# NM_000132.4(F8):c.6028T>C (p.Ser2010Pro)

https://sugi.bio/variant/f8-p-ser2010pro

## Summary

**F8 p.Ser2010Pro (c.6028T>C)** is classified **Uncertain significance** in F8 (ClinVar, Expert panel, 1 submitter; last evaluated 2026-02-06). AlphaMissense: likely benign (0.2872); Very rare (popmax 0.000112%, nfe); Associated with hemophilia A.

**At a glance:** Uncertain significance · review: Expert panel · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.000112%, nfe)

## For patients & families {#patients}

This is a change in the F8 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to hemophilia A.

*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 (Worldwide) |
| Clinical trials | 482 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | F8 is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of Hemophilia A** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Joint swelling — Very frequent (99-80%)
- Arthralgia — Very frequent (99-80%)
- Reduced factor VIII activity — Very frequent (99-80%)
- Bleeding with minor or no trauma — Very frequent (99-80%)
- Thromboembolism — Frequent (79-30%)
- Spontaneous hematomas — Frequent (79-30%)
- Oral cavity bleeding — Frequent (79-30%)
- Joint hemorrhage — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006591/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [F8](https://sugi.bio/atlas/gene/F8/) |
| Protein change (HGVS p.) | p.Ser2010Pro |
| Coding change (HGVS c.) | c.6028T>C |
| MANE Select transcript | [NM_000132](https://www.ncbi.nlm.nih.gov/nuccore/NM_000132) |
| Variant type | single nucleotide variant |
| Location | chrX:154902138-154902138 (GRCh38) |
| ClinVar | [VCV3358853](https://www.ncbi.nlm.nih.gov/clinvar/variation/3358853/) |

**All HGVS expressions:** `LRG_555:g.125586T>C`, `LRG_555t1:c.6028T>C`, `NC_000023.10:g.154130413A>G`, `NC_000023.11:g.154902138A>G`, `NG_011403.2:g.125586T>C`, `NM_000132.4:c.6028T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.2872)
- REVEL 0.599 (indeterminate)
- SaProt LLR -7.231 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 7.904, GERP 1.7, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.3**. 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 0.65** across the covering region of the MANE Select transcript (154,837,600–154,928,668), spanning 91,068 bp. Chi-square p 1.5e-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 **0.000112%** (nfe) · 1/891,671 in the highest group · 1/1,206,210 alleles overall — very rare (popmax 0.000112%, nfe).

*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}

**F8** 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 A** — Definitive (XL)

## Protein context {#protein}

Residue **2010** lies in the f5/8 type a 3 domain; the plastocyanin-like 6 domain.

AlphaFold model confidence (whole protein): pLDDT 61.20, 32% of residues very-high.

**29 experimental structure(s)** (PDB): [12JP](https://www.rcsb.org/structure/12JP), [12JV](https://www.rcsb.org/structure/12JV), [1CFG](https://www.rcsb.org/structure/1CFG), [1D7P](https://www.rcsb.org/structure/1D7P), [1FAC](https://www.rcsb.org/structure/1FAC), [1IQD](https://www.rcsb.org/structure/1IQD) — incl. mutant structure 9D5D.

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

*Describes the biological roles of F8 (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:** p.Ser2010Pro falls in the f5/8 type a 3 domain. In Reactome, F8 is annotated in disease pathway(s) including **Defective F8 accelerates dissociation of the A2 domain**, **Defective F8 binding to the cell membrane**.

**Disease mechanism (Reactome):** F8 loss or alteration is curated in [Defective F8 accelerates dissociation of the A2 domain](https://reactome.org/content/detail/R-HSA-9672387), [Defective F8 binding to the cell membrane](https://reactome.org/content/detail/R-HSA-9672395), [Defective F8 binding to von Willebrand factor](https://reactome.org/content/detail/R-HSA-9672393).

### Pathways affected {#pathways}

F8 participates in **18 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective F8 accelerates dissociation of the A2 domain](https://reactome.org/content/detail/R-HSA-9672387) | curated |
| ⚕ [Defective F8 binding to the cell membrane](https://reactome.org/content/detail/R-HSA-9672395) | curated |
| ⚕ [Defective F8 binding to von Willebrand factor](https://reactome.org/content/detail/R-HSA-9672393) | curated |
| ⚕ [Defective F8 cleavage by thrombin](https://reactome.org/content/detail/R-HSA-9672391) | curated |
| ⚕ [Defective F8 secretion](https://reactome.org/content/detail/R-HSA-9672397) | curated |
| ⚕ [Defective F8 sulfation at Y1699](https://reactome.org/content/detail/R-HSA-9674519) | 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 |
| [Amplification and propagation of coagulation cascade](https://reactome.org/content/detail/R-HSA-9769743) | curated |
| [COPII-mediated vesicle transport](https://reactome.org/content/detail/R-HSA-204005) | curated |
| [Cargo concentration in the ER](https://reactome.org/content/detail/R-HSA-5694530) | curated |
| [Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation](https://reactome.org/content/detail/R-HSA-163841) | curated |
| [Initiation of coagulation cascade](https://reactome.org/content/detail/R-HSA-9769735) | curated |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |
| [Regulation of clotting cascade](https://reactome.org/content/detail/R-HSA-9769739) | curated |
| [None](https://reactome.org/content/detail/R-HSA-140837) | other |
| [None](https://reactome.org/content/detail/R-HSA-140875) | other |

## Clinical significance {#significance}

**Uncertain significance** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2026-02-06.

**Submitter consensus:** unanimous (1/1 Uncertain Significance).

**ClinGen expert panel:** Uncertain Significance — Coagulation Factor Deficiency VCEP (hemophilia A). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2_Supporting`, `PS4_Moderate`, `BS2`.
*Considered but not met:* `PP3`.
Inheritance: X-linked inheritance.

> **Curation rationale (ClinGen, verbatim):** The F8 c.6028T>C (p.Ser2010Pro) variant is completely absent from population databases (gnomAD v2.1.1/gnomAD v3). This missense variant has a REVEL score of 0.599 (>0.6), which does not meet the cut off for PP3. At least three individuals with the p.Ser2010Pro variant and severe hemophilia A have been reported in the literature (PMID:  23306409). However, variant was also identified in an unaffected male with a factor VIII level of 90%. In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8 Rule specification v1.0.0: PS4_Moderate, PM2_Supporting, BS2.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50041 · approved 2026-02-06 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/1215dd51-794b-4904-8dc8-32938d93c1f4).*
*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 |
| --- | --- | --- | --- | --- |
| ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen | Uncertain Significance | reviewed by expert panel | curation | 2026-02-06 |

## Associated conditions {#conditions}

[hemophilia A](https://sugi.bio/atlas/disease/hemophilia-a/).

**Reported phenotype names (ClinVar):** Hereditary factor VIII deficiency disease, HEMOPHILIA, CLASSIC, AUTOSOMAL HEMOPHILIA A, Hemophilia A, Hemophilia A, congenital, HEM A, Factor 8 deficiency, congenital.

## Similar variants {#similar}

Related F8 variant pages (same residue, condition, or type): [F8 c.6429+2T>A](/variant/f8-c-6429-plus-2t-a), [F8 p.Ala111Thr](/variant/f8-p-ala111thr), [F8 p.Ala2220Pro](/variant/f8-p-ala2220pro), [F8 p.Ala415Asp](/variant/f8-p-ala415asp), [F8 p.Ala415Val](/variant/f8-p-ala415val), [F8 p.Arg1768His](/variant/f8-p-arg1768his), [F8 p.Arg1800His](/variant/f8-p-arg1800his), [F8 p.Arg2016Trp](/variant/f8-p-arg2016trp).

### 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 3358853). 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.*