Is F12 p.Leu40= (c.120C>T) pathogenic?

F12 p.Leu40= (c.120C>T) is classified Conflicting classifications of pathogenicity in F12 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-04-24). Rare (popmax 0.304%, afr); Associated with congenital factor XII deficiency.

What condition is associated with F12 p.Leu40= (c.120C>T)?

F12 p.Leu40= (c.120C>T) is associated with congenital factor XII deficiency, hereditary angioedema type 3 (ClinVar).

How common is F12 p.Leu40= (c.120C>T) in the general population?

F12 p.Leu40= (c.120C>T) is rare (popmax 0.304%, afr) (gnomAD).

How is Congenital factor XII deficiency inherited?

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

F12 p.Leu40=

c.120C>T · rs149368999 · VCV904551

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.304%, afr)

Conditions

congenital factor XII deficiency

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 2.8	GERP -1.5, phastCons 1
Overall
CADD	8.619	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.304% African / African-American · 228/75,028 alleles

Filtering AF 0.272% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.259%

Overall 0.0157% 253/1,613,894 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.304%	329
Remaining individualsnot grpmax-eligible	0.0256%	3,906
Middle Eastern	0.0165%	6,062
Admixed American	0.005%	20,009
South Asian	0.00329%	30,359
European (non-Finnish)	0.00017%	589,950

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.Leu40=
Coding: c.120C>T
MANE Select: NM_000505
dbSNP: rs149368999
Type: single nucleotide variant
Location: chr5:177406057 (GRCh38)
Gene constraint: LOEUF 1.286 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.47 · 17 PDB

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

Also linked: hereditary angioedema type 3

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.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-leu40 (accessed [today's date]).

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