Is F12 p.Ala343Pro (c.1027G>C) pathogenic?

F12 p.Ala343Pro (c.1027G>C) is classified Benign/Likely benign in F12 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2025-10-09). AlphaMissense: likely benign (0.0622); Low-frequency (popmax 4.15%, eas); Associated with congenital factor XII deficiency.

What condition is associated with F12 p.Ala343Pro (c.1027G>C)?

F12 p.Ala343Pro (c.1027G>C) is associated with congenital factor XII deficiency (ClinVar).

How common is F12 p.Ala343Pro (c.1027G>C) in the general population?

F12 p.Ala343Pro (c.1027G>C) is low-frequency (popmax 4.15%, eas) (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.Ala343Pro (c.1027G>C)?

AlphaMissense predicts likely benign (score 0.0622) — an in-silico prediction, not a clinical call.

F12 p.Ala343Pro

c.1027G>C · rs183643295 · VCV225352

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.0622 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.15%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital factor XII deficiency

Computational evidence

Protein change
AlphaMissense	0.0622	likely benign
REVEL	0.203	benign-leaning
SaProt	LLR -5.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.32	GERP -3.2
Regional constraint	o/e 0.97	unconstrained · MANE · 7,232 bp · p 0.39 · regional, not allelic
Overall
CADD	3.177	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 4.15% East Asian · 1,857/44,756 alleles

Filtering AF 3.99% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.93%

Overall 0.144% 2,314/1,602,464 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	4.15%	24
Finnishnot grpmax-eligible	0.437%	229
Remaining individualsnot grpmax-eligible	0.178%	560
South Asian	0.0519%	1,929
African / African-American	0.00933%	10,720
Admixed American	0.00671%	14,907
European (non-Finnish)	0.00407%	24,558

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.Ala343Pro
Coding: c.1027G>C
MANE Select: NM_000505
dbSNP: rs183643295
Type: single nucleotide variant
Location: chr5:177404082 (GRCh38)
Gene constraint: LOEUF 1.286 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.47 · 17 PDB
Residue 343: the 'disordered' region

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-ala343pro (accessed [today's date]).

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