Is F8 p.Pro83Arg (c.248C>G) pathogenic?

F8 p.Pro83Arg (c.248C>G) is classified Uncertain significance in F8 (ClinVar, Expert panel, 4 submitters; last evaluated 2025-11-07). AlphaMissense: likely benign (0.2821); Very rare (popmax 0.00871%, amr); Associated with hemophilia A.

What condition is associated with F8 p.Pro83Arg (c.248C>G)?

F8 p.Pro83Arg (c.248C>G) is associated with hemophilia A (ClinVar).

How common is F8 p.Pro83Arg (c.248C>G) in the general population?

F8 p.Pro83Arg (c.248C>G) is very rare (popmax 0.00871%, amr) (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.Pro83Arg (c.248C>G)?

AlphaMissense predicts likely benign (score 0.2821) — an in-silico prediction, not a clinical call.

F8 p.Pro83Arg

c.248C>G · rs781974394 · VCV1684385

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2821 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00871%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hemophilia A

ClinGen expert panel — Coagulation Factor Deficiency VCEP

Uncertain Significance for hemophilia A. Applied ACMG criteria (verbatim):

PP4_Moderate PS4_Moderate PP3

Curation rationale (ClinGen, verbatim)

The NM_000132.4(F8):c.248C>G (p.Pro83Arg) variant is a missense variant in F8 that has been observed in multiple patients in the literature with mild hemophilia A meeting PP4_Moderate and PS4_Moderate (PMID: 29296726, PMID:18403393, PMID:18184865). This variant is predicted to have a deleterious effect with a REVEL score of 0.891, which is greater than the ClinGen CFD threshold (>0.6) meeting PP3. In summary, this variant meets criteria to be classified as a variant of uncertain significance for hemophilia A based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP: PP3. PP4_Moderate, PS4_Moderate.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.2821	likely benign
REVEL	0.917	moderately pathogenic-leaning
SaProt	LLR -8.96	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 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 53 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	23.4	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 0.00871% Admixed American · 4/45,899 alleles

Filtering AF 0.00293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00177%

Overall 0.000745% 9/1,207,706 alleles · very rare exomes 9/1,094,389 · genomes 0/113,317 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00871%	11,475
Ashkenazi Jewishnot grpmax-eligible	0.00456%	21,947
European (non-Finnish)	0.000448%	223,182

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.Pro83Arg
Coding: c.248C>G
MANE Select: NM_000132
dbSNP: rs781974394
Type: single nucleotide variant
Location: chrX:154999496 (GRCh38)
Structure: AlphaFold pLDDT 61.20 · 29 PDB
Residue 83: the f5/8 type a 1 domain; the plastocyanin-like 1 domain; a UniProt-annotated variant site (in hema)

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

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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-pro83arg (accessed [today's date]).

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