TSC2 c.5259+8A>C
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
very rare (popmax 0.000508%, nfe)
Conditions
1
tuberous sclerosis 2
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| Splice region | donor +8 | near-intronic (+8 nt from the splice site) |
|---|---|---|
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP -1.1 | GERP -2.4 |
| Overall | ||
| CADD | 1.19 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.000508%
European (non-Finnish) · 6/1,179,974 alleles
Filtering AF
0.000183%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00012%
Overall
0.000372%
6/1,612,448 alleles · very rare
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
- TSC2
- Coding
- c.5259+8A>C
- MANE Select
- NM_000548
- dbSNP
- rs912835683
- Type
- single nucleotide variant
- Location
- chr16:2088333 (GRCh38)
- Gene constraint
- LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 68.81 · 2 PDB
Disease context
tuberous sclerosis 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsFor Tuberous sclerosis complex (Orphanet):
- Inheritance
- Autosomal dominant
- Onset
- All ages
- Prevalence
- 1-9 / 100 000 (Taiwan, Province of China)
Similar variants
- 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
- TSC2 c.139-1G>A 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-c-5259-plus-8a-c (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown