation of coagulation cascade](https://reactome.org/content/detail/R-HSA-9769735) | curated |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |
| [Post-translational protein phosphorylation](https://reactome.org/content/detail/R-HSA-8957275) | curated |
| [Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)](https://reactome.org/content/detail/R-HSA-381426) | curated |
| [Regulation of clotting cascade](https://reactome.org/content/detail/R-HSA-9769739) | curated |
| [None](https://reactome.org/content/detail/R-HSA-140875) | other |

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (6 Benign, 1 Likely benign).

**Submission history:** 7 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2016-07-06 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |

## Associated conditions {#conditions}

[thrombophilia due to thrombin defect](https://sugi.bio/atlas/disease/thrombophilia-due-to-thrombin-defect/), [congenital factor V deficiency](https://sugi.bio/atlas/disease/congenital-factor-v-deficiency/), [Budd-Chiari syndrome](https://sugi.bio/atlas/disease/budd-chiari-syndrome/), [factor V deficiency](https://sugi.bio/atlas/disease/factor-v-deficiency/).

**Reported phenotype names (ClinVar):** Thrombophilia due to thrombin defect, not specified, Factor V deficiency, Budd-Chiari syndrome, Congenital factor V deficiency, not provided, Thrombosis susceptibility, THROMBOPHILIA DUE TO FACTOR 2 DEFECT, Prothrombin-Related Thrombophilia (Factor II), Prothrombin Thrombophilia.

## Similar variants {#similar}

Related F5 variant pages (same residue, condition, or type): [F5 c.1297-2A>G](/variant/f5-c-1297-minus-2a-g), [F5 p.Arg1030Ter](/variant/f5-p-arg1030ter), [F5 p.Arg146Ter](/variant/f5-p-arg146ter), [F5 p.Arg1621Ter](/variant/f5-p-arg1621ter), [F5 p.Arg1634Ter](/variant/f5-p-arg1634ter), [F5 p.Arg2102His](/variant/f5-p-arg2102his), [F5 p.Arg740Ter](/variant/f5-p-arg740ter), [F5 p.Asp96His](/variant/f5-p-asp96his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 255212). 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.*