F9 p.Arg191His
c.572G>A · rs137852238 · VCV10585
ClinGen expert panel — Coagulation Factor Deficiency VCEP
Pathogenic for hemophilia B. Applied ACMG criteria (verbatim):
PP4_Moderate PM1_Strong PS4_VeryStrong PP3
Curation rationale (ClinGen, verbatim)
The NM_000133.3(F9):c.572G>A predicts a missense change, Arg191His, at the activation residue. This residue is a site for cleavage by FXIa in order to activate FIX and therefore critical for protein function, which meets criteria for PM1_Strong. Over 100 patients meet the F9 phenotype criteria have been reported in the literature (selected PMIDs: 7873393,1972560, 26782891, 27865967, 24375831), meeting PS4_Very strong and PP4_Moderate. The variant has a REVEL score of 0.73 (threshold >0.6), meeting PP3. In summary, the variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency VCEP for F9: PS4_Very Strong, PM1_Strong, PP4_Moderate, PP3.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.1576 | likely benign ⚠ discordant with ClinVar |
|---|---|---|
| REVEL | 0.73 | pathogenic-leaning |
| SaProt | LLR -6.99 | tolerated |
| ⇒ REVEL calls this damaging; AlphaMissense and SaProt do not. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP 4.6, phastCons 1 |
| Regional constraint | o/e 0.57 | unconstrained · MANE · 25 kb · p 2.3e-14 · regional, not allelic |
| Overall | ||
| CADD | 20.8 | 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
- F9
- Protein
- p.Arg191His
- Coding
- c.572G>A
- MANE Select
- NM_000133
- dbSNP
- rs137852238
- Type
- single nucleotide variant
- Location
- chrX:139551113 (GRCh38)
- Structure
- AlphaFold pLDDT 80.45 · 57 PDB
- Residue 191
- a UniProt-annotated variant site (in hemb; moderate; albuquerque, cardiff-1); a UniProt-annotated variant site (in hemb; moderate; chapel-hill, chicago-2); a functional site (cleavage; by factor xia); a disulfide bond
Disease context
hemophilia B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: thrombophilia, X-linked, due to factor 9 defecthemophilia A
For Hemophilia B (Orphanet):
- Inheritance
- X-linked recessive
- Onset
- Childhood, Infancy, Neonatal
- Prevalence
- 1-9 / 100 000 (Europe)
Similar variants
- F9 p.Arg191Cys Pathogenic/Likely pathogenic ★★ ⚠ same residue
- F9 p.Arg191= Likely benign ★ 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
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-arg191his (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown