F8 p.Arg458Cys
c.1372C>T · rs2523950289 · VCV2775446
ClinGen expert panel — Coagulation Factor Deficiency VCEP
Pathogenic for hemophilia A. Applied ACMG criteria (verbatim):
PM2_Supporting PS4_Very PP1 PP3
Curation rationale (ClinGen, verbatim)
The c.1372C>T (p.Arg458Cys) variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3) meeting PM2_Supporting. This missense variant has a REVEL score of 0.839 (>0.6), meeting criteria for PP3. At least 8 mild hemophilia A patients meeting F8-phenotype criteria are reported in the literature (PMID: 25628142, PMID: 18387975, PMID: 16173970, PMID: 17610549) and internal VCEP data. This variant was noted to segregate in a maternal uncle and nephew pair with hemophilia A (PMID: 25628142), which meets criteria for PP1. Additionally, this variant has been associated with a history of an inhibitor in at least one individual (PMID: 17610549). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PS4_Very strong, PP1, PP3, PM2_Supporting.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.2926 | likely benign ⚠ discordant with ClinVar |
|---|---|---|
| REVEL | 0.839 | moderately pathogenic-leaning |
| SaProt | LLR -14.05 | damaging |
| ⇒ REVEL and SaProt call this damaging; AlphaMissense does not. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP 1.5, phastCons 1 |
| Regional constraint | o/e 0.74 | unconstrained · MANE · 38 kb · p 2.6e-06 · regional, not allelic |
| Overall | ||
| CADD | 27.4 | PHRED · no single calibrated threshold — expert panels disagree |
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.Arg458Cys
- Coding
- c.1372C>T
- MANE Select
- NM_000132
- dbSNP
- rs2523950289
- Type
- single nucleotide variant
- Location
- chrX:154966041 (GRCh38)
- Structure
- AlphaFold pLDDT 61.20 · 29 PDB
- Residue 458
- the plastocyanin-like 3 domain; a β-strand; the f5/8 type a 2 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 p.Arg458His Likely pathogenic ★★ ⚠ same residue
- 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
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-arg458cys (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown