F9 p.Ala279Thr
c.835G>A · rs137852247 · VCV216926
ClinGen expert panel — Coagulation Factor Deficiency VCEP
Pathogenic for hemophilia B. Applied ACMG criteria (verbatim):
PP4_Moderate PS4_VeryStrong PM2_Supporting PP3
Curation rationale (ClinGen, verbatim)
The NM_000133.3:c.835G>A variant that results in the Ala279Thr missense change is absent from gnomAD v2.1.1 and v3, meeting PM2_Supporting. More than 59 male patients with mild hemophilia B are reported hemizygous for this variant in the literature, meeting PS4_Very strong and PP4_Moderate criteria (PMID: 29296726, 29656491). It is noted as a founder variant but may also have arisen de novo as a recurrent variant and is found in multiple ethnicities. The variant has a REVEL score of 0.765 (>0.6) which meets the thresholds recommended for PP3. In summary, the 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, PP3, PP4_Moderate, PM2_Supporting.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.26 | likely benign ⚠ discordant with ClinVar |
|---|---|---|
| REVEL | 0.765 | pathogenic-leaning |
| SaProt | LLR -11.09 | damaging |
| ⇒ REVEL and SaProt call this damaging; AlphaMissense does not. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP 5.2, phastCons 1 |
| Regional constraint | o/e 0.57 | unconstrained · MANE · 25 kb · p 2.3e-14 · regional, not allelic |
| Overall | ||
| CADD | 24.4 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
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.Ala279Thr
- Coding
- c.835G>A
- MANE Select
- NM_000133
- dbSNP
- rs137852247
- Type
- single nucleotide variant
- Location
- chrX:139560852 (GRCh38)
- Structure
- AlphaFold pLDDT 80.45 · 57 PDB
- Residue 279
- a UniProt-annotated variant site (in hemb; mild); 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 defecthemophilia A
For Hemophilia B (Orphanet):
- Inheritance
- X-linked recessive
- Onset
- Childhood, Infancy, Neonatal
- Prevalence
- 1-9 / 100 000 (Europe)
Similar variants
- F9 p.Ala279Pro 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.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-ala279thr (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown