Is F9 p.Arg294Gln (c.881G>A) pathogenic?

F9 p.Arg294Gln (c.881G>A) is classified Pathogenic in F9 (ClinVar, Expert panel, 12 submitters; last evaluated 2024-11-01). AlphaMissense: likely benign (0.1903); Very rare (popmax 0.000224%, nfe); Associated with hemophilia B.

What condition is associated with F9 p.Arg294Gln (c.881G>A)?

F9 p.Arg294Gln (c.881G>A) is associated with hemophilia B, thrombophilia, X-linked, due to factor 9 defect, hemophilia A (ClinVar).

How common is F9 p.Arg294Gln (c.881G>A) in the general population?

F9 p.Arg294Gln (c.881G>A) is very rare (popmax 0.000224%, nfe) (gnomAD).

How is Hemophilia B inherited?

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

What do computational predictors say about F9 p.Arg294Gln (c.881G>A)?

AlphaMissense predicts likely benign (score 0.1903) — an in-silico prediction, not a clinical call.

F9 p.Arg294Gln

c.881G>A · rs137852249 · VCV10602

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.1903 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000224%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hemophilia B

ClinGen expert panel — Coagulation Factor Deficiency VCEP

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

PP4_Moderate PS4_VeryStrong PM2_Supporting PS3_Supporting PM1 PP1

Curation rationale (ClinGen, verbatim)

The c.881G>A, p.Arg294Gln variant affects one of the functional domains (aa 227-459; Peptidase S1 domain) in the F9 protein meeting PM1. The variant is absent from male population databases (gnomAD v4.1) meeting PM2_Supporting. At least 30 patients with mild, moderate or severe hemophilia B have been reported in the literature reviewed meeting PS4_Very Strong and PP4_Moderate (PMID: 29296726, 15921378, 8091381). In-vitro functional studies show that the variant causes ER retention of the F9 protein, leading to reduced antigen levels meeting PS3_Supporting. REVEL score for this variant does not fall within the thresholds for pathogenic or benign predictions, and no splicing impact is noted by SpliceAI. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4_Very Strong, PM1, PP4_Moderate, PS3_Supporting, PM2_Supporting.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.1903	likely benign ⚠ discordant with ClinVar
REVEL	0.576	indeterminate
SaProt	LLR -12.99	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 4.9, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 25 kb · p 2.3e-14 · regional, not allelic
Overall
CADD	25.3	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

Grpmax group 0.000224% European (non-Finnish) · 2/892,887 alleles

Filtering AF 3.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000183% 2/1,094,036 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: F9
Protein: p.Arg294Gln
Coding: c.881G>A
MANE Select: NM_000133
dbSNP: rs137852249
Type: single nucleotide variant
Location: chrX:139561566 (GRCh38)
Structure: AlphaFold pLDDT 80.45 · 57 PDB
Residue 294: a UniProt-annotated variant site (in hemb; severe); a UniProt-annotated variant site (in hemb; mild to moderate; dreihacken, penafiel and seattle-4); a β-strand; a disulfide bond; 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

Also linked: thrombophilia, X-linked, due to factor 9 defect hemophilia A

For Hemophilia B (Orphanet):

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

Similar variants

F9 p.Arg294Ter Pathogenic ★★★ same residue
F9 p.Arg294Leu Pathogenic ★ same residue
F9 c.520+13A>G Pathogenic ★★★ same condition
F9 c.88+1G>A Pathogenic ★★★ same condition
F9 c.88+5G>T Likely pathogenic ★★★ same condition
F9 p.Ala279Thr Pathogenic ★★★ ⚠ same condition
F9 p.Ala337Pro Likely pathogenic ★★★ same condition
F9 p.Ala337Thr 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-arg294gln (accessed [today's date]).

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