Is F12 p.Ala207Pro (c.619G>C) pathogenic?

F12 p.Ala207Pro (c.619G>C) is classified Benign/Likely benign in F12 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.048); Common (popmax 98.8%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with congenital factor XII deficiency.

What condition is associated with F12 p.Ala207Pro (c.619G>C)?

F12 p.Ala207Pro (c.619G>C) is associated with congenital factor XII deficiency, hereditary angioedema type 3 (ClinVar).

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.Ala207Pro (c.619G>C)?

AlphaMissense predicts likely benign (score 0.048) — an in-silico prediction, not a clinical call.

F12 p.Ala207Pro

Q: How common is F12 p.Ala207Pro (c.619G>C) in the general population?

F12 p.Ala207Pro (c.619G>C) is common (popmax 98.8%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.619G>C · rs17876030 · VCV256310

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.048 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 98.8%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital factor XII deficiency

Computational evidence

Protein change
AlphaMissense	0.048	likely benign
REVEL	0.098	moderately 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 3.2	GERP -1.4, phastCons 0.39
Regional constraint	o/e 0.97	unconstrained · MANE · 7,232 bp · p 0.39 · regional, not allelic
Overall
CADD	9.303	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 98.8% European (non-Finnish) · 1,163,888/1,178,004 alleles

Filtering AF 98.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 98.6%

Overall 97.7% 1,569,616/1,607,244 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	98.9%	1
European (non-Finnish)grpmax	98.8%	1
Ashkenazi Jewishnot grpmax-eligible	98.7%	1
Remaining individualsnot grpmax-eligible	97.4%	1
Middle Eastern	96.7%	1
South Asian	95.8%	1
African / African-American	95.7%	1
East Asian	91.3%	1
Amishnot grpmax-eligible	88.3%	1
Admixed American	83.8%	1

Finnish 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.Ala207Pro
Coding: c.619G>C
MANE Select: NM_000505
dbSNP: rs17876030
Type: single nucleotide variant
Location: chr5:177404825 (GRCh38)
Gene constraint: LOEUF 1.286 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.47 · 17 PDB
Residue 207: a disulfide bond; a UniProt-annotated variant site (in); the egf-like 2 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-ala207pro (accessed [today's date]).

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