Is F2 p.Pro386Thr (c.1156C>A) pathogenic?

F2 p.Pro386Thr (c.1156C>A) is classified Uncertain significance in F2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-15). AlphaMissense: likely pathogenic (0.6564); Ultra-rare (popmax 0.0176%, nfe); Associated with congenital prothrombin deficiency.

What condition is associated with F2 p.Pro386Thr (c.1156C>A)?

F2 p.Pro386Thr (c.1156C>A) is associated with congenital prothrombin deficiency (ClinVar).

How common is F2 p.Pro386Thr (c.1156C>A) in the general population?

F2 p.Pro386Thr (c.1156C>A) is ultra-rare (popmax 0.0176%, nfe) (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.Pro386Thr (c.1156C>A)?

AlphaMissense predicts likely pathogenic (score 0.6564) — an in-silico prediction, not a clinical call.

F2 p.Pro386Thr

c.1156C>A · VCV3337090

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6564 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0176%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital prothrombin deficiency

Computational evidence

Protein change
AlphaMissense	0.6564	likely pathogenic
REVEL	0.608	indeterminate
SaProt	LLR -13.32	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 20 kb · p 1.8e-12 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0176% European (non-Finnish) · 208/1,179,014 alleles

Filtering AF 0.0156% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0149%

Overall 0.0135% 218/1,610,668 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0176%	5,668
Remaining individualsnot grpmax-eligible	0.0112%	8,913
African / African-American	0.00267%	37,415
Admixed American	0.00167%	59,716

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.Pro386Thr
Coding: c.1156C>A
MANE Select: NM_000506
Type: single nucleotide variant
Location: chr11:46728021 (GRCh38)
Gene constraint: LOEUF 0.552 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 480 PDB
Residue 386: the peptidase s1 domain; a disulfide bond; a UniProt-annotated variant site (confirmed at protein level)

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

For Congenital factor II deficiency (Orphanet):

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

Similar variants

F2 p.Pro386= Likely benign ★ 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-pro386thr (accessed [today's date]).

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