Is F9 p.Arg226Trp (c.676C>T) pathogenic?

F9 p.Arg226Trp (c.676C>T) is classified Pathogenic/Likely pathogenic in F9 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-03-04). AlphaMissense: ambiguous (0.4956); Absent from gnomAD v4.1; Associated with F9-related disorder.

What condition is associated with F9 p.Arg226Trp (c.676C>T)?

F9 p.Arg226Trp (c.676C>T) is associated with F9-related disorder, thrombophilia, X-linked, due to factor 9 defect, hemophilia B (ClinVar).

How common is F9 p.Arg226Trp (c.676C>T) in the general population?

F9 p.Arg226Trp (c.676C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about F9 p.Arg226Trp (c.676C>T)?

AlphaMissense predicts ambiguous (score 0.4956) — an in-silico prediction, not a clinical call.

F9 p.Arg226Trp

c.676C>T · rs137852240 · VCV10590

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

ambiguous

0.4956 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

F9-related disorder

Computational evidence

Protein change
AlphaMissense	0.4956	ambiguous
REVEL	0.792	moderately pathogenic-leaning
SaProt	LLR -12.10	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 3, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 25 kb · p 2.3e-14 · regional, not allelic
Overall
CADD	24.0	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

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.Arg226Trp
Coding: c.676C>T
MANE Select: NM_000133
dbSNP: rs137852240
Type: single nucleotide variant
Location: chrX:139551217 (GRCh38)
Structure: AlphaFold pLDDT 80.45 · 57 PDB
Residue 226: a UniProt-annotated variant site (in hemb; severe; madrid); a UniProt-annotated variant site (in hemb; severe; hilo and novara; no effect on protein abundance; loss of function in blood coagulation); a UniProt-annotated variant site (in hemb; severe; nagoya-1, dernbach, deventer, idaho); a functional site (cleavage; by factor xia); a disulfide bond

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

Disease context

F9-related disorder

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

Similar variants

F9 p.Arg226Gln Pathogenic ★★ ⚠ same residue
F9 p.Arg226= Likely benign ★ 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-arg226trp (accessed [today's date]).

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