Is F2 p.Val272Met (c.814G>A) pathogenic?

F2 p.Val272Met (c.814G>A) is classified Uncertain significance in F2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-20). AlphaMissense: ambiguous (0.4153); Ultra-rare (popmax 0.0164%, mid); Associated with congenital prothrombin deficiency.

What condition is associated with F2 p.Val272Met (c.814G>A)?

F2 p.Val272Met (c.814G>A) is associated with congenital prothrombin deficiency, thrombophilia due to thrombin defect (ClinVar).

How common is F2 p.Val272Met (c.814G>A) in the general population?

F2 p.Val272Met (c.814G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

How is Congenital factor II deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about F2 p.Val272Met (c.814G>A)?

AlphaMissense predicts ambiguous (score 0.4153) — an in-silico prediction, not a clinical call.

F2 p.Val272Met

c.814G>A · rs199558597 · VCV877749

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4153 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

congenital prothrombin deficiency

Computational evidence

Protein change
AlphaMissense	0.4153	ambiguous
REVEL	0.436	indeterminate
SaProt	LLR -8.68	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 0.67, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 20 kb · p 1.8e-12 · regional, not allelic
Overall
CADD	24.1	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00112% 18/1,614,066 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0064%	15,622
African / African-American	0.00534%	18,734
Finnishnot grpmax-eligible	0.00156%	63,996
European (non-Finnish)	0.000678%	147,505

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.Val272Met
Coding: c.814G>A
MANE Select: NM_000506
dbSNP: rs199558597
Type: single nucleotide variant
Location: chr11:46726113 (GRCh38)
Gene constraint: LOEUF 0.552 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 480 PDB
Residue 272: a disulfide bond; the kringle 2 domain

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

Disease context

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

Also linked: thrombophilia due to thrombin defect

For Congenital factor II deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

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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
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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-val272met (accessed [today's date]).

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