Is F2 p.Arg541Trp (c.1621C>T) pathogenic?

F2 p.Arg541Trp (c.1621C>T) is classified Conflicting classifications of pathogenicity in F2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2018-10-12). AlphaMissense: likely benign (0.2095); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with F2 p.Arg541Trp (c.1621C>T)?

F2 p.Arg541Trp (c.1621C>T) is associated with Inborn genetic diseases, thrombophilia due to thrombin defect (ClinVar).

How common is F2 p.Arg541Trp (c.1621C>T) in the general population?

F2 p.Arg541Trp (c.1621C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about F2 p.Arg541Trp (c.1621C>T)?

AlphaMissense predicts likely benign (score 0.2095) — an in-silico prediction, not a clinical call.

F2 p.Arg541Trp

c.1621C>T · rs886048338 · VCV986165

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2095 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2095	likely benign
REVEL	0.589	indeterminate
SaProt	LLR -8.96	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.1	GERP 1.9, phastCons 0.97
Regional constraint	o/e 0.76	unconstrained · MANE · 20 kb · p 1.8e-12 · regional, not allelic
Overall
CADD	26.2	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 8.48e-05% European (non-Finnish) · 1/1,179,804 alleles

Overall 6.2e-05% 1/1,613,854 alleles · very rare exomes 1/1,461,598 · genomes 0/152,256 · 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.Arg541Trp
Coding: c.1621C>T
MANE Select: NM_000506
dbSNP: rs886048338
Type: single nucleotide variant
Location: chr11:46729528 (GRCh38)
Gene constraint: LOEUF 0.552 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 84.37 · 480 PDB
Residue 541: the peptidase s1 domain; a β-strand

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

Also linked: thrombophilia due to thrombin defect

Similar variants

F2 p.Arg541= Conflicting classifications of pathogenicity ★ same residue
F2 p.Arg500Gln Pathogenic ★★ ⚠ same condition
F2 p.Arg596Gln Pathogenic ★★ ⚠ same condition
F2 c.559+5G>A Uncertain significance ★★ same condition
F2 p.Ala17Ser Uncertain significance ★★ ⚠ same condition
F2 p.Ala490Thr Uncertain significance ★★ ⚠ same condition
F2 p.Arg117Gln Uncertain significance ★★ ⚠ same condition
F2 p.Arg124Gln 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-arg541trp (accessed [today's date]).

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