Is F12 p.Gln459Ter (c.1375C>T) pathogenic?

F12 p.Gln459Ter (c.1375C>T) is classified Likely pathogenic in F12 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-13). Very rare (popmax 0.00237%, eas); Associated with congenital factor XII deficiency.

What condition is associated with F12 p.Gln459Ter (c.1375C>T)?

F12 p.Gln459Ter (c.1375C>T) is associated with congenital factor XII deficiency (ClinVar).

How common is F12 p.Gln459Ter (c.1375C>T) in the general population?

F12 p.Gln459Ter (c.1375C>T) is very rare (popmax 0.00237%, eas) (gnomAD).

How is Congenital factor XII deficiency inherited?

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

F12 p.Gln459Ter

c.1375C>T · VCV3779632

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00237%, eas)

Conditions

congenital factor XII deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 11 of 14
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 0.85, phastCons 1
Overall
CADD	45.0	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

Grpmax group 0.00237% East Asian · 1/42,256 alleles

Overall 0.000142% 2/1,413,334 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00237%	42,256
African / African-American	0.00135%	74,038

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: F12
Protein: p.Gln459Ter
Coding: c.1375C>T
MANE Select: NM_000505
Type: single nucleotide variant
Location: chr5:177403493 (GRCh38)
Gene constraint: LOEUF 1.286 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.47 · 17 PDB
Residue 459: a disulfide bond; the peptidase s1 domain

Full F12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital factor XII deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital factor XII deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

F12 p.Thr328Lys Pathogenic ★★ ⚠ same condition
F12 p.Gly360Val Uncertain significance ★★ ⚠ same condition
F12 p.Leu120His Uncertain significance ★★ ⚠ same condition
F12 c.398-12C>T Benign/Likely benign ★★ same condition
F12 c.-4T>C Benign/Likely benign ★★ same condition
F12 c.-8C>T Likely benign ★★ same condition
F12 p.Ala207Pro Benign/Likely benign ★★ same condition
F12 p.Ala252= Benign/Likely benign ★★ 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/f12-p-gln459ter (accessed [today's date]).

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