F8 p.Arg602Ter
c.1804C>T · rs137852424 · VCV10232
ClinGen expert panel — Coagulation Factor Deficiency VCEP
Pathogenic for hemophilia A. Applied ACMG criteria (verbatim):
PVS1 PP4_Moderate PM2_Supporting PS4_VeryStrong
Curation rationale (ClinGen, verbatim)
The c.1804C>T (p.Arg602Ter) variant is a nonsense variant that is predicted to introduce a premature stop codon in exon 12 and expected to result in nonsense-mediated mRNA decay. This variant is absent from males in gnomAD v2.1.1 and v3.1.1, which meets criteria for PM2_Supporting. More than 25 patients with moderate-severe hemophilia A are reported in the literature and internal laboratory data, meeting criteria for PS4_Very Strong and PP4_Moderate (PMID: 29296726, 18387975, 18691168, 16769589, 8639447, 20331761). 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: PVS1, PS4_Very Strong, PP4_Moderate, PM2_Supporting.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Consequence | nonsense (stop-gain) | predicted loss-of-function in a haploinsufficient gene (ClinGen) |
|---|---|---|
| NMD | predicted | premature termination codon in exon 12 of 26 |
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 4.2 | GERP -1.2, phastCons 0.9 |
| Overall | ||
| CADD | 34.0 | PHRED · no single calibrated threshold — expert panels disagree |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- F8
- Protein
- p.Arg602Ter
- Coding
- c.1804C>T
- MANE Select
- NM_000132
- dbSNP
- rs137852424
- Type
- single nucleotide variant
- Location
- chrX:154953991 (GRCh38)
- Structure
- AlphaFold pLDDT 61.20 · 29 PDB
- Residue 602
- the plastocyanin-like 4 domain; a UniProt-annotated variant site (in hema; mild familial); an α-helix; the f5/8 type a 2 domain
Disease context
hemophilia A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: hemophilia B
For Hemophilia A (Orphanet):
- Inheritance
- X-linked recessive
- Onset
- Childhood, Infancy, Neonatal
- Prevalence
- 1-9 / 100 000 (Worldwide)
Similar variants
- F8 p.Arg602Gly Pathogenic/Likely pathogenic ★★ ⚠ same residue
- F8 p.Arg602Gln Likely benign ★ 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
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-arg602ter (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown