F9 p.Leu369Pro
c.1106T>C · rs1603267393 · VCV626973
ClinGen expert panel — Coagulation Factor Deficiency VCEP
Likely Pathogenic for hemophilia B. Applied ACMG criteria (verbatim):
PM2_Supporting PS4_moderate PP3
Curation rationale (ClinGen, verbatim)
The F9 c.1106T>C, p.Leu369Pro is completely absent from gnomAD v2.1.1 and v3.1.2, meeting PM2_Supporting. The computational predictor REVEL gives a score of 0.948 and has a SpliceAI score of 0, meeting PP3 criteria (>=0.6). This variant has been reported in 5 probands meeting phenotypic criteria for hemophilia B (PS4_moderate; EAHAD Database, PMID: 31064749, PMID: 19699296). In summary, this variant meets the criteria to be classified as likely pathogenic for hemophilia B based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP ClinGen Coagulation Factor Deficiency VCEP F9 (version 1.0.0, released 10/5/2023): PS4, PM2_Supporting, PP3.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9555 | likely pathogenic ✓ concordant with ClinVar · top 8% in F9 |
|---|---|---|
| REVEL | 0.948 | strongly pathogenic-leaning |
| SaProt | LLR -15.26 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 6.2 | GERP 5.1, phastCons 1 |
| Regional constraint | o/e 0.57 | unconstrained · MANE · 25 kb · p 2.3e-14 · regional, not allelic |
| Overall | ||
| CADD | 24.8 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
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.Leu369Pro
- Coding
- c.1106T>C
- MANE Select
- NM_000133
- dbSNP
- rs1603267393
- Type
- single nucleotide variant
- Location
- chrX:139561791 (GRCh38)
- Structure
- AlphaFold pLDDT 80.45 · 57 PDB
- Residue 369
- 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 defecthemophilia A
For Hemophilia B (Orphanet):
- Inheritance
- X-linked recessive
- Onset
- Childhood, Infancy, Neonatal
- Prevalence
- 1-9 / 100 000 (Europe)
Similar variants
- F9 p.Leu369Phe Uncertain significance ★★★ ⚠ same residue
- F9 p.Leu369= 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-leu369pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown