Is F2 p.Arg431Pro (c.1292G>C) pathogenic?

F2 p.Arg431Pro (c.1292G>C) is classified Uncertain significance in F2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). AlphaMissense: likely pathogenic (0.9681); Very rare (popmax 0.0079%, nfe); Associated with Inborn genetic diseases.

What condition is associated with F2 p.Arg431Pro (c.1292G>C)?

F2 p.Arg431Pro (c.1292G>C) is associated with Inborn genetic diseases (ClinVar).

How common is F2 p.Arg431Pro (c.1292G>C) in the general population?

F2 p.Arg431Pro (c.1292G>C) is very rare (popmax 0.0079%, nfe) (gnomAD).

What do computational predictors say about F2 p.Arg431Pro (c.1292G>C)?

AlphaMissense predicts likely pathogenic (score 0.9681) — an in-silico prediction, not a clinical call.

F2 p.Arg431Pro

c.1292G>C · VCV4619029

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9681 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0079%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9681	likely pathogenic
REVEL	0.938	strongly pathogenic-leaning
SaProt	LLR -9.30	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 20 kb · p 1.8e-12 · regional, not allelic
Overall
CADD	34.0	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 0.0079% European (non-Finnish) · 93/1,177,560 alleles

Filtering AF 0.00657% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00609%

Overall 0.00579% 93/1,607,598 alleles · very rare exomes 93/1,455,532 · genomes 0/152,066 · joint denominator

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.Arg431Pro
Coding: c.1292G>C
MANE Select: NM_000506
Type: single nucleotide variant
Location: chr11:46728157 (GRCh38)
Gene constraint: LOEUF 0.552 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 480 PDB
Residue 431: the peptidase s1 domain; a β-strand; a UniProt-annotated variant site (in fa2d; himi-2)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

F2 p.Arg431His Likely pathogenic ★ ⚠ same residue
F2 p.Ala490Thr Uncertain significance ★★ ⚠ same condition
F2 p.Arg217Gln Uncertain significance ★★ ⚠ same condition
F2 p.Arg224Cys Uncertain significance ★★ ⚠ same condition
F2 p.Arg35Trp Uncertain significance ★★ ⚠ same condition
F2 p.Ile438Thr Uncertain significance ★★ ⚠ same condition
F2 p.Pro471Thr Uncertain significance ★★ ⚠ same condition
F2 p.Thr488Met 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-arg431pro (accessed [today's date]).

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