Is F12 p.Ser369= (c.1107G>C) pathogenic?

F12 p.Ser369= (c.1107G>C) is classified Conflicting classifications of pathogenicity in F12 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-07-22). Ultra-rare (popmax 0.0341%, nfe); Associated with hereditary angioedema type 3.

What condition is associated with F12 p.Ser369= (c.1107G>C)?

F12 p.Ser369= (c.1107G>C) is associated with hereditary angioedema type 3, congenital factor XII deficiency (ClinVar).

How common is F12 p.Ser369= (c.1107G>C) in the general population?

F12 p.Ser369= (c.1107G>C) is ultra-rare (popmax 0.0341%, nfe) (gnomAD).

F12 p.Ser369=

c.1107G>C · rs141473119 · VCV352992

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0341%, nfe)

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 -2.5	GERP -3.8
Overall
CADD	6.317	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0341% European (non-Finnish) · 402/1,179,678 alleles

Filtering AF 0.0313% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0302%

Overall 0.0621% 996/1,602,648 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.7%	59
Remaining individualsnot grpmax-eligible	0.133%	751
European (non-Finnish)grpmax	0.0341%	2,935
African / African-American	0.00667%	14,984
Finnishnot grpmax-eligible	0.00563%	17,775

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser369=
Coding: c.1107G>C
MANE Select: NM_000505
dbSNP: rs141473119
Type: single nucleotide variant
Location: chr5:177404002 (GRCh38)
Gene constraint: LOEUF 1.286 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.47 · 17 PDB
Residue 369: a disulfide bond

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-ser369 (accessed [today's date]).

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