F8 p.Leu725Gln
c.2174T>A · VCV4953774
Likely pathogenic
Single submitter
Classification
Likely pathogenic
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
AlphaMissense
likely pathogenic
0.9382 · ACMG-weighted
gnomAD v4.1
Absent
absent from gnomAD v4.1
Missense predictors
3/3 damaging
AlphaMissense, REVEL, SaProt
Conditions
1
F8-related disorders
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9382 | likely pathogenic ✓ concordant with ClinVar · top 3% in F8 |
|---|---|---|
| REVEL | 0.869 | moderately pathogenic-leaning |
| SaProt | LLR -13.77 | 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 1.7, phastCons 1 |
| Regional constraint | o/e 0.74 | unconstrained · MANE · 38 kb · p 2.6e-06 · regional, not allelic |
| Overall | ||
| CADD | 25.4 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
gnomAD v4.1 · exomes + genomes
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.Leu725Gln
- Coding
- c.2174T>A
- MANE Select
- NM_000132
- Type
- single nucleotide variant
- Location
- chrX:154931616 (GRCh38)
- Structure
- AlphaFold pLDDT 61.20 · 29 PDB
- Residue 725
- the plastocyanin-like 4 domain; a UniProt-annotated variant site (in hema; severe); a β-strand; the f5/8 type a 2 domain
Disease context
F8-related disorders
Similar variants
- F8 p.Arg1708Cys Pathogenic ★★ ⚠ same condition
- F8 p.Arg1960Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
- F8 p.Arg2169His Pathogenic ★★ ⚠ same condition
- F8 p.Arg2326Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
- F8 p.Arg602Gly Pathogenic/Likely pathogenic ★★ ⚠ same condition
- F8 p.Arg717Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
- F8 p.Glu291Lys Pathogenic ★★ ⚠ same condition
- F8 p.Tyr1802Cys Pathogenic/Likely 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-leu725gln (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown