Is TSC1 p.Ala2= (c.6C>T) pathogenic?

TSC1 p.Ala2= (c.6C>T) is classified Benign/Likely benign in TSC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-30). Very rare (popmax 8.47e-05%, nfe); Associated with tuberous sclerosis 1.

What condition is associated with TSC1 p.Ala2= (c.6C>T)?

TSC1 p.Ala2= (c.6C>T) is associated with tuberous sclerosis 1, hereditary neoplastic syndrome (ClinVar).

How common is TSC1 p.Ala2= (c.6C>T) in the general population?

TSC1 p.Ala2= (c.6C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Tuberous sclerosis complex inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

TSC1 p.Ala2=

c.6C>T · VCV4071182

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

tuberous sclerosis 1

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 6.2	GERP 1.1, phastCons 1
Overall
CADD	12.79	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,024 alleles

Overall 0.000124% 2/1,614,124 alleles · very rare exomes 2/1,461,824 · genomes 0/152,300 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,500
European (non-Finnish)grpmax	8.47e-05%	1,180,025

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: TSC1
Protein: p.Ala2=
Coding: c.6C>T
MANE Select: NM_000368
Type: single nucleotide variant
Location: chr9:132928867 (GRCh38)
Gene constraint: LOEUF 0.227 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.55 · 5 PDB

Full TSC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

tuberous sclerosis 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Tuberous sclerosis complex (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-9 / 100 000 (Taiwan, Province of China)

Similar variants

TSC1 p.Ala2Val Uncertain significance ★★ ⚠ same residue
TSC1 p.Ala2Thr Uncertain significance ★ ⚠ same residue
TSC1 c.1029+1G>A Pathogenic/Likely pathogenic ★★ same condition
TSC1 c.1029+1G>C Pathogenic/Likely pathogenic ★★ same condition
TSC1 c.107-1G>A Pathogenic/Likely pathogenic ★★ same condition
TSC1 c.1141+1G>A Likely pathogenic ★★ same condition
TSC1 c.1264-1G>A Pathogenic/Likely pathogenic ★★ same condition
TSC1 c.1439-1G>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/tsc1-p-ala2 (accessed [today's date]).

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