Is F2 p.Val588Ile (c.1762G>A) pathogenic?

F2 p.Val588Ile (c.1762G>A) is classified Uncertain significance in F2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-06). AlphaMissense: likely benign (0.2187); Very rare (popmax 0.00167%, amr); Associated with pregnancy loss, recurrent, susceptibility to, 2.

What condition is associated with F2 p.Val588Ile (c.1762G>A)?

F2 p.Val588Ile (c.1762G>A) is associated with pregnancy loss, recurrent, susceptibility to, 2, thrombophilia due to thrombin defect, congenital prothrombin deficiency (ClinVar).

How common is F2 p.Val588Ile (c.1762G>A) in the general population?

F2 p.Val588Ile (c.1762G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about F2 p.Val588Ile (c.1762G>A)?

AlphaMissense predicts likely benign (score 0.2187) — an in-silico prediction, not a clinical call.

F2 p.Val588Ile

c.1762G>A · VCV3599613

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2187 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

pregnancy loss, recurrent, susceptibility to, 2

Computational evidence

Protein change
AlphaMissense	0.2187	likely benign
REVEL	0.671	pathogenic-leaning
SaProt	LLR -7.36	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 20 kb · p 1.8e-12 · regional, not allelic
Overall
CADD	28.4	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 0.00167% Admixed American · 1/59,998 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00149% 24/1,614,098 alleles · very rare exomes 24/1,461,894 · genomes 0/152,204 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00937%	10,668
Remaining individualsnot grpmax-eligible	0.0032%	31,250
Admixed Americangrpmax	0.00167%	59,998
African / African-American	0.00133%	75,020
European (non-Finnish)	0.0011%	90,772
South Asian	0.0011%	91,076

Finnish 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.Val588Ile
Coding: c.1762G>A
MANE Select: NM_000506
Type: single nucleotide variant
Location: chr11:46739301 (GRCh38)
Gene constraint: LOEUF 0.552 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 480 PDB
Residue 588: the peptidase s1 domain; a β-strand

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

Disease context

pregnancy loss, recurrent, susceptibility to, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: thrombophilia due to thrombin defect congenital prothrombin deficiency ischemic stroke

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-val588ile (accessed [today's date]).

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