Is F12 p.Arg196Cys (c.586C>T) pathogenic?

F12 p.Arg196Cys (c.586C>T) is classified Uncertain significance in F12 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.164); Very rare (popmax 8.48e-05%, nfe); Associated with congenital factor XII deficiency.

What condition is associated with F12 p.Arg196Cys (c.586C>T)?

F12 p.Arg196Cys (c.586C>T) is associated with congenital factor XII deficiency (ClinVar).

How common is F12 p.Arg196Cys (c.586C>T) in the general population?

F12 p.Arg196Cys (c.586C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Congenital factor XII deficiency inherited?

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

What do computational predictors say about F12 p.Arg196Cys (c.586C>T)?

AlphaMissense predicts likely benign (score 0.164) — an in-silico prediction, not a clinical call.

F12 p.Arg196Cys

c.586C>T · rs2481042401 · VCV2572099

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.164 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital factor XII deficiency

Computational evidence

Protein change
AlphaMissense	0.164	likely benign
REVEL	0.306	indeterminate
SaProt	LLR -10.34	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP -4.2, phastCons 0.004
Regional constraint	o/e 0.97	unconstrained · MANE · 7,232 bp · p 0.39 · regional, not allelic
Overall
CADD	17.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,122 alleles

Overall 6.86e-05% 1/1,457,672 alleles · very rare

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.Arg196Cys
Coding: c.586C>T
MANE Select: NM_000505
dbSNP: rs2481042401
Type: single nucleotide variant
Location: chr5:177404858 (GRCh38)
Gene constraint: LOEUF 1.286 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.47 · 17 PDB
Residue 196: a disulfide bond; the egf-like 2 domain; a β-strand

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

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.398-12C>T Benign/Likely benign ★★ same condition
F12 c.-4T>C Benign/Likely benign ★★ same condition
F12 c.-8C>T Likely benign ★★ same condition
F12 p.Ala207Pro Benign/Likely benign ★★ same condition
F12 p.Ala252= 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-arg196cys (accessed [today's date]).

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