Is F8 p.Arg446Gln (c.1337G>A) pathogenic?

F8 p.Arg446Gln (c.1337G>A) is classified Uncertain significance in F8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-29). AlphaMissense: likely benign (0.1103); Ultra-rare (popmax 0.0846%, sas); Associated with hemophilia A.

What condition is associated with F8 p.Arg446Gln (c.1337G>A)?

F8 p.Arg446Gln (c.1337G>A) is associated with hemophilia A, thrombophilia, X-linked, due to factor 8 defect (ClinVar).

How common is F8 p.Arg446Gln (c.1337G>A) in the general population?

F8 p.Arg446Gln (c.1337G>A) is ultra-rare (popmax 0.0846%, sas) (gnomAD).

How is Hemophilia A inherited?

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

What do computational predictors say about F8 p.Arg446Gln (c.1337G>A)?

AlphaMissense predicts likely benign (score 0.1103) — an in-silico prediction, not a clinical call.

F8 p.Arg446Gln

c.1337G>A · rs781889613 · VCV1685799

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1103 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0846%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hemophilia A

Computational evidence

Protein change
AlphaMissense	0.1103	likely benign
REVEL	0.573	indeterminate
SaProt	LLR -8.54	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 5.8	GERP 0.64, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 38 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	24.2	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 0.0846% South Asian · 48/56,770 alleles

Filtering AF 0.0654% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0587%

Overall 0.00472% 57/1,208,717 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0846%	1,183
Remaining individualsnot grpmax-eligible	0.0021%	47,554
European (non-Finnish)	0.000895%	111,775

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: F8
Protein: p.Arg446Gln
Coding: c.1337G>A
MANE Select: NM_000132
dbSNP: rs781889613
Type: single nucleotide variant
Location: chrX:154966076 (GRCh38)
Structure: AlphaFold pLDDT 61.20 · 29 PDB
Residue 446: the plastocyanin-like 3 domain; a β-strand; the f5/8 type a 2 domain

Full F8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: thrombophilia, X-linked, due to factor 8 defect

For Hemophilia A (Orphanet):

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

Similar variants

F8 p.Arg446Ter Pathogenic ★★ same residue
F8 c.6429+2T>A Pathogenic ★★★ same condition
F8 p.Ala111Thr Likely pathogenic ★★★ same condition
F8 p.Ala2220Pro Pathogenic ★★★ same condition
F8 p.Ala415Asp Likely pathogenic ★★★ same condition
F8 p.Ala415Val Pathogenic ★★★ ⚠ same condition
F8 p.Arg1768His Pathogenic ★★★ ⚠ same condition
F8 p.Arg1800His 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/f8-p-arg446gln (accessed [today's date]).

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