F8 p.Ala111Val
c.332C>T · VCV3380944
ClinGen expert panel — Coagulation Factor Deficiency VCEP
Uncertain Significance for hemophilia A. Applied ACMG criteria (verbatim):
PM2_Supporting PM5_Supporting PS4_Moderate PP3
Curation rationale (ClinGen, verbatim)
The NM_000132.4(F8):c.332C>T (p.Ala111Val) variant is a missense variant in F8 that is absent from population databases (gnomAD v2.1.1/gnomAD v3; PM2_Supporting) and is predicted to have a deleterious effect (REVEL score of 0.968), which is greater than the ClinGen CFD threshold for PP3 (>0.6). The variant has been observed in at least two probands with mild to moderate hemophilia A with type 2N von Willebrand disease ruled out (PMID:11857744, External laboratory data; PS4_Moderate). Another missense variant (c.331G>A, p.Ala111Thr, CAID:CA414919991) in the same codon has been classified as likely pathogenic for hemophilia A by the ClinGen Coagulation Factor Deficiency VCEP (PM5_Supporting) with agreement in splicing predictors show no splicing impact. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for hemophilia A. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel (specifications version 1.0.0) for F8: PS4_Moderate, PM5_Supporting, PM2_Supporting, PP3.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.6506 | likely pathogenic |
|---|---|---|
| REVEL | 0.968 | strongly pathogenic-leaning |
| SaProt | LLR -10.99 | 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 1.4, phastCons 1 |
| Regional constraint | o/e 0.56 | unconstrained · MANE · 53 kb · p 1.5e-11 · regional, not allelic |
| Overall | ||
| CADD | 26.1 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification
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.Ala111Val
- Coding
- c.332C>T
- MANE Select
- NM_000132
- Type
- single nucleotide variant
- Location
- chrX:154997029 (GRCh38)
- Structure
- AlphaFold pLDDT 61.20 · 29 PDB
- Residue 111
- a β-strand; the f5/8 type a 1 domain; the plastocyanin-like 1 domain; a UniProt-annotated variant site (in hema; severe); a UniProt-annotated variant site (in hema; moderate)
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.Ala111Thr Likely pathogenic ★★★ same residue
- F8 c.6429+2T>A 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
- F8 p.Arg1800His Pathogenic ★★★ same condition
- F8 p.Arg2016Trp 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-ala111val (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown