F8 p.Arg503His
c.1508G>A · rs35383156 · VCV368123
ClinGen expert panel — Coagulation Factor Deficiency VCEP
Benign for hemophilia A. Applied ACMG criteria (verbatim):
BA1
Curation rationale (ClinGen, verbatim)
The c.1508G>A (p.Arg503His) variant is reported at an MAF of 0.01797(342/19037 alleles) in the African/African-American population in gnomAD v2.1.1 with 94 hemizygotes and 3 homozygotes, meeting BA1 criteria of MAF >0.000333. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: BA1.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.0724 | likely benign |
|---|---|---|
| REVEL | 0.429 | indeterminate |
| SaProt | LLR -8.29 | tolerated |
| ⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 1.6 | GERP 0.38, phastCons 0.99 |
| Regional constraint | o/e 0.74 | unconstrained · MANE · 38 kb · p 2.6e-06 · regional, not allelic |
| Overall | ||
| CADD | 20.5 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 1.78% | 56 |
| Admixed American | 0.136% | 737 |
| Remaining individualsnot grpmax-eligible | 0.133% | 751 |
| Middle Eastern | 0.0925% | 1,081 |
| South Asian | 0.0195% | 5,140 |
| European (non-Finnish) | 0.0088% | 11,367 |
| Ashkenazi Jewishnot grpmax-eligible | 0.00455% | 21,963 |
| East Asian | 0.00296% | 33,727 |
| Finnishnot grpmax-eligible | 0.00215% | 46,463 |
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.Arg503His
- Coding
- c.1508G>A
- MANE Select
- NM_000132
- dbSNP
- rs35383156
- Type
- single nucleotide variant
- Location
- chrX:154961104 (GRCh38)
- Structure
- AlphaFold pLDDT 61.20 · 29 PDB
- Residue 503
- the plastocyanin-like 3 domain; a UniProt-annotated variant site (in hema; benign); a β-strand; the f5/8 type a 2 domain
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 p.Arg503fs 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-arg503his (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown