TOP3A p.Val186Phe
c.556G>T · VCV4070593
Likely pathogenic
Single submitter
Classification
Likely pathogenic
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
AlphaMissense
likely pathogenic
0.6857 · ACMG-weighted
gnomAD v4.1
Absent
absent from gnomAD v4.1
Missense predictors
2/3 damaging
AlphaMissense, REVEL, SaProt
Computational evidence
| Protein change | ||
| AlphaMissense | 0.6857 | likely pathogenic ✓ concordant with ClinVar |
|---|---|---|
| REVEL | 0.26 | benign-leaning |
| SaProt | LLR -10.93 | damaging |
| ⇒ AlphaMissense and SaProt call this damaging; REVEL does not. | ||
| Splicing | ||
| SpliceAI | <0.2 | all four deltas below 0.2 · C>G here scores Δ0.30 · evaluated, not missing |
| Constraint at this position | ||
| Conservation | phyloP -0.34 | GERP -2.7 |
| Regional constraint | o/e 0.86 | unconstrained · MANE · 40 kb · p 4.4e-07 · regional, not allelic |
| Overall | ||
| CADD | 22.1 | 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
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- TOP3A
- Protein
- p.Val186Phe
- Coding
- c.556G>T
- MANE Select
- NM_004618
- Type
- single nucleotide variant
- Location
- chr17:18302667 (GRCh38)
- Gene constraint
- LOEUF 0.737 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 84.14 · 2 PDB
- Residue 186
- a UniProt-annotated variant site (in peob5); an α-helix
Similar variants
- TOP3A p.Val186Ile Uncertain significance ★ ⚠ same residue
- TOP3A c.990+1G>T Likely pathogenic ★★ same type
- TOP3A p.Arg135Ter Pathogenic/Likely pathogenic ★★ same type
- TOP3A p.Arg177Ter Pathogenic/Likely pathogenic ★★ same type
- TOP3A p.Arg338Ter Pathogenic/Likely pathogenic ★★ same type
- TOP3A p.Ala622Thr Uncertain significance ★★ ⚠ same type
- TOP3A p.Ala642Val Uncertain significance ★★ ⚠ same type
- TOP3A p.Ala941Thr 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/top3a-p-val186phe (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown