Is F9 p.Arg46Ser (c.138G>Y) pathogenic?

F9 p.Arg46Ser (c.138G>Y) is classified Pathogenic in F9 (ClinVar, No assertion criteria, 1 submitter; last evaluated 1986-08-01). Absent from gnomAD v4.1; Associated with hemophilia B.

What condition is associated with F9 p.Arg46Ser (c.138G>Y)?

F9 p.Arg46Ser (c.138G>Y) is associated with hemophilia B (ClinVar).

How common is F9 p.Arg46Ser (c.138G>Y) in the general population?

F9 p.Arg46Ser (c.138G>Y) is absent from gnomAD v4.1 (gnomAD).

How is Hemophilia B inherited?

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

F9 p.Arg46Ser

c.138G>Y · rs2520744315 · VCV10565

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hemophilia B

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 0.96	GERP -2.6, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 25 kb · p 2.3e-14 · regional, not allelic

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: F9
Protein: p.Arg46Ser
Coding: c.138G>Y
MANE Select: NM_000133
dbSNP: rs2520744315
Type: single nucleotide variant
Location: chrX:139537059 (GRCh38)
Structure: AlphaFold pLDDT 80.45 · 57 PDB
Residue 46: a UniProt-annotated variant site (in hemb; severe); a UniProt-annotated variant site (in hemb; severe; cambridge; impaired processing of the propeptide; impaired gamma-carboxylation; decreased protein abundance; loss of function in blood coagulation)

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.Arg46Thr Uncertain significance ★ ⚠ same residue
F9 p.Arg46Trp Uncertain significance ★ ⚠ 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-arg46ser (accessed [today's date]).

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