Is F8 p.Arg550Cys (c.1648C>T) pathogenic?

F8 p.Arg550Cys (c.1648C>T) is classified Pathogenic/Likely pathogenic in F8 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-01-31). AlphaMissense: ambiguous (0.5165); Very rare (popmax 0.000224%, nfe); Associated with mild hemophilia A.

What condition is associated with F8 p.Arg550Cys (c.1648C>T)?

F8 p.Arg550Cys (c.1648C>T) is associated with mild hemophilia A, hemophilia A (ClinVar).

How common is F8 p.Arg550Cys (c.1648C>T) in the general population?

F8 p.Arg550Cys (c.1648C>T) is very rare (popmax 0.000224%, nfe) (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.Arg550Cys (c.1648C>T)?

AlphaMissense predicts ambiguous (score 0.5165) — an in-silico prediction, not a clinical call.

F8 p.Arg550Cys

c.1648C>T · rs137852417 · VCV10223

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.5165 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000224%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

mild hemophilia A

Computational evidence

Protein change
AlphaMissense	0.5165	ambiguous
REVEL	0.749	pathogenic-leaning
SaProt	LLR -9.98	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP -3.4, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 38 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	21.1	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 0.000224% European (non-Finnish) · 2/892,689 alleles

Filtering AF 3.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000166% 2/1,206,680 alleles · very rare

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.Arg550Cys
Coding: c.1648C>T
MANE Select: NM_000132
dbSNP: rs137852417
Type: single nucleotide variant
Location: chrX:154957061 (GRCh38)
Structure: AlphaFold pLDDT 61.20 · 29 PDB
Residue 550: the plastocyanin-like 3 domain; a UniProt-annotated variant site (in hema; mild/moderate); a UniProt-annotated variant site (in hema; mild); a disulfide bond; 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

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

Also linked: hemophilia A

For Hemophilia A (Orphanet):

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

Similar variants

F8 p.Arg550His Pathogenic ★★★ ⚠ same residue
F8 p.Arg550Gly Likely 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

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-arg550cys (accessed [today's date]).

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