Is TSC2 p.Leu89Phe (c.267G>T) pathogenic?

TSC2 p.Leu89Phe (c.267G>T) is classified Uncertain significance in TSC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-22). AlphaMissense: ambiguous (0.3434); Very rare (popmax 0.00228%, eas); Associated with tuberous sclerosis.

What condition is associated with TSC2 p.Leu89Phe (c.267G>T)?

TSC2 p.Leu89Phe (c.267G>T) is associated with tuberous sclerosis, tuberous sclerosis 2, hereditary neoplastic syndrome (ClinVar).

How common is TSC2 p.Leu89Phe (c.267G>T) in the general population?

TSC2 p.Leu89Phe (c.267G>T) is very rare (popmax 0.00228%, eas) (gnomAD).

How is Tuberous sclerosis complex inherited?

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

What do computational predictors say about TSC2 p.Leu89Phe (c.267G>T)?

AlphaMissense predicts ambiguous (score 0.3434) — an in-silico prediction, not a clinical call.

TSC2 p.Leu89Phe

c.267G>T · rs1286845026 · VCV1794674

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3434 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00228%, eas)

Conditions

tuberous sclerosis

Computational evidence

Protein change
AlphaMissense	0.3434	ambiguous
REVEL	0.409	indeterminate
SaProt	LLR -9.90	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -0.51, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	20.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00228% East Asian · 1/43,892 alleles

Overall 0.000126% 2/1,592,316 alleles · very rare exomes 1/1,440,070 · genomes 1/152,246 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00228%	43,892
African / African-American	0.00134%	74,616

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.Leu89Phe
Coding: c.267G>T
MANE Select: NM_000548
dbSNP: rs1286845026
Type: single nucleotide variant
Location: chr16:2053383 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 89: the 'required for interaction with tsc1' region

Full TSC2 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 2 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.Leu89= Benign/Likely benign ★★ same residue
TSC2 p.Leu89_Gln90delinsPheTer 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
TSC2 c.138+2T>C 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-leu89phe (accessed [today's date]).

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