Is F12 p.Gly116= (c.348C>A) pathogenic?

F12 p.Gly116= (c.348C>A) is classified Conflicting classifications of pathogenicity in F12 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-11-13). Rare (popmax 0.284%, afr); Associated with hereditary angioedema type 3.

What condition is associated with F12 p.Gly116= (c.348C>A)?

F12 p.Gly116= (c.348C>A) is associated with hereditary angioedema type 3, congenital factor XII deficiency (ClinVar).

How common is F12 p.Gly116= (c.348C>A) in the general population?

F12 p.Gly116= (c.348C>A) is rare (popmax 0.284%, afr) (gnomAD).

F12 p.Gly116=

c.348C>A · rs140243617 · VCV353003

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.284%, 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
Constraint at this position
Conservation	phyloP 0.79	GERP -4.3, phastCons 1
Overall
CADD	1.709	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.284% African / African-American · 213/75,068 alleles

Filtering AF 0.252% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.24%

Overall 0.0258% 417/1,614,192 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.284%	352
South Asian	0.157%	637
Middle Eastern	0.148%	674
Remaining individualsnot grpmax-eligible	0.0288%	3,473
Admixed American	0.00833%	12,006
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
European (non-Finnish)	0.00229%	43,705
East Asian	0.00223%	44,892

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.Gly116=
Coding: c.348C>A
MANE Select: NM_000505
dbSNP: rs140243617
Type: single nucleotide variant
Location: chr5:177405372 (GRCh38)
Gene constraint: LOEUF 1.286 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.47 · 17 PDB
Residue 116: a disulfide bond; the egf-like 1 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.Gly116Asp Uncertain significance ★ ⚠ same residue
F12 p.Gly116Ser Uncertain significance ★ ⚠ same residue
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

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-gly116 (accessed [today's date]).

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