Is F2 p.Pro411= (c.1233G>A) pathogenic?

F2 p.Pro411= (c.1233G>A) is classified Benign/Likely benign in F2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). Common (popmax 10.3%, mid) — too common for a highly-penetrant pathogenic allele; Associated with congenital prothrombin deficiency.

What condition is associated with F2 p.Pro411= (c.1233G>A)?

F2 p.Pro411= (c.1233G>A) is associated with congenital prothrombin deficiency, thrombophilia due to thrombin defect (ClinVar).

How is Congenital factor II deficiency inherited?

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

F2 p.Pro411=

Q: How common is F2 p.Pro411= (c.1233G>A) in the general population?

F2 p.Pro411= (c.1233G>A) is common (popmax 10.3%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1233G>A · rs5898 · VCV256312

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 10.3%, mid) — too common for a highly-penetrant pathogenic allele

Conditions

congenital prothrombin 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 -11	GERP -3.3
Overall
CADD	0.912	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 10.3% Middle Eastern · 622/6,058 alleles

Filtering AF 9.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.33%

Overall 7.87% 126,667/1,610,160 alleles · common exomes 116,640/1,458,160 · genomes 10,027/152,000 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	17.4%	6
Middle Easterngrpmax	10.3%	10
Ashkenazi Jewishnot grpmax-eligible	9.47%	11
European (non-Finnish)	8.75%	11
Finnishnot grpmax-eligible	7.55%	13
Remaining individualsnot grpmax-eligible	7.49%	13
South Asian	6.41%	16
Admixed American	3.8%	26
African / African-American	3.25%	31
East Asian	0.0357%	2,802

Amish 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: F2
Protein: p.Pro411=
Coding: c.1233G>A
MANE Select: NM_000506
dbSNP: rs5898
Type: single nucleotide variant
Location: chr11:46728098 (GRCh38)
Gene constraint: LOEUF 0.552 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 480 PDB
Residue 411: the peptidase s1 domain; an α-helix

Full F2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital prothrombin deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: thrombophilia due to thrombin defect

For Congenital factor II deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

F2 p.Arg461Trp Pathogenic/Likely pathogenic ★★ same condition
F2 p.Arg500Gln Pathogenic ★★ ⚠ same condition
F2 p.Arg581Cys Pathogenic/Likely pathogenic ★★ same condition
F2 p.Arg596Gln Pathogenic ★★ ⚠ same condition
F2 p.Gln387Ter Pathogenic/Likely pathogenic ★★ same condition
F2 c.559+5G>A Uncertain significance ★★ same condition
F2 p.Ala17Ser Uncertain significance ★★ ⚠ same condition
F2 p.Arg117Gln Uncertain significance ★★ ⚠ 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/f2-p-pro411 (accessed [today's date]).

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