Is F5 p.Arg345Trp (c.1033C>T) pathogenic?

F5 p.Arg345Trp (c.1033C>T) is classified Conflicting classifications of pathogenicity in F5 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.3119); Ultra-rare (popmax 0.0999%, sas); Associated with thrombophilia due to thrombin defect.

What condition is associated with F5 p.Arg345Trp (c.1033C>T)?

F5 p.Arg345Trp (c.1033C>T) is associated with thrombophilia due to thrombin defect, thrombophilia due to activated protein C resistance, congenital factor V deficiency (ClinVar).

How common is F5 p.Arg345Trp (c.1033C>T) in the general population?

F5 p.Arg345Trp (c.1033C>T) is ultra-rare (popmax 0.0999%, sas) (gnomAD).

What do computational predictors say about F5 p.Arg345Trp (c.1033C>T)?

AlphaMissense predicts likely benign (score 0.3119) — an in-silico prediction, not a clinical call.

F5 p.Arg345Trp

c.1033C>T · rs746260106 · VCV874622

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.3119 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0999%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

thrombophilia due to thrombin defect

Computational evidence

Protein change
AlphaMissense	0.3119	likely benign
REVEL	0.631	indeterminate
SaProt	LLR -9.27	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 45 kb · p 0.00099 · regional, not allelic
Overall
CADD	27.2	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 0.0999% South Asian · 91/91,076 alleles

Filtering AF 0.0833% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0771%

Overall 0.0132% 213/1,614,006 alleles · ultra-rare exomes 205/1,461,828 · genomes 8/152,178 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0999%	1,001
Admixed American	0.03%	3,334
European (non-Finnish)	0.00822%	12,165
Remaining individualsnot grpmax-eligible	0.008%	12,500
East Asian	0.00446%	22,432

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: F5
Protein: p.Arg345Trp
Coding: c.1033C>T
MANE Select: NM_000130
dbSNP: rs746260106
Type: single nucleotide variant
Location: chr1:169555267 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.57 · 23 PDB

Full F5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

thrombophilia due to thrombin defect — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: thrombophilia due to activated protein C resistance congenital factor V deficiency Budd-Chiari syndrome factor V deficiency

Similar variants

F5 p.Arg345Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
F5 c.1297-2A>G Pathogenic/Likely pathogenic ★★ same condition
F5 p.Arg1030Ter Pathogenic ★★ same condition
F5 p.Arg146Ter Pathogenic/Likely pathogenic ★★ same condition
F5 p.Arg1621Ter Pathogenic/Likely pathogenic ★★ same condition
F5 p.Arg1634Ter Pathogenic/Likely pathogenic ★★ same condition
F5 p.Arg2102His Pathogenic/Likely pathogenic ★★ same condition
F5 p.Arg740Ter 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/f5-p-arg345trp (accessed [today's date]).

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