F8 p.Ser2010Pro
c.6028T>C · VCV3358853
ClinGen expert panel — Coagulation Factor Deficiency VCEP
Uncertain Significance for hemophilia A. Applied ACMG criteria (verbatim):
PM2_Supporting PS4_Moderate BS2
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.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.2872 | likely benign |
|---|---|---|
| REVEL | 0.599 | indeterminate |
| SaProt | LLR -7.23 | tolerated |
| ⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 7.9 | GERP 1.7, phastCons 1 |
| Regional constraint | o/e 0.65 | unconstrained · MANE · 91 kb · p 1.5e-14 · regional, not allelic |
| Overall | ||
| CADD | 23.3 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- F8
- Protein
- p.Ser2010Pro
- Coding
- c.6028T>C
- MANE Select
- NM_000132
- Type
- single nucleotide variant
- Location
- chrX:154902138 (GRCh38)
- Structure
- AlphaFold pLDDT 61.20 · 29 PDB
- Residue 2010
- the f5/8 type a 3 domain; the plastocyanin-like 6 domain
Disease context
hemophilia A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsFor Hemophilia A (Orphanet):
- Inheritance
- X-linked recessive
- Onset
- Childhood, Infancy, Neonatal
- Prevalence
- 1-9 / 100 000 (Worldwide)
Similar variants
- F8 c.6429+2T>A Pathogenic ★★★ same condition
- F8 p.Ala111Thr Likely pathogenic ★★★ same condition
- F8 p.Ala2220Pro Pathogenic ★★★ same condition
- F8 p.Ala415Asp Likely pathogenic ★★★ same condition
- F8 p.Ala415Val Pathogenic ★★★ ⚠ same condition
- F8 p.Arg1768His Pathogenic ★★★ ⚠ same condition
- F8 p.Arg1800His Pathogenic ★★★ same condition
- F8 p.Arg2016Trp Pathogenic ★★★ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/f8-p-ser2010pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown