# NM_000504.4(F10):c.1120T>C (p.Ser374Pro)

https://sugi.bio/variant/f10-p-ser374pro

## Summary

**F10 p.Ser374Pro (c.1120T>C)** is classified **Pathogenic** in F10 (ClinVar, No assertion criteria, 1 submitter; last evaluated 1995-08-01). AlphaMissense: likely pathogenic (0.7349); Absent from gnomAD v4.1; Associated with factor X deficiency.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs121964941 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the F10 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to 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.*

|  |  |
| --- | --- |
| Clinical trials | 4 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0023100/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.Ser374Pro |
| Coding change (HGVS c.) | c.1120T>C |
| MANE Select transcript | [NM_000504](https://www.ncbi.nlm.nih.gov/nuccore/NM_000504) |
| dbSNP | [rs121964941](https://www.ncbi.nlm.nih.gov/snp/rs121964941/) |
| Variant type | single nucleotide variant |
| Location | chr13:113149170-113149170 (GRCh38) |
| ClinVar | [VCV12060](https://www.ncbi.nlm.nih.gov/clinvar/variation/12060/) |

**All HGVS expressions:** `LRG_548:g.31372T>C`, `NC_000013.10:g.113803484T>C`, `NC_000013.11:g.113149170T>C`, `NG_009258.1:g.31372T>C`, `NM_000504.4:c.1120T>C`, `NM_001312674.2:c.988T>C`, `NM_001312675.2:c.*111T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.7349) — concordant with the pathogenic call
- REVEL 0.573 (indeterminate)
- SaProt LLR -14.375 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 4.999, GERP 0.884, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 22.0**. 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 0.75** across the covering region of the MANE Select transcript (113,139,380–113,149,514), spanning 10,134 bp. Chi-square p 2.9e-09. 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: **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}

**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 **374** lies in the peptidase s1 domain; an α-helix; a UniProt-annotated variant site (in fa10d; marseille; decreased cleavage by factor ixa; normal catalytic efficiency for prothrombin).

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.Ser374Pro 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}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 1995-08-01.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1995-08-01 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Factor X deficiency, F10 DEFICIENCY.

## Similar variants {#similar}

Related F10 variant pages (same residue, condition, or type): [F10 p.Glu54Gly](/variant/f10-p-glu54gly), [F10 p.Gly21Arg](/variant/f10-p-gly21arg), [F10 p.Arg291Gln](/variant/f10-p-arg291gln), [F10 p.Glu69Lys](/variant/f10-p-glu69lys), [F10 p.Thr358Met](/variant/f10-p-thr358met), [F10 p.Arg27His](/variant/f10-p-arg27his), [F10 p.Asp463His](/variant/f10-p-asp463his), [F10 p.Cys277Ser](/variant/f10-p-cys277ser).

### 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 12060). 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.*