Is F2 p.Arg596Gln (c.1787G>A) pathogenic?

F2 p.Arg596Gln (c.1787G>A) is classified Pathogenic in F2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-26). AlphaMissense: likely benign (0.2416); Very rare (popmax 8.47e-05%, nfe); Associated with thrombophilia due to thrombin defect.

What condition is associated with F2 p.Arg596Gln (c.1787G>A)?

F2 p.Arg596Gln (c.1787G>A) is associated with thrombophilia due to thrombin defect, congenital prothrombin deficiency (ClinVar).

How common is F2 p.Arg596Gln (c.1787G>A) in the general population?

F2 p.Arg596Gln (c.1787G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about F2 p.Arg596Gln (c.1787G>A)?

AlphaMissense predicts likely benign (score 0.2416) — an in-silico prediction, not a clinical call.

F2 p.Arg596Gln

c.1787G>A · rs387907201 · VCV692073

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2416 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thrombophilia due to thrombin defect

Computational evidence

Protein change
AlphaMissense	0.2416	likely benign ⚠ discordant with ClinVar
REVEL	0.697	pathogenic-leaning
SaProt	LLR -5.14	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 20 kb · p 1.8e-12 · regional, not allelic
Overall
CADD	32.0	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 8.47e-05% European (non-Finnish) · 1/1,180,032 alleles

Overall 6.2e-05% 1/1,614,140 alleles · very rare exomes 1/1,461,894 · genomes 0/152,246 · joint denominator

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.Arg596Gln
Coding: c.1787G>A
MANE Select: NM_000506
dbSNP: rs387907201
Type: single nucleotide variant
Location: chr11:46739326 (GRCh38)
Gene constraint: LOEUF 0.552 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 480 PDB
Residue 596: the peptidase s1 domain; a β-strand

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

Disease context

thrombophilia due to thrombin defect — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital prothrombin deficiency

Similar variants

F2 p.Arg596Trp Pathogenic ★ ⚠ same residue
F2 p.Arg596Leu Pathogenic ⚠ 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.Gln387Ter Pathogenic/Likely pathogenic ★★ same condition
F2 c.559+5G>A Uncertain significance ★★ same condition
F2 p.Ala17Ser 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-arg596gln (accessed [today's date]).

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