Is F2 p.Arg124Gln (c.371G>A) pathogenic?

F2 p.Arg124Gln (c.371G>A) is classified Uncertain significance in F2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2020-05-26). AlphaMissense: likely benign (0.0765); Ultra-rare (popmax 0.0478%, nfe); Associated with thrombophilia due to thrombin defect.

What condition is associated with F2 p.Arg124Gln (c.371G>A)?

F2 p.Arg124Gln (c.371G>A) is associated with thrombophilia due to thrombin defect, congenital prothrombin deficiency (ClinVar).

How common is F2 p.Arg124Gln (c.371G>A) in the general population?

F2 p.Arg124Gln (c.371G>A) is ultra-rare (popmax 0.0478%, nfe) (gnomAD).

What do computational predictors say about F2 p.Arg124Gln (c.371G>A)?

AlphaMissense predicts likely benign (score 0.0765) — an in-silico prediction, not a clinical call.

F2 p.Arg124Gln

c.371G>A · rs139148365 · VCV1033061

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0765 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0478%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thrombophilia due to thrombin defect

Computational evidence

Protein change
AlphaMissense	0.0765	likely benign
REVEL	0.117	moderately benign-leaning
SaProt	LLR -7.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP -2.7, phastCons 0.07
Regional constraint	o/e 0.76	unconstrained · MANE · 20 kb · p 1.8e-12 · regional, not allelic
Overall
CADD	10.6	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 0.0478% European (non-Finnish) · 564/1,180,026 alleles

Filtering AF 0.0445% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0432%

Overall 0.0371% 599/1,613,960 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0478%	2,092
Remaining individualsnot grpmax-eligible	0.0224%	4,463
African / African-American	0.012%	8,322
Admixed American	0.00667%	14,999
South Asian	0.00549%	18,217
East Asian	0.00446%	22,444
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604

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.Arg124Gln
Coding: c.371G>A
MANE Select: NM_000506
dbSNP: rs139148365
Type: single nucleotide variant
Location: chr11:46723234 (GRCh38)
Gene constraint: LOEUF 0.552 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 480 PDB
Residue 124: a disulfide bond; the kringle 1 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.Arg124Trp Uncertain significance ★ ⚠ 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
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-arg124gln (accessed [today's date]).

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