Is F8 p.Thr294Arg (c.881C>G) pathogenic?

F8 p.Thr294Arg (c.881C>G) is classified Likely pathogenic in F8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-10). AlphaMissense: ambiguous (0.5264); Absent from gnomAD v4.1.

How common is F8 p.Thr294Arg (c.881C>G) in the general population?

F8 p.Thr294Arg (c.881C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about F8 p.Thr294Arg (c.881C>G)?

AlphaMissense predicts ambiguous (score 0.5264) — an in-silico prediction, not a clinical call.

F8 p.Thr294Arg

c.881C>G · rs137852401 · VCV2428659

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5264 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5264	ambiguous
REVEL	0.872	moderately pathogenic-leaning
SaProt	LLR -10.45	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 53 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	25.1	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

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.Thr294Arg
Coding: c.881C>G
MANE Select: NM_000132
dbSNP: rs137852401
Type: single nucleotide variant
Location: chrX:154969459 (GRCh38)
Structure: AlphaFold pLDDT 61.20 · 29 PDB
Residue 294: a UniProt-annotated variant site (in hema; moderate); a disulfide bond; 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

Similar variants

F8 p.Thr294Lys Uncertain significance ★ ⚠ same residue
F8 p.Thr294Ile Pathogenic ⚠ 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-thr294arg (accessed [today's date]).

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