Is F2 p.Pro471Ala (c.1411C>G) pathogenic?

F2 p.Pro471Ala (c.1411C>G) is classified Uncertain significance in F2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-10). AlphaMissense: likely benign (0.1049); Ultra-rare (popmax 0.0178%, eas); Associated with congenital prothrombin deficiency.

What condition is associated with F2 p.Pro471Ala (c.1411C>G)?

F2 p.Pro471Ala (c.1411C>G) is associated with congenital prothrombin deficiency (ClinVar).

How common is F2 p.Pro471Ala (c.1411C>G) in the general population?

F2 p.Pro471Ala (c.1411C>G) is ultra-rare (popmax 0.0178%, eas) (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.Pro471Ala (c.1411C>G)?

AlphaMissense predicts likely benign (score 0.1049) — an in-silico prediction, not a clinical call.

F2 p.Pro471Ala

c.1411C>G · VCV3669143

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1049 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital prothrombin deficiency

Computational evidence

Protein change
AlphaMissense	0.1049	likely benign
REVEL	0.716	pathogenic-leaning
SaProt	LLR -8.93	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.1, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 20 kb · p 1.8e-12 · regional, not allelic
Overall
CADD	23.3	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 0.0178% East Asian · 8/44,892 alleles

Filtering AF 0.00883% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.00211% 34/1,614,092 alleles · ultra-rare exomes 33/1,461,862 · genomes 1/152,230 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,612
African / African-American	0.00801%	12,492
Remaining individualsnot grpmax-eligible	0.0032%	31,245
European (non-Finnish)	0.00144%	69,414
South Asian	0.0011%	91,088

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.Pro471Ala
Coding: c.1411C>G
MANE Select: NM_000506
Type: single nucleotide variant
Location: chr11:46728776 (GRCh38)
Gene constraint: LOEUF 0.552 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 480 PDB
Residue 471: the peptidase s1 domain; an α-helix

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.Pro471Thr Uncertain significance ★★ ⚠ same residue
F2 p.Pro471= Likely benign ★ same residue
F2 p.Pro471Ser 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

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-pro471ala (accessed [today's date]).

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