Is TSC2 p.Leu722= (c.2166C>T) pathogenic?

TSC2 p.Leu722= (c.2166C>T) is classified Benign/Likely benign in TSC2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-07). Very rare (popmax 0.00223%, eas); Associated with tuberous sclerosis 2.

What condition is associated with TSC2 p.Leu722= (c.2166C>T)?

TSC2 p.Leu722= (c.2166C>T) is associated with tuberous sclerosis 2, tuberous sclerosis, hereditary neoplastic syndrome (ClinVar).

How common is TSC2 p.Leu722= (c.2166C>T) in the general population?

TSC2 p.Leu722= (c.2166C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Tuberous sclerosis complex inherited?

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

TSC2 p.Leu722=

c.2166C>T · rs1009050362 · VCV1093381

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

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 1.8	GERP 0.67, phastCons 1
Overall
CADD	9.663	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,880 alleles

Overall 0.000186% 3/1,614,140 alleles · very rare exomes 3/1,461,792 · genomes 0/152,348 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,880
Finnishnot grpmax-eligible	0.00156%	63,954
European (non-Finnish)	8.47e-05%	1,180,043

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.Leu722=
Coding: c.2166C>T
MANE Select: NM_000548
dbSNP: rs1009050362
Type: single nucleotide variant
Location: chr16:2072309 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 722: 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 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.Leu722Phe Uncertain significance ★★ ⚠ same residue
TSC2 p.Leu722Val Uncertain significance ★ ⚠ same residue
TSC2 p.Leu722fs Pathogenic ★ 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

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-leu722 (accessed [today's date]).

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