Is F8 p.Leu523= (c.1569G>T) pathogenic?

F8 p.Leu523= (c.1569G>T) is classified Pathogenic/Likely pathogenic in F8 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-03-01). Very rare (popmax 0.00435%, amr); Associated with hemophilia A.

What condition is associated with F8 p.Leu523= (c.1569G>T)?

F8 p.Leu523= (c.1569G>T) is associated with hemophilia A (ClinVar).

How common is F8 p.Leu523= (c.1569G>T) in the general population?

F8 p.Leu523= (c.1569G>T) is very rare (popmax 0.00435%, amr) (gnomAD).

How is Hemophilia A inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

F8 p.Leu523=

c.1569G>T · rs782733685 · VCV439678

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00435%, amr)

Conditions

hemophilia A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.83	acceptor gain · deltas
Pangolin	Δ0.70	gain · loss 0.65 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.16	GERP -3.3, phastCons 0.78
Overall
CADD	19.08	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00435% Admixed American · 2/45,968 alleles

Filtering AF 0.000721% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00027%

Overall 0.000182% 2/1,097,347 alleles · very rare

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.Leu523=
Coding: c.1569G>T
MANE Select: NM_000132
dbSNP: rs782733685
Type: single nucleotide variant
Location: chrX:154957140 (GRCh38)
Structure: AlphaFold pLDDT 61.20 · 29 PDB
Residue 523: the plastocyanin-like 3 domain; the f5/8 type a 2 domain

Full F8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hemophilia A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-leu523 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown