F8 p.Val2092=
c.6276G>A · rs199522131 · VCV810971
ClinGen expert panel — Coagulation Factor Deficiency VCEP
Benign for hemophilia A. Applied ACMG criteria (verbatim):
PP3 BA1
Curation rationale (ClinGen, verbatim)
The c.6276G>A (p.Val2092=) variant is a synonymous variant that is predicted to impact splicing. The Grpmax FAF in gnomAD v4.1.0 is 0.0006600 which is higher than the ClinGen Coagulation Factor Deficiency VCEP threshold (>=0.000333) for BA1, and therefore meets this criterion (BA1). The computational predictor Splice AI gives a score of 0.46 for acceptor gain, which is above the CFD VCEP threshold of >= 0.2, evidence that correlates with impact to F8 function meeting PP3. Due to conflicting evidence, this variant is classified as benign for Hemophilia A based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP F8 Version 2.0.0 specifications: BA1, PP3.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| Splicing | ||
| SpliceAI | Δ0.46 | acceptor gain · deltas |
|---|---|---|
| Pangolin | Δ0.20 | gain · loss 0.05 · agrees with SpliceAI · independent |
| Constraint at this position | ||
| Conservation | phyloP -0.14 | GERP 0.67, phastCons 0.45 |
| Overall | ||
| CADD | 15.69 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.0876% | 1,142 |
| Remaining individualsnot grpmax-eligible | 0.0126% | 7,927 |
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
- F8
- Protein
- p.Val2092=
- Coding
- c.6276G>A
- MANE Select
- NM_000132
- dbSNP
- rs199522131
- Type
- single nucleotide variant
- Location
- chrX:154896230 (GRCh38)
- Structure
- AlphaFold pLDDT 61.20 · 29 PDB
- Residue 2092
- the f5/8 type c 1 domain; a disulfide bond; a β-strand
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.Val2092Glu Likely 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
- F8 p.Arg1800His 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-val2092 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown