# NM_000504.4(F10):c.1032C>T (p.Pro344=)

https://sugi.bio/variant/f10-p-pro344

## Summary

**F10 p.Pro344= (c.1032C>T)** is classified **Conflicting classifications of pathogenicity** in F10 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-11-22). Rare (popmax 0.175%, nfe); Associated with congenital factor X deficiency.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs41286610 · 3 submitters · 1 linked condition · rare (popmax 0.175%, nfe)

## For patients & families {#patients}

This is a change in the F10 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to congenital factor X 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 | F10 is a diagnostic-grade gene on 3 Genomics England panels |

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

- Prolonged prothrombin time — Obligate (100%)
- Reduced factor X activity — Obligate (100%)
- Prolonged bleeding after surgery — Very frequent (99-80%)
- Prolonged bleeding after dental extraction — Very frequent (99-80%)
- Gingival bleeding — Frequent (79-30%)
- Epistaxis — Frequent (79-30%)
- Menorrhagia — Occasional (29-5%)
- Hematuria — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006404/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [F10](https://sugi.bio/atlas/gene/F10/) |
| Protein change (HGVS p.) | p.Pro344= |
| Coding change (HGVS c.) | c.1032C>T |
| MANE Select transcript | [NM_000504](https://www.ncbi.nlm.nih.gov/nuccore/NM_000504) |
| dbSNP | [rs41286610](https://www.ncbi.nlm.nih.gov/snp/rs41286610/) |
| Variant type | single nucleotide variant |
| Location | chr13:113149082-113149082 (GRCh38) |
| ClinVar | [VCV883936](https://www.ncbi.nlm.nih.gov/clinvar/variation/883936/) |

**All HGVS expressions:** `LRG_548:g.31284C>T`, `LRG_548t1:c.1032C>T`, `NC_000013.10:g.113803396C>T`, `NC_000013.11:g.113149082C>T`, `NG_009258.1:g.31284C>T`, `NM_000504.4:c.1032C>T`, `NM_001312674.2:c.900C>T`, `NM_001312675.2:c.*23C>T`

## Computational & population evidence {#evidence}

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

- **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 -6.982, GERP -3.81 — fast-evolving / accelerated position
- CADD: **PHRED 2.158**. 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 **0.175%** (nfe) · FAF95 0.168% · FAF99 0.166% · 2,062/1,180,006 in the highest group · 2,263/1,613,262 alleles overall — rare (popmax 0.175%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.175% | 572 |
| Remaining individuals (not grpmax-eligible) | 0.118% | 845 |
| Finnish (not grpmax-eligible) | 0.106% | 943 |
| Admixed American | 0.04% | 2,501 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0338% | 2,961 |
| African / African-American | 0.028% | 3,573 |
| Middle Eastern | 0.0165% | 6,062 |
| South Asian | 0.00439% | 22,769 |

*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}

**F10** population constraint: LOEUF 0.968, pLI 9.9027e-06, missense-Z 2.0575. *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):

- **congenital factor X deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **344** lies in the peptidase s1 domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 80.47, 55% of residues very-high.

**192 experimental structure(s)** (PDB): [13ES](https://www.rcsb.org/structure/13ES), [13EU](https://www.rcsb.org/structure/13EU), [1C5M](https://www.rcsb.org/structure/1C5M), [1EZQ](https://www.rcsb.org/structure/1EZQ), [1F0R](https://www.rcsb.org/structure/1F0R), [1F0S](https://www.rcsb.org/structure/1F0S) — incl. mutant structure 8RE5.

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

*Describes the biological roles of F10 (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:** F10's established molecular role includes serine-type endopeptidase activity. p.Pro344= falls in the peptidase s1 domain. In Reactome, F10 is annotated in disease pathway(s) including **Defective F9 variant does not activate FX**, **Defective cofactor function of FVIIIa variant**.

**Disease mechanism (Reactome):** F10 loss or alteration is curated in [Defective F9 variant does not activate FX](https://reactome.org/content/detail/R-HSA-9673202), [Defective cofactor function of FVIIIa variant](https://reactome.org/content/detail/R-HSA-9672396), [Defective factor IX causes thrombophilia](https://reactome.org/content/detail/R-HSA-9672383).

### Pathways affected {#pathways}

F10 participates in **12 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [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 |
| [Amplification and propagation of coagulation cascade](https://reactome.org/content/detail/R-HSA-9769743) | 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 |
| [None](https://reactome.org/content/detail/R-HSA-140875) | other |

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

**Molecular function:** serine-type endopeptidase activity, phospholipid binding.

**Biological process:** positive regulation of TOR signaling.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-11-22.

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

**Submission history:** 3 submissions (2018–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2023-07-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-22 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Hereditary factor X deficiency disease, not provided, not specified, none provided, STUART-PROWER FACTOR DEFICIENCY, Congenital factor X deficiency, AllHighlyPenetrant.

## Similar variants {#similar}

Related F10 variant pages (same residue, condition, or type): [F10 p.Glu54Gly](/variant/f10-p-glu54gly), [F10 p.Gly363Ser](/variant/f10-p-gly363ser), [F10 p.Gly450Arg](/variant/f10-p-gly450arg), [F10 p.Arg291Gln](/variant/f10-p-arg291gln), [F10 p.Glu306Lys](/variant/f10-p-glu306lys), [F10 p.Gly106=](/variant/f10-p-gly106), [F10 p.Gly154Arg](/variant/f10-p-gly154arg), [F10 p.Pro472Leu](/variant/f10-p-pro472leu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 883936). 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.*