Is F2 p.Arg533Pro (c.1598G>C) pathogenic?

F2 p.Arg533Pro (c.1598G>C) is classified Uncertain significance in F2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-03). AlphaMissense: likely benign (0.2819); Very rare (popmax 0.00133%, afr); Associated with congenital prothrombin deficiency.

What condition is associated with F2 p.Arg533Pro (c.1598G>C)?

F2 p.Arg533Pro (c.1598G>C) is associated with congenital prothrombin deficiency (ClinVar).

How common is F2 p.Arg533Pro (c.1598G>C) in the general population?

F2 p.Arg533Pro (c.1598G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Congenital factor II deficiency inherited?

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

What do computational predictors say about F2 p.Arg533Pro (c.1598G>C)?

AlphaMissense predicts likely benign (score 0.2819) — an in-silico prediction, not a clinical call.

F2 p.Arg533Pro

c.1598G>C · rs1361766713 · VCV2629094

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2819 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital prothrombin deficiency

Computational evidence

Protein change
AlphaMissense	0.2819	likely benign
REVEL	0.529	indeterminate
SaProt	LLR -8.60	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 0.85, phastCons 0.001
Regional constraint	o/e 0.76	unconstrained · MANE · 20 kb · p 1.8e-12 · regional, not allelic
Overall
CADD	16.61	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,920 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000558% 9/1,613,918 alleles · very rare exomes 8/1,461,784 · genomes 1/152,134 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,920
European (non-Finnish)	0.000678%	147,496

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.Arg533Pro
Coding: c.1598G>C
MANE Select: NM_000506
dbSNP: rs1361766713
Type: single nucleotide variant
Location: chr11:46729505 (GRCh38)
Gene constraint: LOEUF 0.552 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 480 PDB
Residue 533: 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

For Congenital factor II deficiency (Orphanet):

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

Similar variants

F2 p.Arg533Gln Uncertain significance ★★ ⚠ same residue
F2 p.Arg533Trp Uncertain significance ★ ⚠ same residue
F2 p.Arg533= Likely benign ★ same residue
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

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-arg533pro (accessed [today's date]).

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