Is F8 p.Arg245Trp (c.733C>T) pathogenic?

F8 p.Arg245Trp (c.733C>T) is classified Conflicting classifications of pathogenicity in F8 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-05-01). AlphaMissense: likely benign (0.0964); Very rare (popmax 0.00219%, amr); Associated with hemophilia B.

What condition is associated with F8 p.Arg245Trp (c.733C>T)?

F8 p.Arg245Trp (c.733C>T) is associated with hemophilia B, thrombophilia, X-linked, due to factor 8 defect (ClinVar).

How common is F8 p.Arg245Trp (c.733C>T) in the general population?

F8 p.Arg245Trp (c.733C>T) is very rare (popmax 0.00219%, amr) (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 F8 p.Arg245Trp (c.733C>T)?

AlphaMissense predicts likely benign (score 0.0964) — an in-silico prediction, not a clinical call.

F8 p.Arg245Trp

c.733C>T · rs781943956 · VCV627370

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0964 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00219%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hemophilia B

Computational evidence

Protein change
AlphaMissense	0.0964	likely benign
REVEL	0.319	indeterminate
SaProt	LLR -7.97	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.7	GERP -1.6
Regional constraint	o/e 0.56	unconstrained · MANE · 53 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	3.685	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 0.00219% Admixed American · 1/45,746 alleles

Filtering AF 0.000565% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000412%

Overall 0.000992% 12/1,209,686 alleles · very rare exomes 9/1,097,912 · genomes 3/111,774 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00219%	45,746
African / African-American	0.00175%	57,125
European (non-Finnish)	0.00112%	89,501

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.Arg245Trp
Coding: c.733C>T
MANE Select: NM_000132
dbSNP: rs781943956
Type: single nucleotide variant
Location: chrX:154984741 (GRCh38)
Structure: AlphaFold pLDDT 61.20 · 29 PDB
Residue 245: the f5/8 type a 1 domain; the plastocyanin-like 2 domain

Full F8 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 8 defect

For Hemophilia B (Orphanet):

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

Similar variants

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F8 p.Arg612Cys Pathogenic ★★★ ⚠ same condition
F8 p.Asn1739= Likely pathogenic ★★★ same condition
F8 p.Gln2208Glu Pathogenic ★★★ ⚠ same condition
F8 p.Gly1729Glu Likely pathogenic ★★★ ⚠ same condition
F8 p.Leu327Val Pathogenic ★★★ ⚠ same condition
F8 p.Lys108Thr Likely 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-arg245trp (accessed [today's date]).

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