# NM_000504.4(F10):c.348C>T (p.Phe116=)

https://sugi.bio/variant/f10-p-phe116

## Summary

**F10 p.Phe116= (c.348C>T)** is classified **Conflicting classifications of pathogenicity** in F10 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2021-08-24). Ultra-rare (popmax 0.0164%, mid); Associated with congenital factor X deficiency.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs747030511 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0164%, mid)

## 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 2 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.Phe116= |
| Coding change (HGVS c.) | c.348C>T |
| MANE Select transcript | [NM_000504](https://www.ncbi.nlm.nih.gov/nuccore/NM_000504) |
| dbSNP | [rs747030511](https://www.ncbi.nlm.nih.gov/snp/rs747030511/) |
| Variant type | single nucleotide variant |
| Location | chr13:113139448-113139448 (GRCh38) |
| ClinVar | [VCV311272](https://www.ncbi.nlm.nih.gov/clinvar/variation/311272/) |

**All HGVS expressions:** `LRG_548:g.21650C>T`, `LRG_548t1:c.348C>T`, `NC_000013.10:g.113793762C>T`, `NC_000013.11:g.113139448C>T`, `NG_009258.1:g.21650C>T`, `NM_000504.4:c.348C>T`, `NM_001312674.2:c.348C>T`, `NM_001312675.2:c.348C>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 -14.155, GERP -3.51 — fast-evolving / accelerated position
- CADD: **PHRED 1.519**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.22 donor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0164%** (mid) · FAF95 0.00429% · FAF99 0.00295% · 1/6,082 in the highest group · 56/1,613,698 alleles overall — ultra-rare (popmax 0.0164%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0164% | 6,082 |
| Admixed American | 0.01% | 9,995 |
| African / African-American | 0.00668% | 14,972 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,617 |
| European (non-Finnish) | 0.00322% | 31,049 |
| South Asian | 0.0022% | 45,531 |

*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 **116** lies in a β-strand; the egf-like 1; calcium-binding domain.

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.Phe116= falls in the egf-like 1; calcium-binding 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 2021-08-24.

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

**Submission history:** 2 submissions (2018–2021); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-08-24 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |

## 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 specified, AllHighlyPenetrant, Congenital factor X deficiency, STUART-PROWER FACTOR DEFICIENCY.

## 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 2026-10-14); 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 311272). 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.*