F9 p.Val257Ile
c.769G>A · rs200608775 · VCV225354
ClinGen expert panel — Coagulation Factor Deficiency VCEP
Benign for hemophilia B. Applied ACMG criteria (verbatim):
BA1
Curation rationale (ClinGen, verbatim)
The c.769G>A variant in F9 is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 257 (p.Val257Ile). The highest population minor allele frequency in gnomAD v2.1.1 is 0.001548 (23/14862 alleles) in the East Asian population a grpmax FAF for exomes = 0.001015 and genomes = 0.0003535, which is higher than the ClinGen Coagulation Factor Deficiency VCEP threshold (>=0.0000556) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign for Hemophilia B based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP for F9 (version 1.0.0, released 10/5/2023): BA1.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.0601 | likely benign |
|---|---|---|
| REVEL | 0.483 | indeterminate |
| SaProt | LLR -4.46 | tolerated |
| ⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP -0.89 | GERP -11 |
| Regional constraint | o/e 0.57 | unconstrained · MANE · 25 kb · p 2.3e-14 · regional, not allelic |
| Overall | ||
| CADD | 0.003 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| East Asiangrpmax | 0.601% | 166 |
| Middle Eastern | 0.023% | 4,350 |
| Remaining individualsnot grpmax-eligible | 0.0126% | 7,933 |
| African / African-American | 0.0122% | 8,172 |
| Finnishnot grpmax-eligible | 0.0086% | 11,624 |
| Admixed American | 0.00437% | 22,867 |
| European (non-Finnish) | 0.000894% | 111,812 |
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.Val257Ile
- Coding
- c.769G>A
- MANE Select
- NM_000133
- dbSNP
- rs200608775
- Type
- single nucleotide variant
- Location
- chrX:139560786 (GRCh38)
- Structure
- AlphaFold pLDDT 80.45 · 57 PDB
- Residue 257
- a β-strand; a disulfide bond; the peptidase s1 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 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
- F9 p.Arg191His 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-val257ile (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown