Is TSC1 p.Ala83= (c.249C>T) pathogenic?

TSC1 p.Ala83= (c.249C>T) is classified Benign/Likely benign in TSC1 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-01-09). Ultra-rare (popmax 0.04%, afr); Associated with tuberous sclerosis.

What condition is associated with TSC1 p.Ala83= (c.249C>T)?

TSC1 p.Ala83= (c.249C>T) is associated with tuberous sclerosis, tuberous sclerosis 1, hereditary neoplastic syndrome (ClinVar).

How common is TSC1 p.Ala83= (c.249C>T) in the general population?

TSC1 p.Ala83= (c.249C>T) is ultra-rare (popmax 0.04%, afr) (gnomAD).

How is Tuberous sclerosis complex inherited?

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

TSC1 p.Ala83=

c.249C>T · rs145783693 · VCV386172

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.04%, afr)

Conditions

tuberous sclerosis

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 -1.7	GERP -3.3
Overall
CADD	9.029	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.04% African / African-American · 30/74,908 alleles

Filtering AF 0.0288% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0249%

Overall 0.00335% 54/1,614,042 alleles · ultra-rare exomes 37/1,461,888 · genomes 17/152,154 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.04%	2,497
East Asian	0.00891%	11,223
Remaining individualsnot grpmax-eligible	0.0064%	15,622
South Asian	0.00439%	22,773
European (non-Finnish)	0.00102%	98,336

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.Ala83=
Coding: c.249C>T
MANE Select: NM_000368
dbSNP: rs145783693
Type: single nucleotide variant
Location: chr9:132925701 (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 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: tuberous sclerosis 1 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.Ala83Pro Uncertain significance ★★ ⚠ same residue
TSC1 p.Ala83Val Uncertain significance ★★ ⚠ same residue
TSC1 p.Ala83Asp Uncertain significance ★ ⚠ same residue
TSC1 p.Ala83Thr Conflicting classifications of pathogenicity ★ ⚠ 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

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-ala83 (accessed [today's date]).

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