F9 p.Val174Met
c.520G>A · rs1603265504 · VCV811516
ClinGen expert panel — Coagulation Factor Deficiency VCEP
Likely Pathogenic for hemophilia B. Applied ACMG criteria (verbatim):
PM2_Supporting PS4_Moderate PM1 PP3
Curation rationale (ClinGen, verbatim)
The NM_000133.4(F9):c.520G>A (p.Val174Met) missense variant is completely absent from gnomAD v2.1.1 and v3.1.2 meeting criteria for PM2_Supporting. The variant has a REVEL score of 0.811 (>0.6) meeting criteria for PP3. The variant changes the last nucleotide of exon 5 and SpliceAI predicts a donor loss of intron 5 (delta score of 0.66) meeting criteria for PM1. At least four probands with moderate or severe hemophilia B are reported in the literature and internal laboratory data (PMID: 1680287; doi: 10.5336/medsci.2020-75066), meeting criteria for PS4. In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9 (Released 10/5/2023): PM1, PS4_Moderate, PP3, PM2_Supporting.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.1569 | likely benign ⚠ discordant with ClinVar |
|---|---|---|
| REVEL | 0.811 | moderately pathogenic-leaning |
| SaProt | LLR -8.59 | tolerated |
| ⇒ REVEL calls this damaging; AlphaMissense and SaProt do not. | ||
| Splicing | ||
| SpliceAI | Δ0.66 | donor loss · deltas |
| Pangolin | Δ0.40 | loss · gain 0.04 · agrees with SpliceAI · independent |
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP 4.8, phastCons 1 |
| Regional constraint | o/e 0.57 | unconstrained · MANE · 25 kb · p 2.3e-14 · regional, not allelic |
| Overall | ||
| CADD | 32.0 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
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.Val174Met
- Coding
- c.520G>A
- MANE Select
- NM_000133
- dbSNP
- rs1603265504
- Type
- single nucleotide variant
- Location
- chrX:139548491 (GRCh38)
- Structure
- AlphaFold pLDDT 80.45 · 57 PDB
- Residue 174
- a β-strand
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.Val174= Likely benign ★ same residue
- F9 p.Val174fs Likely 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
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-val174met (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown