# NM_000133.4(F9):c.484C>A (p.Arg162=)

https://sugi.bio/variant/f9-p-arg162

## Summary

**F9 p.Arg162= (c.484C>A)** is classified **Pathogenic** in F9 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-20). Absent from gnomAD v4.1; Associated with thrombophilia, X-linked, due to factor 9 defect.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 2 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the F9 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to thrombophilia, X-linked, due to factor 9 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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024725/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.Arg162= |
| Coding change (HGVS c.) | c.484C>A |
| MANE Select transcript | [NM_000133](https://www.ncbi.nlm.nih.gov/nuccore/NM_000133) |
| Variant type | single nucleotide variant |
| Location | chrX:139548455-139548455 (GRCh38) |
| ClinVar | [VCV3759690](https://www.ncbi.nlm.nih.gov/clinvar/variation/3759690/) |

**All HGVS expressions:** `LRG_556:g.22720C>A`, `LRG_556t1:c.484C>A`, `NC_000023.10:g.138630614C>A`, `NC_000023.11:g.139548455C>A`, `NG_007994.1:g.22720C>A`, `NM_000133.4:c.484C>A`, `NM_001313913.2:c.370C>A`

## 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 loss** (Δ 0.57) — consistent with the pathogenic call
- Conservation: phyloP 2.712, GERP 2.94, phastCons 0.031 — highly conserved position (PP3-type support)
- CADD: **PHRED 3.695**. 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 **0.57**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.57**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.30** (loss), gain 0.00 / loss 0.30. 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 3/3, triplosensitivity 0/3. *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 **162** lies in a β-strand; the egf-like 2 domain.

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. p.Arg162= falls in the egf-like 2 domain. 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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-03-20.

**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 | 2024-03-20 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Thrombophilia, X-linked, due to factor 9 defect, Hereditary factor IX deficiency disease, Christmas Disease, F9 DEFICIENCY, FACTOR IX DEFICIENCY, PLASMA THROMBOPLASTIN COMPONENT DEFICIENCY, Hemophilia B.

## Same-residue context {#hotspot}

Residue **162** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [F9 p.Arg162Ter](/variant/f9-p-arg162ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related F9 variant pages (same residue, condition, or type): [F9 p.Arg162Ter](/variant/f9-p-arg162ter), [F9 p.Arg162Gln](/variant/f9-p-arg162gln), [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 2026-10-14); 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 3759690). 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.*