F9 p.Arg75Ter
c.223C>T · rs137852227 · VCV10572
ClinGen expert panel — Coagulation Factor Deficiency VCEP
Pathogenic for hemophilia B. Applied ACMG criteria (verbatim):
PVS1 PP4_Moderate PM2_Supporting PS4_Very
Curation rationale (ClinGen, verbatim)
The F9 c.223C>T; p.Arg75Ter causes a protein truncation that is expected to undergo NMD, meeting PVS1. The variant is completely absent from gnomAD v2.1.1 and v3.1.1, meeting PM2_Supporting. Over 75 patients are reported in the literature with moderate-severe hemophilia B, some with a history of inhibitors to factor replacement products, meeting F9 phenotype criteria for PS4_Very strong and PP4_Moderate (EAHAD database; PMID: 29296726). 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 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 2 of 8 |
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 1.7 | GERP 2.3, phastCons 0.99 |
| Overall | ||
| CADD | 35.0 | 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
- F9
- Protein
- p.Arg75Ter
- Coding
- c.223C>T
- MANE Select
- NM_000133
- dbSNP
- rs137852227
- Type
- single nucleotide variant
- Location
- chrX:139537144 (GRCh38)
- Structure
- AlphaFold pLDDT 80.45 · 57 PDB
- Residue 75
- a UniProt-annotated variant site (in hemb; mild); an α-helix; the gla domain
Disease context
hemophilia B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: thrombophilia, X-linked, due to factor 9 defect
For Hemophilia B (Orphanet):
- Inheritance
- X-linked recessive
- Onset
- Childhood, Infancy, Neonatal
- Prevalence
- 1-9 / 100 000 (Europe)
Similar variants
- F9 p.Arg75Gln Pathogenic ★★★ ⚠ same residue
- F9 c.520+13A>G Pathogenic ★★★ same condition
- F9 c.88+1G>A Pathogenic ★★★ same condition
- F9 c.88+5G>T Likely pathogenic ★★★ same condition
- F9 p.Ala279Thr Pathogenic ★★★ ⚠ same condition
- F9 p.Ala337Pro Likely pathogenic ★★★ ⚠ same condition
- F9 p.Ala337Thr Pathogenic ★★★ ⚠ same condition
- F9 p.Ala337Val 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/f9-p-arg75ter (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown