Is F9 p.Pro324fs (c.969_975del) pathogenic?

F9 p.Pro324fs (c.969975del) is classified Pathogenic in F9 (ClinVar, Expert panel, 1 submitter; last evaluated 2024-12-06). Associated with hemophilia B.

What condition is associated with F9 p.Pro324fs (c.969_975del)?

F9 p.Pro324fs (c.969_975del) is associated with hemophilia B (ClinVar).

How is Hemophilia B inherited?

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

F9 p.Pro324fs

c.969_975del · VCV3390364

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

hemophilia B

ClinGen expert panel — Coagulation Factor Deficiency VCEP

Pathogenic for hemophilia B. Applied ACMG criteria (verbatim):

PVS1 PP4_Moderate PM2_Supporting

Curation rationale (ClinGen, verbatim)

The NM_000133.4(F9):c.969_975del variant deletes 7bp in exon 8 of the F9 gene, causing a frameshift and premature termination of translation. NMD is not predicted to occur, but the truncation of the peptidase S1 domain is expected to be detrimental to protein function (PVS1). The variant is absent from gnomAD v2.1 (PM2_Supporting). The variant is reported in at least one individual with severe Hemophilia B with full gene sequencing and deletion/duplication analysis in the literature (PP4_Moderate - PMID: 26612714). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency VCEP for F9: PVS1, PP4_Moderate, PM2_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.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	escapes	premature termination codon in the last exon (8 of 8) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.1	GERP -2.5, phastCons 0.028

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: F9
Protein: p.Pro324fs
Coding: c.969_975del
MANE Select: NM_000133
Type: Deletion
Location: chrX:139561653 (GRCh38)
Structure: AlphaFold pLDDT 80.45 · 57 PDB
Residue 324: an α-helix; the peptidase s1 domain

Full F9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For Hemophilia B (Orphanet):

Inheritance: X-linked recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

F9 p.Pro324= Likely benign ★ same residue
F9 c.838+1_838+16del Pathogenic/Likely pathogenic ★★ same condition
F9 p.Ser182fs Pathogenic ★★ same condition
F9 c.392-7_392-4del Uncertain significance ★★ same condition
F9 p.Arg364fs Pathogenic ★ same condition
F9 p.Asn245fs Pathogenic ★ same condition
F9 p.Cys382fs Pathogenic ★ same condition
F9 p.Gly94fs 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/f9-p-pro324fs (accessed [today's date]).

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