TSC2 p.Lys258=
c.774G>A · rs137854875 · VCV2630731
Uncertain significance
Multiple submitters
Classification
Uncertain significance
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 3 submitters
gnomAD v4.1
Absent
absent from gnomAD v4.1
Conditions
3
TSC2-related disorder
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| Splicing | ||
| SpliceAI | Δ0.86 | donor gain · deltas |
|---|---|---|
| Pangolin | Δ0.84 | loss · gain 0.35 · SpliceAI calls gain · independent |
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP 1.7, phastCons 1 |
| Overall | ||
| CADD | 28.3 | PHRED · no single calibrated threshold — expert panels disagree |
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
- TSC2
- Protein
- p.Lys258=
- Coding
- c.774G>A
- MANE Select
- NM_000548
- dbSNP
- rs137854875
- Type
- single nucleotide variant
- Location
- chr16:2056769 (GRCh38)
- Gene constraint
- LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 68.81 · 2 PDB
- Residue 258
- an α-helix; the 'required for interaction with tsc1' region; a UniProt-annotated variant site (in tsc2)
Disease context
TSC2-related disorder
Also linked: tuberous sclerosis 2hereditary neoplastic syndrome
Similar variants
- TSC2 p.Lys258Gln Uncertain significance ★★ ⚠ same residue
- TSC2 c.1257+1G>A Pathogenic ★★ same condition
- TSC2 c.1258-2A>G Pathogenic ★★ same condition
- TSC2 c.1361+1G>A Pathogenic/Likely pathogenic ★★ same condition
- TSC2 c.1361+1G>T Pathogenic/Likely pathogenic ★★ same condition
- TSC2 c.1362-1G>A Pathogenic ★★ same condition
- TSC2 c.138+2T>C Pathogenic ★★ same condition
- TSC2 c.138+5G>A 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/tsc2-p-lys258 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown