Is F8 p.Ser1445Pro (c.4333T>C) pathogenic?

F8 p.Ser1445Pro (c.4333T>C) is classified Likely benign in F8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-14). AlphaMissense: likely benign (0.0857); Rare (popmax 0.413%, afr); Associated with hemophilia A.

What condition is associated with F8 p.Ser1445Pro (c.4333T>C)?

F8 p.Ser1445Pro (c.4333T>C) is associated with hemophilia A (ClinVar).

How common is F8 p.Ser1445Pro (c.4333T>C) in the general population?

F8 p.Ser1445Pro (c.4333T>C) is rare (popmax 0.413%, afr) (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.Ser1445Pro (c.4333T>C)?

AlphaMissense predicts likely benign (score 0.0857) — an in-silico prediction, not a clinical call.

F8 p.Ser1445Pro

c.4333T>C · rs146153504 · VCV1330979

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0857 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.413%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hemophilia A

Computational evidence

Protein change
AlphaMissense	0.0857	likely benign
REVEL	0.647	pathogenic-leaning
SaProt	LLR -6.97	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -2.5, phastCons 0.95
Regional constraint	o/e 0.99	unconstrained · MANE · 2,842 bp · p 0.74 · regional, not allelic
Overall
CADD	7.955	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 0.413% African / African-American · 236/57,175 alleles

Filtering AF 0.37% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.353%

Overall 0.023% 278/1,209,895 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.413%	242
Admixed American	0.0546%	1,830
Remaining individualsnot grpmax-eligible	0.0294%	3,401
Middle Eastern	0.023%	4,354
European (non-Finnish)	0.000223%	447,577

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.Ser1445Pro
Coding: c.4333T>C
MANE Select: NM_000132
dbSNP: rs146153504
Type: single nucleotide variant
Location: chrX:154929457 (GRCh38)
Structure: AlphaFold pLDDT 61.20 · 29 PDB
Residue 1445: the 'b' region

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 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
F8 p.Arg2016Trp 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-ser1445pro (accessed [today's date]).

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