Is F8 p.Arg2109Pro (c.6326G>C) pathogenic?

F8 p.Arg2109Pro (c.6326G>C) is classified Likely pathogenic in F8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-03). AlphaMissense: likely pathogenic (0.866); Absent from gnomAD v4.1.

How common is F8 p.Arg2109Pro (c.6326G>C) in the general population?

F8 p.Arg2109Pro (c.6326G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about F8 p.Arg2109Pro (c.6326G>C)?

AlphaMissense predicts likely pathogenic (score 0.866) — an in-silico prediction, not a clinical call.

F8 p.Arg2109Pro

c.6326G>C · rs781947839 · VCV2683561

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.866 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.866	likely pathogenic ✓ concordant with ClinVar · top 7% in F8
REVEL	0.877	moderately pathogenic-leaning
SaProt	LLR -7.72	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 91 kb · p 1.5e-14 · regional, not allelic
Overall
CADD	25.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: F8
Protein: p.Arg2109Pro
Coding: c.6326G>C
MANE Select: NM_000132
dbSNP: rs781947839
Type: single nucleotide variant
Location: chrX:154896180 (GRCh38)
Structure: AlphaFold pLDDT 61.20 · 29 PDB
Residue 2109: the f5/8 type c 1 domain; a UniProt-annotated variant site (in hema; mild); a disulfide bond; a β-strand

Full F8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

F8 p.Arg2109Cys Likely pathogenic ★ ⚠ same residue
F8 p.Arg2109His Uncertain significance ★ ⚠ same residue
F8 c.6429+2T>A Pathogenic ★★★ same type
F8 p.Ala111Thr Likely pathogenic ★★★ same type
F8 p.Ala2220Pro Pathogenic ★★★ same type
F8 p.Ala415Asp Likely pathogenic ★★★ same type
F8 p.Ala415Val Pathogenic ★★★ ⚠ same type
F8 p.Arg1768His Pathogenic ★★★ ⚠ same type

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-arg2109pro (accessed [today's date]).

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