Is F8 p.Leu326= (c.978A>G) pathogenic?

F8 p.Leu326= (c.978A>G) is classified Uncertain significance in F8 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). Very rare (popmax 0.00175%, afr); Associated with hemophilia A.

What condition is associated with F8 p.Leu326= (c.978A>G)?

F8 p.Leu326= (c.978A>G) is associated with hemophilia A (ClinVar).

How common is F8 p.Leu326= (c.978A>G) in the general population?

F8 p.Leu326= (c.978A>G) is very rare (popmax 0.00175%, afr) (gnomAD).

How is Hemophilia A inherited?

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

F8 p.Leu326=

c.978A>G · rs782374508 · VCV872025

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00175%, afr)

Conditions

hemophilia A

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 -3.6	GERP -3.2
Overall
CADD	1.68	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00175% African / African-American · 1/57,180 alleles

Filtering AF 0.000105% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.1e-05%

Overall 0.000413% 5/1,209,499 alleles · very rare exomes 4/1,097,552 · genomes 1/111,947 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00175%	57,180
European (non-Finnish)	0.000447%	223,677

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.Leu326=
Coding: c.978A>G
MANE Select: NM_000132
dbSNP: rs782374508
Type: single nucleotide variant
Location: chrX:154969362 (GRCh38)
Structure: AlphaFold pLDDT 61.20 · 29 PDB
Residue 326: a UniProt-annotated variant site (in hema); a β-strand; the f5/8 type a 1 domain; the plastocyanin-like 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-leu326 (accessed [today's date]).

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