# NM_000133.4(F9):c.520G>A (p.Val174Met)

https://sugi.bio/variant/f9-p-val174met

## Summary

**F9 p.Val174Met (c.520G>A)** is classified **Likely pathogenic** in F9 (ClinVar, Expert panel, 4 submitters; last evaluated 2024-11-05). AlphaMissense: likely benign (0.1569); Absent from gnomAD v4.1; Associated with hemophilia B.

**At a glance:** Likely pathogenic · review: Expert panel · rsID rs1603265504 · 4 submitters · 2 linked conditions · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the F9 gene that is considered likely disease-causing, submitted by 4 submitters, and is linked to hemophilia B.

*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) | X-linked recessive |
| Age of onset (of this condition) | Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 171 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | F9 is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of Hemophilia B** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hematuria — Very frequent (99-80%)
- Poor wound healing — Very frequent (99-80%)
- Intracranial hemorrhage — Very frequent (99-80%)
- Prolonged bleeding time — Very frequent (99-80%)
- Prolonged partial thromboplastin time — Very frequent (99-80%)
- Spontaneous, recurrent epistaxis — Very frequent (99-80%)
- Prolonged bleeding after surgery — Very frequent (99-80%)
- Joint hemorrhage — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0008732/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [F9](https://sugi.bio/atlas/gene/F9/) |
| Protein change (HGVS p.) | p.Val174Met |
| Coding change (HGVS c.) | c.520G>A |
| MANE Select transcript | [NM_000133](https://www.ncbi.nlm.nih.gov/nuccore/NM_000133) |
| dbSNP | [rs1603265504](https://www.ncbi.nlm.nih.gov/snp/rs1603265504/) |
| Variant type | single nucleotide variant |
| Location | chrX:139548491-139548491 (GRCh38) |
| ClinVar | [VCV811516](https://www.ncbi.nlm.nih.gov/clinvar/variation/811516/) |

**All HGVS expressions:** `LRG_556:g.22756G>A`, `LRG_556t1:c.520G>A`, `NC_000023.10:g.138630650G>A`, `NC_000023.11:g.139548491G>A`, `NG_007994.1:g.22756G>A`, `NM_000133.3:c.520G>A`, `NM_000133.4:c.520G>A`, `NM_001313913.2:c.406G>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.1569) — ⚠ discordant with the pathogenic call
- REVEL 0.811 (moderately pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -8.594 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** REVEL calls this damaging; AlphaMissense and SaProt do not
- SpliceAI predicts **donor loss** (Δ 0.66) — consistent with the pathogenic call
- Conservation: phyloP 11.769, GERP 4.78, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 32.0**. 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.*
- Regional missense constraint: **o/e 0.57** across the covering region of the MANE Select transcript (139,537,046–139,562,068), spanning 25,022 bp. Chi-square p 2.3e-14. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.66**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.66**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.40** (loss), gain 0.04 / loss 0.40. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**F9** population constraint: ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *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):

- **hemophilia B** — Definitive (XL)
- **thrombophilia, X-linked, due to factor 9 defect** — Limited (XL)

## Protein context {#protein}

Residue **174** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 80.45, 51% of residues very-high.

**57 experimental structure(s)** (PDB): [1CFH](https://www.rcsb.org/structure/1CFH), [1CFI](https://www.rcsb.org/structure/1CFI), [1EDM](https://www.rcsb.org/structure/1EDM), [1IXA](https://www.rcsb.org/structure/1IXA), [1MGX](https://www.rcsb.org/structure/1MGX), [1NL0](https://www.rcsb.org/structure/1NL0) — incl. mutant structure 2WPH.

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

*Describes the biological roles of F9 (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:** F9's established molecular role includes endopeptidase activity. In Reactome, F9 is annotated in disease pathway(s) including **Defective F9 activation**, **Defective F9 secretion**.

**Disease mechanism (Reactome):** F9 loss or alteration is curated in [Defective F9 activation](https://reactome.org/content/detail/R-HSA-9673221), [Defective F9 secretion](https://reactome.org/content/detail/R-HSA-9673218), [Defective F9 variant does not activate FX](https://reactome.org/content/detail/R-HSA-9673202).

### Pathways affected {#pathways}

F9 participates in **16 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective F9 activation](https://reactome.org/content/detail/R-HSA-9673221) | curated |
| ⚕ [Defective F9 secretion](https://reactome.org/content/detail/R-HSA-9673218) | curated |
| ⚕ [Defective F9 variant does not activate FX](https://reactome.org/content/detail/R-HSA-9673202) | curated |
| ⚕ [Defective cofactor function of FVIIIa variant](https://reactome.org/content/detail/R-HSA-9672396) | curated |
| ⚕ [Defective factor IX causes thrombophilia](https://reactome.org/content/detail/R-HSA-9672383) | curated |
| ⚕ [Defective gamma-carboxylation of F9](https://reactome.org/content/detail/R-HSA-9673240) | curated |
| [Amplification and propagation of coagulation cascade](https://reactome.org/content/detail/R-HSA-9769743) | curated |
| [FXIIa, PKa-dependent activation of coagulation pathway](https://reactome.org/content/detail/R-HSA-9935598) | curated |
| [Gamma-carboxylation of protein precursors](https://reactome.org/content/detail/R-HSA-159740) | curated |
| [Initiation of coagulation cascade](https://reactome.org/content/detail/R-HSA-9769735) | curated |
| [Regulation of clotting cascade](https://reactome.org/content/detail/R-HSA-9769739) | curated |
| [Removal of aminoterminal propeptides from gamma-carboxylated proteins](https://reactome.org/content/detail/R-HSA-159782) | curated |
| [Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus](https://reactome.org/content/detail/R-HSA-159763) | curated |
| [None](https://reactome.org/content/detail/R-HSA-140834) | other |
| [None](https://reactome.org/content/detail/R-HSA-140837) | other |
| [Protein hydroxylation](https://reactome.org/content/detail/R-HSA-9629569) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** endopeptidase activity, calcium ion binding, metal ion binding.

**Biological process:** proteolysis, blood coagulation, zymogen activation.

## Clinical significance {#significance}

**Likely pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2024-11-05.

**Submitter consensus:** conflicting (3 Likely pathogenic, 1 Likely Pathogenic).

**Submission history:** 4 submissions (2019–2025); classifications have been stable.

**ClinGen expert panel:** Likely Pathogenic — Coagulation Factor Deficiency VCEP (hemophilia B). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2_Supporting`, `PS4_Moderate`, `PM1`, `PP3`.
Inheritance: X-linked inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_000133.4(F9):c.520G>A (p.Val174Met) missense variant is completely absent from gnomAD v2.1.1 and v3.1.2 meeting criteria for PM2_Supporting. The variant has a REVEL score of 0.811 (>0.6) meeting criteria for PP3. The variant changes the last nucleotide of exon 5 and SpliceAI predicts a donor loss of intron 5 (delta score of 0.66) meeting criteria for PM1. At least four probands with moderate or severe hemophilia B are reported in the literature and internal laboratory data (PMID: 1680287; doi: 10.5336/medsci.2020-75066), meeting criteria for PS4. In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9 (Released 10/5/2023): PM1, PS4_Moderate, PP3, PM2_Supporting.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50041 · approved 2024-11-05 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/057e3f28-6e3a-42f3-91c9-53d21cc20e9d).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Likely pathogenic | criteria provided, single submitter | clinical testing | 2019-07-01 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-09-08 |
| ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen | Likely Pathogenic | reviewed by expert panel | curation | 2024-11-05 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-09-02 |

## Associated conditions {#conditions}

[hemophilia B](https://sugi.bio/atlas/disease/hemophilia-b/), [thrombophilia, X-linked, due to factor 9 defect](https://sugi.bio/atlas/disease/thrombophilia-x-linked-due-to-factor-9-defect/).

**Reported phenotype names (ClinVar):** Hereditary factor IX deficiency disease, not specified, Thrombophilia, X-linked, due to factor 9 defect, Christmas Disease, PLASMA THROMBOPLASTIN COMPONENT DEFICIENCY, F9 DEFICIENCY, FACTOR IX DEFICIENCY, Hemophilia B, AllHighlyPenetrant.

## Same-residue context {#hotspot}

Residue **174** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [F9 p.Val174fs](/variant/f9-p-val174fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related F9 variant pages (same residue, condition, or type): [F9 p.Val174=](/variant/f9-p-val174), [F9 p.Val174fs](/variant/f9-p-val174fs), [F9 c.520+13A>G](/variant/f9-c-520-plus-13a-g), [F9 c.88+1G>A](/variant/f9-c-88-plus-1g-a), [F9 c.88+5G>T](/variant/f9-c-88-plus-5g-t), [F9 p.Ala279Thr](/variant/f9-p-ala279thr), [F9 p.Ala337Pro](/variant/f9-p-ala337pro), [F9 p.Ala337Thr](/variant/f9-p-ala337thr).

### 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 811516). 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.*