Is F2 p.Leu609Pro (c.1826T>C) pathogenic?

F2 p.Leu609Pro (c.1826T>C) is classified Likely pathogenic in F2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-02-01). AlphaMissense: likely pathogenic (0.9898); Very rare (popmax 0.000254%, nfe); Associated with Prolonged prothrombin time.

What condition is associated with F2 p.Leu609Pro (c.1826T>C)?

F2 p.Leu609Pro (c.1826T>C) is associated with Prolonged prothrombin time (ClinVar).

How common is F2 p.Leu609Pro (c.1826T>C) in the general population?

F2 p.Leu609Pro (c.1826T>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about F2 p.Leu609Pro (c.1826T>C)?

AlphaMissense predicts likely pathogenic (score 0.9898) — an in-silico prediction, not a clinical call.

F2 p.Leu609Pro

c.1826T>C · rs1592422740 · VCV627173

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9898 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Prolonged prothrombin time

Computational evidence

Protein change
AlphaMissense	0.9898	likely pathogenic ✓ concordant with ClinVar · top 6% in F2
REVEL	0.883	moderately pathogenic-leaning
SaProt	LLR -14.38	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 20 kb · p 1.8e-12 · regional, not allelic
Overall
CADD	29.4	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

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,024 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,888 alleles · very rare

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.Leu609Pro
Coding: c.1826T>C
MANE Select: NM_000506
dbSNP: rs1592422740
Type: single nucleotide variant
Location: chr11:46739365 (GRCh38)
Gene constraint: LOEUF 0.552 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 480 PDB
Residue 609: the peptidase s1 domain; an α-helix

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

Disease context

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

Similar variants

F2 p.Arg314His Likely pathogenic ★★ ⚠ same condition
F2 p.Lys345del Likely pathogenic ★ same condition
F2 p.Arg461Trp Pathogenic/Likely pathogenic ★★ same type
F2 p.Arg500Gln Pathogenic ★★ ⚠ same type
F2 p.Arg581Cys Pathogenic/Likely pathogenic ★★ same type
F2 p.Arg596Gln Pathogenic ★★ ⚠ same type
F2 p.Gln387Ter Pathogenic/Likely pathogenic ★★ same type
F2 c.559+5G>A Uncertain significance ★★ same type

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-leu609pro (accessed [today's date]).

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