Is F12 p.Val568= (c.1704G>A) pathogenic?

F12 p.Val568= (c.1704G>A) is classified Conflicting classifications of pathogenicity in F12 (ClinVar, Conflicting submitters, 1 submitter; last evaluated 2018-01-13). Ultra-rare (popmax 0.0851%, sas); Associated with congenital factor XII deficiency.

What condition is associated with F12 p.Val568= (c.1704G>A)?

F12 p.Val568= (c.1704G>A) is associated with congenital factor XII deficiency, hereditary angioedema type 3 (ClinVar).

How common is F12 p.Val568= (c.1704G>A) in the general population?

F12 p.Val568= (c.1704G>A) is ultra-rare (popmax 0.0851%, sas) (gnomAD).

How is Congenital factor XII deficiency inherited?

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

F12 p.Val568=

c.1704G>A · rs536390950 · VCV904430

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0851%, sas)

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 -0.8	GERP -4.6, phastCons 0.006
Overall
CADD	9.634	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0851% South Asian · 77/90,478 alleles

Filtering AF 0.0698% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0641%

Overall 0.00553% 89/1,610,082 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0851%	1,175
Ashkenazi Jewishnot grpmax-eligible	0.00677%	14,764
Remaining individualsnot grpmax-eligible	0.00642%	15,575
Admixed American	0.00336%	29,802
European (non-Finnish)	0.000339%	294,640

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.Val568=
Coding: c.1704G>A
MANE Select: NM_000505
dbSNP: rs536390950
Type: single nucleotide variant
Location: chr5:177402436 (GRCh38)
Gene constraint: LOEUF 1.286 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.47 · 17 PDB
Residue 568: a β-strand; a disulfide bond; the peptidase s1 domain

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-val568 (accessed [today's date]).

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