F8 p.Ile1901=
c.5703C>A · rs782721473 · VCV1685787
ClinGen expert panel — Coagulation Factor Deficiency VCEP
Benign for hemophilia A. Applied ACMG criteria (verbatim):
BP4_Supporting BA1
Curation rationale (ClinGen, verbatim)
The c.5703C>A variant in F8 is a synonymous (silent) variant (p.Ile1901=) that is not predicted by SpliceAI to impact splicing. This variant is located in Exon 17, within the A3 domain of FVIII. However, BP7 was not applied as the nucleotide is conserved. This variant has been reported in 1 proband with mild Hemophilia A. However, PS4_Supporting cannot be applied because VWD 2N was not ruled out (PMID: 16128892) and BA1 was met. The c.5703C>A (p.Ile1901=) variant is reported at an MAF of 0.007915 (151/19078 alleles) in the South Asian population in gnomAD v2.1.1 with 105 hemizygotes, meeting BA1 criteria of MAF >= 0.000333. The computational predictor REVEL has a score of 0 which is below the threshold of 0.3, and the splice site predictor Splice AI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on F8 function (BP4_Supporting). In summary, this variant meets the criteria to be classified as benign for Hemophilia A based on the ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8 (version 1.0.0, released 10/5/2023): BA1, BP4_Supporting.
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 carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 2.3 | GERP -2, phastCons 1 |
| Overall | ||
| CADD | 4.807 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.788% | 127 |
| Middle Eastern | 0.138% | 725 |
| Remaining individualsnot grpmax-eligible | 0.0483% | 2,070 |
| European (non-Finnish) | 0.000335% | 298,252 |
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.Ile1901=
- Coding
- c.5703C>A
- MANE Select
- NM_000132
- dbSNP
- rs782721473
- Type
- single nucleotide variant
- Location
- chrX:154904408 (GRCh38)
- Structure
- AlphaFold pLDDT 61.20 · 29 PDB
- Residue 1901
- the f5/8 type a 3 domain; the plastocyanin-like 6 domain; a UniProt-annotated variant site (in hema; mild); a β-strand
Disease context
hemophilia A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: thrombophilia, X-linked, due to factor 8 defect
For Hemophilia A (Orphanet):
- Inheritance
- X-linked recessive
- Onset
- Childhood, Infancy, Neonatal
- Prevalence
- 1-9 / 100 000 (Worldwide)
Similar variants
- 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
- 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-ile1901 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown