F8 p.Leu327Pro
c.980T>C · rs137852407 · VCV10199
ClinGen expert panel — Coagulation Factor Deficiency VCEP
Likely Pathogenic for hemophilia A. Applied ACMG criteria (verbatim):
PM2_Supporting PS4_Moderate PP3 PM5
Curation rationale (ClinGen, verbatim)
The c.980T>C (p.Leu327Pro) variant is absent from males in population databases (gnomAD v2.1.1/gnomAD v3). The variant has been reported in two probands with severe hemophilia A meeting phenotypic criteria for F8 in PMID: 8644728 and 26897466. This missense variant has a REVEL score of 0.926 (>0.6). A pathogenic variant, Leu327Val, is reported at the same residue meeting PM5. In summary, based on the evidence available at this time, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PP3, PS4_Moderate, PM2_Supporting, PM5.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9498 | likely pathogenic ✓ concordant with ClinVar · top 3% in F8 |
|---|---|---|
| REVEL | 0.926 | moderately pathogenic-leaning |
| SaProt | LLR -14.77 | 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 11 | GERP 1.6, phastCons 1 |
| Regional constraint | o/e 0.74 | unconstrained · MANE · 38 kb · p 2.6e-06 · 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
- F8
- Protein
- p.Leu327Pro
- Coding
- c.980T>C
- MANE Select
- NM_000132
- dbSNP
- rs137852407
- Type
- single nucleotide variant
- Location
- chrX:154969360 (GRCh38)
- Structure
- AlphaFold pLDDT 61.20 · 29 PDB
- Residue 327
- a UniProt-annotated variant site (in hema; severe); a UniProt-annotated variant site (in hema; mild); a disulfide bond; a β-strand; the f5/8 type a 1 domain; the plastocyanin-like 2 domain
Disease context
hemophilia A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsFor Hemophilia A (Orphanet):
- Inheritance
- X-linked recessive
- Onset
- Childhood, Infancy, Neonatal
- Prevalence
- 1-9 / 100 000 (Worldwide)
Similar variants
- F8 p.Leu327Gln Likely pathogenic ★★★ same residue
- F8 p.Leu327Val Pathogenic ★★★ ⚠ same residue
- F8 c.6429+2T>A Pathogenic ★★★ same condition
- F8 p.Ala111Thr Likely pathogenic ★★★ same condition
- F8 p.Ala2220Pro Pathogenic ★★★ same condition
- F8 p.Ala415Asp Likely pathogenic ★★★ same condition
- F8 p.Ala415Val Pathogenic ★★★ ⚠ same condition
- F8 p.Arg1768His 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/f8-p-leu327pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown