Is F8 p.Arg458His (c.1373G>A) pathogenic?

F8 p.Arg458His (c.1373G>A) is classified Likely pathogenic in F8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-02). AlphaMissense: likely benign (0.1419); Ultra-rare (popmax 0.0229%, mid); Associated with hemophilia A.

What condition is associated with F8 p.Arg458His (c.1373G>A)?

F8 p.Arg458His (c.1373G>A) is associated with hemophilia A (ClinVar).

How common is F8 p.Arg458His (c.1373G>A) in the general population?

F8 p.Arg458His (c.1373G>A) is ultra-rare (popmax 0.0229%, mid) (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.Arg458His (c.1373G>A)?

AlphaMissense predicts likely benign (score 0.1419) — an in-silico prediction, not a clinical call.

F8 p.Arg458His

c.1373G>A · rs782052307 · VCV2571387

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1419 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0229%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hemophilia A

Computational evidence

Protein change
AlphaMissense	0.1419	likely benign ⚠ discordant with ClinVar
REVEL	0.587	indeterminate
SaProt	LLR -11.96	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.8	GERP 0.59, phastCons 0.94
Regional constraint	o/e 0.74	unconstrained · MANE · 38 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	22.8	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 0.0229% Middle Eastern · 1/4,371 alleles

Filtering AF 0.00473% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00423%

Overall 0.00496% 60/1,209,199 alleles · ultra-rare exomes 59/1,097,227 · genomes 1/111,972 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0229%	4,371
European (non-Finnish)	0.00604%	16,567
Remaining individualsnot grpmax-eligible	0.0042%	23,784
African / African-American	0.0035%	28,590
Admixed American	0.00219%	45,723

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.Arg458His
Coding: c.1373G>A
MANE Select: NM_000132
dbSNP: rs782052307
Type: single nucleotide variant
Location: chrX:154966040 (GRCh38)
Structure: AlphaFold pLDDT 61.20 · 29 PDB
Residue 458: 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

For Hemophilia A (Orphanet):

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

Similar variants

F8 p.Arg458Cys 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-arg458his (accessed [today's date]).

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