F8 p.Arg2016Trp
c.6046C>T · rs137852453 · VCV10304
ClinGen expert panel — Coagulation Factor Deficiency VCEP
Pathogenic for hemophilia A. Applied ACMG criteria (verbatim):
PP4_Moderate PM2_Supporting PS4_VeryStrong PP3
Curation rationale (ClinGen, verbatim)
The c.6046C>T (p.Arg2016Trp) variant is completely absent from gnomAD v2.1.1 and gnomAD v3 meeting PM2_Supporting. This missense variant has a REVEL score of 0.822 (>0.6) meeting PP3 criteria. More than 46 probands are reported with the variant and moderate-severe hemophilia A in the literature and internal laboratory data (PMID: 29296726, 20102490, 18387975), meeting F8 phenotype criteria. This variant has been associated with discrepant factor VIII activity levels (PMID: 32232366). This variant has also been reported in individuals with a history of inhibitor development to factor replacement therapy (EAHAD database). 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: PS4_Very Strong, PP4_Moderate, PP3, PM2_Supporting.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.4219 | ambiguous |
|---|---|---|
| REVEL | 0.822 | moderately pathogenic-leaning |
| SaProt | LLR -11.06 | damaging |
| ⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call. | ||
| Splicing | ||
| SpliceAI | <0.2 | all four deltas below 0.2 · G>C here scores Δ0.40 · evaluated, not missing |
| Pangolin | Δ0.38 | loss · gain 0.01 · SpliceAI below 0.2 · independent |
| Constraint at this position | ||
| Conservation | phyloP 1.9 | GERP -0.22, phastCons 1 |
| Regional constraint | o/e 0.65 | unconstrained · MANE · 91 kb · p 1.5e-14 · regional, not allelic |
| Overall | ||
| CADD | 23.1 | 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.Arg2016Trp
- Coding
- c.6046C>T
- MANE Select
- NM_000132
- dbSNP
- rs137852453
- Type
- single nucleotide variant
- Location
- chrX:154902120 (GRCh38)
- Structure
- AlphaFold pLDDT 61.20 · 29 PDB
- Residue 2016
- the f5/8 type a 3 domain; the plastocyanin-like 6 domain; a UniProt-annotated variant site (in hema; severe familial); a UniProt-annotated variant site (in hema; severe/moderate/mild); a β-strand
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.Arg2016Gln 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-arg2016trp (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown