Is F12 p.Thr424= (c.1272G>C) pathogenic?

F12 p.Thr424= (c.1272G>C) is classified Benign/Likely benign in F12 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-25). Low-frequency (popmax 1.59%, afr); Associated with hereditary angioedema type 3.

What condition is associated with F12 p.Thr424= (c.1272G>C)?

F12 p.Thr424= (c.1272G>C) is associated with hereditary angioedema type 3, congenital factor XII deficiency (ClinVar).

How common is F12 p.Thr424= (c.1272G>C) in the general population?

F12 p.Thr424= (c.1272G>C) is low-frequency (popmax 1.59%, afr) (gnomAD).

F12 p.Thr424=

c.1272G>C · rs61737766 · VCV352988

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.59%, afr)

Conditions

hereditary angioedema type 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.45	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP -4.1	GERP -4.2
Overall
CADD	5.781	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.59% African / African-American · 1,189/74,950 alleles

Filtering AF 1.51% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.48%

Overall 0.0874% 1,404/1,605,790 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.59%	63
Remaining individualsnot grpmax-eligible	0.145%	691
Admixed American	0.125%	798
Middle Eastern	0.0586%	1,705
South Asian	0.011%	9,071
European (non-Finnish)	0.00314%	31,870

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.Thr424=
Coding: c.1272G>C
MANE Select: NM_000505
dbSNP: rs61737766
Type: single nucleotide variant
Location: chr5:177403596 (GRCh38)
Gene constraint: LOEUF 1.286 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.47 · 17 PDB
Residue 424: a disulfide bond; the peptidase s1 domain; a β-strand

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

Disease context

hereditary angioedema type 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital factor XII deficiency

Similar variants

F12 p.Thr328Lys Pathogenic ★★ ⚠ same condition
F12 p.Gly360Val Uncertain significance ★★ ⚠ same condition
F12 p.Leu120His Uncertain significance ★★ ⚠ same condition
F12 c.1019-28T>C Benign ★★ same condition
F12 c.1251-9C>T Benign/Likely benign ★★ same condition
F12 c.1681-7G>A Benign/Likely benign ★★ same condition
F12 c.398-12C>T Benign/Likely benign ★★ same condition
F12 c.-4T>C 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-thr424 (accessed [today's date]).

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