Is F8 p.Val345Ala (c.1034T>C) pathogenic?

F8 p.Val345Ala (c.1034T>C) is classified Conflicting classifications of pathogenicity in F8 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-03-26). AlphaMissense: ambiguous (0.4704); Absent from gnomAD v4.1; Associated with hemophilia B.

What condition is associated with F8 p.Val345Ala (c.1034T>C)?

F8 p.Val345Ala (c.1034T>C) is associated with hemophilia B (ClinVar).

How common is F8 p.Val345Ala (c.1034T>C) in the general population?

F8 p.Val345Ala (c.1034T>C) is absent from gnomAD v4.1 (gnomAD).

How is Hemophilia B inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about F8 p.Val345Ala (c.1034T>C)?

AlphaMissense predicts ambiguous (score 0.4704) — an in-silico prediction, not a clinical call.

F8 p.Val345Ala

c.1034T>C · rs1189348665 · VCV627195

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4704 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hemophilia B

Computational evidence

Protein change
AlphaMissense	0.4704	ambiguous
REVEL	0.939	strongly pathogenic-leaning
SaProt	LLR -11.73	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 11	GERP 1.5, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 38 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	24.2	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.Val345Ala
Coding: c.1034T>C
MANE Select: NM_000132
dbSNP: rs1189348665
Type: single nucleotide variant
Location: chrX:154966663 (GRCh38)
Structure: AlphaFold pLDDT 61.20 · 29 PDB
Residue 345: a UniProt-annotated variant site (in hema); a UniProt-annotated variant site (in hema; severe); a disulfide bond; a β-strand; 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

Disease context

hemophilia B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hemophilia B (Orphanet):

Inheritance: X-linked recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

F8 p.Val345Leu Pathogenic same residue
F8 p.Arg602Ter Pathogenic ★★★ same condition
F8 p.Arg612Cys Pathogenic ★★★ ⚠ same condition
F8 p.Asn1739= Likely pathogenic ★★★ same condition
F8 p.Leu327Val Pathogenic ★★★ ⚠ same condition
F8 p.Trp2248Cys Pathogenic ★★★ same condition
F8 p.Tyr365Cys Pathogenic ★★★ ⚠ same condition
F8 p.Ala723Thr 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-val345ala (accessed [today's date]).

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