Is F2 p.Arg596Leu (c.1787G>T) pathogenic?

F2 p.Arg596Leu (c.1787G>T) is classified Pathogenic in F2 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2012-06-21). AlphaMissense: likely pathogenic (0.6818); Absent from gnomAD v4.1; Associated with thrombophilia due to thrombin defect.

What condition is associated with F2 p.Arg596Leu (c.1787G>T)?

F2 p.Arg596Leu (c.1787G>T) is associated with thrombophilia due to thrombin defect (ClinVar).

How common is F2 p.Arg596Leu (c.1787G>T) in the general population?

F2 p.Arg596Leu (c.1787G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about F2 p.Arg596Leu (c.1787G>T)?

AlphaMissense predicts likely pathogenic (score 0.6818) — an in-silico prediction, not a clinical call.

F2 p.Arg596Leu

c.1787G>T · rs387907201 · VCV31922

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6818 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thrombophilia due to thrombin defect

Computational evidence

Protein change
AlphaMissense	0.6818	likely pathogenic ✓ concordant with ClinVar
REVEL	0.767	pathogenic-leaning
SaProt	LLR -4.36	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does 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	26.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: F2
Protein: p.Arg596Leu
Coding: c.1787G>T
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

Similar variants

F2 p.Arg596Gln Pathogenic ★★ ⚠ same residue
F2 p.Arg596Trp Pathogenic ★ ⚠ same residue
F2 p.Arg500Gln 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
F2 p.Arg124Gln Uncertain significance ★★ ⚠ same condition
F2 p.Arg533Gln 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-arg596leu (accessed [today's date]).

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