Is F9 p.Arg449Gln (c.1346G>A) pathogenic?

F9 p.Arg449Gln (c.1346G>A) is classified Uncertain significance in F9 (ClinVar, Expert panel, 7 submitters; last evaluated 2025-09-05). AlphaMissense: likely benign (0.0875); Ultra-rare (popmax 0.023%, mid); Associated with hemophilia B.

What condition is associated with F9 p.Arg449Gln (c.1346G>A)?

F9 p.Arg449Gln (c.1346G>A) is associated with hemophilia B, thrombophilia, X-linked, due to factor 9 defect (ClinVar).

How common is F9 p.Arg449Gln (c.1346G>A) in the general population?

F9 p.Arg449Gln (c.1346G>A) is ultra-rare (popmax 0.023%, mid) (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.Arg449Gln (c.1346G>A)?

AlphaMissense predicts likely benign (score 0.0875) — an in-silico prediction, not a clinical call.

F9 p.Arg449Gln

c.1346G>A · rs143018900 · VCV1685804

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0875 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.023%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hemophilia B

ClinGen expert panel — Coagulation Factor Deficiency VCEP

Uncertain Significance for hemophilia B. Applied ACMG criteria (verbatim):

PS4

Curation rationale (ClinGen, verbatim)

The c.1346G>A, p.Arg449Gln variant is reported with a Grpmax of 0.0001042 in gnomAD v2.1.1 with 7 hemizygotes meets the BA1 threshold of 0.0000556. However, this code was not applied due to the number of reported very mild hemophilia B cases being similar to the number of hemizygotes in gnomAD. There are at least 6 published cases in the literature and >1 unpublished case in the EAHAD Database with this variant and very mild hemophilia B meeting PS4 (PMID: 31267011, 31272859, 8091381, 10739381, 8076946, 8320491). Typically, the PS4 code would not be applied when criteria for BA1 is met, but an exception was made for this variant given the number of known cases of very mild hemophilia B, which could lead to affected or undiagnosed individuals in control populations. In summary, this variant meets criteria to be classified as variant of uncertain significance. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PS4.

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

Computational evidence

Protein change
AlphaMissense	0.0875	likely benign
REVEL	0.588	indeterminate
SaProt	LLR -8.83	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.57	GERP -0.23
Regional constraint	o/e 0.57	unconstrained · MANE · 25 kb · p 2.3e-14 · regional, not allelic
Overall
CADD	14.45	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.023% Middle Eastern · 1/4,351 alleles

Filtering AF 0.0121% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0095%

Overall 0.00529% 64/1,209,277 alleles · ultra-rare exomes 55/1,097,710 · genomes 9/111,567 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.023%	4,351
African / African-American	0.021%	4,759
South Asian	0.0176%	5,675
East Asian	0.00889%	11,244
European (non-Finnish)	0.00402%	24,856
Admixed American	0.00219%	45,730
Remaining individualsnot grpmax-eligible	0.0021%	47,611

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.Arg449Gln
Coding: c.1346G>A
MANE Select: NM_000133
dbSNP: rs143018900
Type: single nucleotide variant
Location: chrX:139562031 (GRCh38)
Structure: AlphaFold pLDDT 80.45 · 57 PDB
Residue 449: a UniProt-annotated variant site (in hemb; mild); 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

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

For Hemophilia B (Orphanet):

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

Similar variants

F9 p.Arg449Trp Uncertain significance ★★★ ⚠ same residue
F9 p.Arg449= 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-arg449gln (accessed [today's date]).

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