Is F12 p.Ala252= (c.756C>T) pathogenic?

F12 p.Ala252= (c.756C>T) is classified Benign/Likely benign in F12 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-12). Common (popmax 5.35%, afr) — too common for a highly-penetrant pathogenic allele; Associated with hereditary angioedema type 3.

What condition is associated with F12 p.Ala252= (c.756C>T)?

F12 p.Ala252= (c.756C>T) is associated with hereditary angioedema type 3, congenital factor XII deficiency (ClinVar).

F12 p.Ala252=

Q: How common is F12 p.Ala252= (c.756C>T) in the general population?

F12 p.Ala252= (c.756C>T) is common (popmax 5.35%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.756C>T · rs41309752 · VCV352998

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 5.35%, afr) — too common for a highly-penetrant pathogenic allele

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
Constraint at this position
Conservation	phyloP -4.1	GERP -4.3
Overall
CADD	2.54	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.35% African / African-American · 4,008/74,924 alleles

Filtering AF 5.21% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.15%

Overall 0.878% 14,071/1,603,096 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.35%	19
South Asian	4.11%	24
Middle Eastern	3.04%	33
Ashkenazi Jewishnot grpmax-eligible	2.22%	45
Remaining individualsnot grpmax-eligible	1.26%	79
Admixed American	0.924%	108
European (non-Finnish)	0.354%	283
Finnishnot grpmax-eligible	0.0604%	1,657
East Asian	0.0359%	2,782

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.Ala252=
Coding: c.756C>T
MANE Select: NM_000505
dbSNP: rs41309752
Type: single nucleotide variant
Location: chr5:177404543 (GRCh38)
Gene constraint: LOEUF 1.286 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.47 · 17 PDB
Residue 252: a disulfide bond; the kringle domain; a turn

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-ala252 (accessed [today's date]).

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