Is F2 p.Arg314Cys (c.940C>T) pathogenic?

F2 p.Arg314Cys (c.940C>T) is classified Pathogenic in F2 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-12-18). AlphaMissense: likely pathogenic (0.7977); Very rare (popmax 0.00167%, amr); Associated with thrombophilia due to thrombin defect.

What condition is associated with F2 p.Arg314Cys (c.940C>T)?

F2 p.Arg314Cys (c.940C>T) is associated with thrombophilia due to thrombin defect, congenital prothrombin deficiency (ClinVar).

How common is F2 p.Arg314Cys (c.940C>T) in the general population?

F2 p.Arg314Cys (c.940C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about F2 p.Arg314Cys (c.940C>T)?

AlphaMissense predicts likely pathogenic (score 0.7977) — an in-silico prediction, not a clinical call.

F2 p.Arg314Cys

c.940C>T · rs121918477 · VCV13303

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7977 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

thrombophilia due to thrombin defect

Computational evidence

Protein change
AlphaMissense	0.7977	likely pathogenic ✓ concordant with ClinVar
REVEL	0.85	moderately pathogenic-leaning
SaProt	LLR -10.54	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 7.5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 20 kb · p 1.8e-12 · regional, not allelic
Overall
CADD	26.8	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 · 1/60,028 alleles

Overall 0.000186% 3/1,614,060 alleles · very rare exomes 3/1,461,758 · genomes 0/152,302 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,028
Finnishnot grpmax-eligible	0.00156%	64,004
European (non-Finnish)	8.47e-05%	1,179,958

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.Arg314Cys
Coding: c.940C>T
MANE Select: NM_000506
dbSNP: rs121918477
Type: single nucleotide variant
Location: chr11:46726563 (GRCh38)
Gene constraint: LOEUF 0.552 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 480 PDB
Residue 314: a functional site (cleavage; by factor xa); a UniProt-annotated variant site (in fa2d; barcelona/madrid); a UniProt-annotated variant site (in fa2d; padua-1)

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.Arg314His Likely pathogenic ★★ ⚠ same residue
F2 p.Arg314Ser 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

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-arg314cys (accessed [today's date]).

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