# NM_000133.4(F9):c.130C>T (p.Pro44Ser)

https://sugi.bio/variant/f9-p-pro44ser

## Summary

**F9 p.Pro44Ser (c.130C>T)** is classified **Likely benign** in F9 (ClinVar, Expert panel, 3 submitters; last evaluated 2025-08-15). AlphaMissense: likely benign (0.1148); Very rare (popmax 0.00594%, eas); Associated with hemophilia B.

**At a glance:** Likely benign · review: Expert panel · rsID rs776894974 · 3 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00594%, eas)

## For patients & families {#patients}

This is a change in the F9 gene that is classified as likely benign — not considered disease-causing, submitted by 3 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.Pro44Ser |
| Coding change (HGVS c.) | c.130C>T |
| MANE Select transcript | [NM_000133](https://www.ncbi.nlm.nih.gov/nuccore/NM_000133) |
| dbSNP | [rs776894974](https://www.ncbi.nlm.nih.gov/snp/rs776894974/) |
| Variant type | single nucleotide variant |
| Location | chrX:139537051-139537051 (GRCh38) |
| ClinVar | [VCV1085717](https://www.ncbi.nlm.nih.gov/clinvar/variation/1085717/) |

**All HGVS expressions:** `LRG_556:g.11316C>T`, `NC_000023.10:g.138619210C>T`, `NC_000023.11:g.139537051C>T`, `NG_007994.1:g.11316C>T`, `NM_000133.4:c.130C>T`, `NM_001313913.2:c.130C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1148)
- REVEL 0.144 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.805 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.34, GERP 3.35 — weakly conserved position
- CADD: **PHRED 14.45**. 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: **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 **0.00594%** (eas) · FAF95 0.000983% · FAF99 0.000368% · 2/33,682 in the highest group · 2/1,207,787 alleles overall — very rare (popmax 0.00594%, eas).

*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}


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 benign** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2025-08-15.

**Submitter consensus:** conflicting (2 Likely benign, 1 Likely Benign).

**Submission history:** 3 submissions (2021–2025); classifications have been stable.

**ClinGen expert panel:** Likely Benign — Coagulation Factor Deficiency VCEP (hemophilia B). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `BS1`, `BP4`.
Inheritance: X-linked inheritance.

> **Curation rationale (ClinGen, verbatim):** The c.130C>T; p.Pro44Ser variant has a Grpmax MAF of 0.00005825 in gnomAD v2.1.1 meeting BS1. The variant also has a REVEL score of 0.144 and Splice AI scores: Acceptor Loss: 0.00, Donor Loss: 0.05, Acceptor Gain: 0.00, Donor Gain: 0.00, meeting BP4. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: BS1, BP4.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50041 · approved 2025-08-15 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/b6a6a78e-c328-47bf-a216-244b17937741).*
*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 |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Likely benign | no assertion criteria provided | clinical testing | 2021-10-19 |
| ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen | Likely Benign | reviewed by expert panel | curation | 2025-08-15 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-02-29 |

## 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, Thrombophilia, X-linked, due to factor 9 defect, Hemophilia B, Christmas Disease, F9 DEFICIENCY, FACTOR IX DEFICIENCY, PLASMA THROMBOPLASTIN COMPONENT DEFICIENCY.

## Similar variants {#similar}

Related F9 variant pages (same residue, condition, or type): [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), [F9 p.Ala337Val](/variant/f9-p-ala337val), [F9 p.Arg191His](/variant/f9-p-arg191his).

### 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 1085717). 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.*