Is F2 p.Arg431His (c.1292G>A) pathogenic?

F2 p.Arg431His (c.1292G>A) is classified Likely pathogenic in F2 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-07-02). AlphaMissense: likely pathogenic (0.6068); Very rare (popmax 0.00223%, eas); Associated with F2-related disorder.

What condition is associated with F2 p.Arg431His (c.1292G>A)?

F2 p.Arg431His (c.1292G>A) is associated with F2-related disorder (ClinVar).

How common is F2 p.Arg431His (c.1292G>A) in the general population?

F2 p.Arg431His (c.1292G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about F2 p.Arg431His (c.1292G>A)?

AlphaMissense predicts likely pathogenic (score 0.6068) — an in-silico prediction, not a clinical call.

F2 p.Arg431His

c.1292G>A · rs121918482 · VCV13308

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6068 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

F2-related disorder

Computational evidence

Protein change
AlphaMissense	0.6068	likely pathogenic ✓ concordant with ClinVar
REVEL	0.91	moderately pathogenic-leaning
SaProt	LLR -6.66	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	33.0	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 0.00223% East Asian · 1/44,804 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00055% 8/1,455,532 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,804
Admixed American	0.00169%	59,160
South Asian	0.00112%	89,120
European (non-Finnish)	0.000425%	235,512

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.Arg431His
Coding: c.1292G>A
MANE Select: NM_000506
dbSNP: rs121918482
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 disulfide bond; 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

F2-related disorder

Similar variants

F2 p.Arg431Pro Uncertain significance ★ ⚠ same residue
F2 c.1472+3G>C Uncertain significance ★ same condition
F2 p.Gly362Arg Uncertain significance ★ ⚠ same condition
F2 p.Leu152fs Likely pathogenic ★ same condition
F2 p.Arg314His Likely pathogenic ★★ ⚠ same type
F2 p.Arg461Trp Pathogenic/Likely pathogenic ★★ same type
F2 p.Arg500Gln Pathogenic ★★ ⚠ same type
F2 p.Arg581Cys Pathogenic/Likely pathogenic ★★ same type

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-arg431his (accessed [today's date]).

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