Is F8 p.Ile438Phe (c.1312A>T) pathogenic?

F8 p.Ile438Phe (c.1312A>T) is classified Conflicting classifications of pathogenicity in F8 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-07-30). AlphaMissense: likely benign (0.2813); Absent from gnomAD v4.1; Associated with thrombophilia, X-linked, due to factor 8 defect.

What condition is associated with F8 p.Ile438Phe (c.1312A>T)?

F8 p.Ile438Phe (c.1312A>T) is associated with thrombophilia, X-linked, due to factor 8 defect, hemophilia A (ClinVar).

How common is F8 p.Ile438Phe (c.1312A>T) in the general population?

F8 p.Ile438Phe (c.1312A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about F8 p.Ile438Phe (c.1312A>T)?

AlphaMissense predicts likely benign (score 0.2813) — an in-silico prediction, not a clinical call.

F8 p.Ile438Phe

c.1312A>T · rs1258333672 · VCV2920965

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2813 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thrombophilia, X-linked, due to factor 8 defect

Computational evidence

Protein change
AlphaMissense	0.2813	likely benign
REVEL	0.886	moderately pathogenic-leaning
SaProt	LLR -13.46	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.2	GERP 1.4, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 38 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	24.3	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.Ile438Phe
Coding: c.1312A>T
MANE Select: NM_000132
dbSNP: rs1258333672
Type: single nucleotide variant
Location: chrX:154966101 (GRCh38)
Structure: AlphaFold pLDDT 61.20 · 29 PDB
Residue 438: the plastocyanin-like 3 domain; a UniProt-annotated variant site (in hema; not severe); the f5/8 type a 2 domain

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

Disease context

thrombophilia, X-linked, due to factor 8 defect — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hemophilia A

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-ile438phe (accessed [today's date]).

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