# NM_000504.4(F10):c.212T>C (p.Phe71Ser)

https://sugi.bio/variant/f10-p-phe71ser

## Summary

**F10 p.Phe71Ser (c.212T>C)** is classified **Likely pathogenic** in F10 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.8201); Very rare (popmax 0.00167%, amr); Associated with congenital factor X deficiency.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs773214680 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the F10 gene that is considered likely disease-causing, submitted by 1 submitter, 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.Phe71Ser |
| Coding change (HGVS c.) | c.212T>C |
| MANE Select transcript | [NM_000504](https://www.ncbi.nlm.nih.gov/nuccore/NM_000504) |
| dbSNP | [rs773214680](https://www.ncbi.nlm.nih.gov/snp/rs773214680/) |
| Variant type | single nucleotide variant |
| Location | chr13:113129593-113129593 (GRCh38) |
| ClinVar | [VCV2572143](https://www.ncbi.nlm.nih.gov/clinvar/variation/2572143/) |

**All HGVS expressions:** `LRG_548:g.11795T>C`, `LRG_548t1:c.212T>C`, `NC_000013.10:g.113783907T>C`, `NC_000013.11:g.113129593T>C`, `NG_009258.1:g.11795T>C`, `NG_128567.1:g.470T>C`, `NM_000504.4:c.212T>C`, `NM_001312674.2:c.212T>C`, `NM_001312675.2:c.212T>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.8201) — concordant with the pathogenic call
- REVEL 0.96 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.946 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.596, GERP 1.89, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 26.8**. 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 1.08** across the covering region of the MANE Select transcript (113,122,856–113,139,379), spanning 16,523 bp. Chi-square p 0.36. 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 **0.00167%** (amr) · 1/60,030 in the highest group · 3/1,461,850 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00167% | 60,030 |
| South Asian | 0.0011% | 91,080 |
| European (non-Finnish) | 8.47e-05% | 1,180,006 |

*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 **71** lies in the gla domain; a β-strand.

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.Phe71Ser falls in the gla 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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology | Likely pathogenic | criteria provided, single submitter | clinical testing |  |

## 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, STUART-PROWER FACTOR DEFICIENCY, Congenital factor X 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 2026-10-11); 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 2572143). 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.*