Is F8 p.Val445Ile (c.1333G>A) pathogenic?

F8 p.Val445Ile (c.1333G>A) is classified Uncertain significance in F8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-01). AlphaMissense: likely benign (0.1563); Absent from gnomAD v4.1.

How common is F8 p.Val445Ile (c.1333G>A) in the general population?

F8 p.Val445Ile (c.1333G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about F8 p.Val445Ile (c.1333G>A)?

AlphaMissense predicts likely benign (score 0.1563) — an in-silico prediction, not a clinical call.

F8 p.Val445Ile

c.1333G>A · VCV3380767

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1563 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1563	likely benign
REVEL	0.459	indeterminate
SaProt	LLR -9.22	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 5.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 38 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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.Val445Ile
Coding: c.1333G>A
MANE Select: NM_000132
Type: single nucleotide variant
Location: chrX:154966080 (GRCh38)
Structure: AlphaFold pLDDT 61.20 · 29 PDB
Residue 445: the plastocyanin-like 3 domain; a β-strand; the f5/8 type a 2 domain

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

Similar variants

F8 p.Val445fs 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
F8 p.Arg1800His 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-val445ile (accessed [today's date]).

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