Is F8 p.Lys249Ter (c.745A>T) pathogenic?

F8 p.Lys249Ter (c.745A>T) is classified Likely pathogenic in F8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-01). Absent from gnomAD v4.1; Associated with hemophilia A.

What condition is associated with F8 p.Lys249Ter (c.745A>T)?

F8 p.Lys249Ter (c.745A>T) is associated with hemophilia A (ClinVar).

How common is F8 p.Lys249Ter (c.745A>T) in the general population?

F8 p.Lys249Ter (c.745A>T) is absent from gnomAD v4.1 (gnomAD).

How is Hemophilia A inherited?

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

F8 p.Lys249Ter

c.745A>T · rs2523969776 · VCV2637904

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hemophilia A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 6 of 26
Splicing
SpliceAI	Δ0.20	donor loss · deltas
Pangolin	Δ0.29	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 1.7	GERP -1.6, phastCons 0.99
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

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.Lys249Ter
Coding: c.745A>T
MANE Select: NM_000132
dbSNP: rs2523969776
Type: single nucleotide variant
Location: chrX:154984729 (GRCh38)
Structure: AlphaFold pLDDT 61.20 · 29 PDB
Residue 249: 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 A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hemophilia A (Orphanet):

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

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-lys249ter (accessed [today's date]).

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