Is TSC2 p.Ala447= (c.1341G>T) pathogenic?

TSC2 p.Ala447= (c.1341G>T) is classified Benign/Likely benign in TSC2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-18). Very rare (popmax 0.00133%, afr); Associated with tuberous sclerosis 2.

What condition is associated with TSC2 p.Ala447= (c.1341G>T)?

TSC2 p.Ala447= (c.1341G>T) is associated with tuberous sclerosis 2, tuberous sclerosis, lymphangioleiomyomatosis (ClinVar).

How common is TSC2 p.Ala447= (c.1341G>T) in the general population?

TSC2 p.Ala447= (c.1341G>T) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Tuberous sclerosis complex inherited?

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

TSC2 p.Ala447=

c.1341G>T · rs141609319 · VCV1138694

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

tuberous sclerosis 2

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 0.04	GERP -3.9
Overall
CADD	2.85	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,006 alleles

Overall 0.000124% 2/1,610,102 alleles · very rare exomes 2/1,457,740 · genomes 0/152,362 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,006
European (non-Finnish)	8.49e-05%	1,178,028

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
Protein: p.Ala447=
Coding: c.1341G>T
MANE Select: NM_000548
dbSNP: rs141609319
Type: single nucleotide variant
Location: chr16:2062580 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 447: an α-helix

Full TSC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

tuberous sclerosis 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: tuberous sclerosis lymphangioleiomyomatosis isolated focal cortical dysplasia type II 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

TSC2 p.Ala447Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Ala447Gly Uncertain significance ★ ⚠ same residue
TSC2 p.Ala447Ser Uncertain significance ★ ⚠ same residue
TSC2 p.Ala447Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Ala447Val Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Ala447fs Pathogenic ★ same residue
TSC2 c.1257+1G>A Pathogenic ★★ same condition
TSC2 c.1258-2A>G 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-ala447 (accessed [today's date]).

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