F9 p.Ala337Thr
c.1009G>A · rs137852253 · VCV626950
ClinGen expert panel — Coagulation Factor Deficiency VCEP
Pathogenic for hemophilia B. Applied ACMG criteria (verbatim):
PM2_Supporting PS4_VeryStrong PP3
Curation rationale (ClinGen, verbatim)
The c.1009G>A (NM_000133.4) variant in F9 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 337 (p.Ala337Thr). This variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3). This variant has been reported in at least 8 unique probands with mild to severe hemophilia B (PMID: 8091381; PMID: 11013449; PMID: 2726481), meeting phenotypic criteria for F9. The computational predictor REVEL gives a score of 0.783, which is above the threshold of 0.6, evidence that correlates with impact to F9 function (PP3). 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: PS4_Very Strong + PM2_Supporting + PP3. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 1.0.0., Released 10/5/2023).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.2273 | likely benign ⚠ discordant with ClinVar |
|---|---|---|
| REVEL | 0.783 | moderately pathogenic-leaning |
| SaProt | LLR -7.62 | 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 10 | GERP 4.2, phastCons 1 |
| Regional constraint | o/e 0.57 | unconstrained · MANE · 25 kb · p 2.3e-14 · regional, not allelic |
| Overall | ||
| CADD | 25.4 | 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.Ala337Thr
- Coding
- c.1009G>A
- MANE Select
- NM_000133
- dbSNP
- rs137852253
- Type
- single nucleotide variant
- Location
- chrX:139561694 (GRCh38)
- Structure
- AlphaFold pLDDT 80.45 · 57 PDB
- Residue 337
- the peptidase s1 domain
Disease context
hemophilia B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: hemophilia A
For Hemophilia B (Orphanet):
- Inheritance
- X-linked recessive
- Onset
- Childhood, Infancy, Neonatal
- Prevalence
- 1-9 / 100 000 (Europe)
Similar variants
- F9 p.Ala337Pro Likely pathogenic ★★★ ⚠ same residue
- F9 p.Ala337Val 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.Arg191His Pathogenic ★★★ ⚠ same condition
- F9 p.Arg294Gln 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-ala337thr (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown