Is F2 p.Arg198Cys (c.592C>T) pathogenic?

F2 p.Arg198Cys (c.592C>T) is classified Uncertain significance in F2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-06). AlphaMissense: likely benign (0.2794); Ultra-rare (popmax 0.0919%, afr).

How common is F2 p.Arg198Cys (c.592C>T) in the general population?

F2 p.Arg198Cys (c.592C>T) is ultra-rare (popmax 0.0919%, afr) (gnomAD).

What do computational predictors say about F2 p.Arg198Cys (c.592C>T)?

AlphaMissense predicts likely benign (score 0.2794) — an in-silico prediction, not a clinical call.

F2 p.Arg198Cys

c.592C>T · VCV4911434

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2794 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0919%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2794	likely benign
REVEL	0.388	indeterminate
SaProt	LLR -8.79	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP 0.39, phastCons 0.043
Regional constraint	o/e 0.76	unconstrained · MANE · 20 kb · p 1.8e-12 · regional, not allelic
Overall
CADD	21.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0919% African / African-American · 69/75,044 alleles

Filtering AF 0.0745% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0682%

Overall 0.00545% 88/1,613,450 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0919%	1,088
Middle Eastern	0.0171%	5,840
Remaining individualsnot grpmax-eligible	0.0064%	15,617
Admixed American	0.00333%	30,009
South Asian	0.0011%	91,072
European (non-Finnish)	0.000932%	107,276

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.Arg198Cys
Coding: c.592C>T
MANE Select: NM_000506
Type: single nucleotide variant
Location: chr11:46725891 (GRCh38)
Gene constraint: LOEUF 0.552 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 480 PDB
Residue 198: a functional site (cleavage; by thrombin)

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

Similar variants

F2 p.Arg198= Likely benign ★ same residue
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
F2 p.Arg596Gln Pathogenic ★★ ⚠ same type
F2 p.Gln387Ter Pathogenic/Likely pathogenic ★★ same type
F2 c.559+5G>A Uncertain significance ★★ 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-arg198cys (accessed [today's date]).

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