# NM_000130.5(F5):c.1609C>T (p.Gln537Ter)

https://sugi.bio/variant/f5-p-gln537ter

## Summary

**F5 p.Gln537Ter (c.1609C>T)** is classified **Pathogenic** in F5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-19). Very rare (popmax 8.49e-05%, nfe); Associated with congenital factor V deficiency.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 8.49e-05%, nfe)

## For patients & families {#patients}

This is a change in the F5 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to congenital factor V 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 |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Diagnostic panels | F5 is a diagnostic-grade gene on 4 Genomics England panels |

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

- Epistaxis — Frequent (79-30%)
- Joint hemorrhage — Frequent (79-30%)
- Menorrhagia — Occasional (29-5%)
- Gingival bleeding — Occasional (29-5%)
- Hematuria — Occasional (29-5%)
- Bruising susceptibility — Occasional (29-5%)
- Persistent bleeding after trauma — Occasional (29-5%)
- Gastrointestinal hemorrhage — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002237/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.Gln537Ter |
| Coding change (HGVS c.) | c.1609C>T |
| MANE Select transcript | [NM_000130](https://www.ncbi.nlm.nih.gov/nuccore/NM_000130) |
| Variant type | single nucleotide variant |
| Location | chr1:169549803-169549803 (GRCh38) |
| ClinVar | [VCV3616544](https://www.ncbi.nlm.nih.gov/clinvar/variation/3616544/) |

**All HGVS expressions:** `LRG_553:g.41729C>T`, `LRG_553t1:c.1609C>T`, `NC_000001.10:g.169519041G>A`, `NC_000001.11:g.169549803G>A`, `NG_011806.1:g.41729C>T`, `NM_000130.5:c.1609C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 0.71) — consistent with the pathogenic call
- Conservation: phyloP 11.809, GERP 1.61, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.704, pLI 5.2212e-24. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 10 of 25**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 57.0**. 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 **0.02**, acceptor gain **0.00**, donor gain **0.71**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.71**.
- Pangolin: Δ**0.48** (gain), gain 0.48 / loss 0.35. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **8.49e-05%** (nfe) · 1/1,177,412 in the highest group · 1/1,611,204 alleles overall — very rare (popmax 8.49e-05%, nfe).

*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 **537** lies in the plastocyanin-like 4 domain; the f5/8 type a 2 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.Gln537Ter falls in the plastocyanin-like 4 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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-19.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-19 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Congenital factor V deficiency, Hereditary factor V deficiency disease, LABILE FACTOR DEFICIENCY, OWREN PARAHEMOPHILIA, PARAHEMOPHILIA.

## 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 3616544). 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.*