Conflicting classifications of pathogenicity
Conflicting submitters
Classification
Conflicting classifications of pathogenicity
ClinVar
Review
Conflicting submitters ★☆☆☆
ClinVar · 4 submitters
gnomAD v4.1
Rare
low-frequency (popmax 2.44%, nfe)
Conditions
2
thrombophilia due to thrombin defect
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -20 | GERP -3.8 |
| Overall | ||
| CADD | 0.331 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
2.44%
European (non-Finnish) · 28,833/1,179,912 alleles
Filtering AF
2.42%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 2.41%
Overall
2.02%
32,653/1,613,962 alleles · low-frequency
exomes 30,320/1,461,750 · genomes 2,333/152,212 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 2.44% | 41 |
| Finnishnot grpmax-eligible | 2.08% | 48 |
| Amishnot grpmax-eligible | 1.86% | 54 |
| Remaining individualsnot grpmax-eligible | 1.76% | 57 |
| Ashkenazi Jewishnot grpmax-eligible | 0.942% | 106 |
| Middle Eastern | 0.825% | 121 |
| Admixed American | 0.793% | 126 |
| African / African-American | 0.403% | 248 |
| South Asian | 0.291% | 344 |
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.Pro534=
- Coding
- c.1602G>A
- MANE Select
- NM_000506
- dbSNP
- rs5900
- Type
- single nucleotide variant
- Location
- chr11:46729509 (GRCh38)
- Gene constraint
- LOEUF 0.552 · pLI 0.15 (gnomAD)
- Structure
- AlphaFold pLDDT 84.37 · 480 PDB
- Residue 534
- the peptidase s1 domain; an α-helix
Similar variants
- F2 p.Pro534Leu Uncertain significance ★ ⚠ same residue
- F2 p.Arg461Trp Pathogenic/Likely pathogenic ★★ same condition
- F2 p.Arg500Gln Pathogenic ★★ ⚠ same condition
- F2 p.Arg581Cys Pathogenic/Likely pathogenic ★★ same condition
- F2 p.Arg596Gln Pathogenic ★★ ⚠ same condition
- F2 p.Gln387Ter Pathogenic/Likely pathogenic ★★ same condition
- F2 c.559+5G>A Uncertain significance ★★ same condition
- F2 p.Ala17Ser 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-pro534 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown