Is TSC2 p.Glu32= (c.96G>A) pathogenic?

TSC2 p.Glu32= (c.96G>A) is classified Conflicting classifications of pathogenicity in TSC2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-02-25). Very rare (popmax 0.000593%, nfe); Associated with tuberous sclerosis 2.

What condition is associated with TSC2 p.Glu32= (c.96G>A)?

TSC2 p.Glu32= (c.96G>A) is associated with tuberous sclerosis 2, tuberous sclerosis, hereditary neoplastic syndrome (ClinVar).

How common is TSC2 p.Glu32= (c.96G>A) in the general population?

TSC2 p.Glu32= (c.96G>A) is very rare (popmax 0.000593%, nfe) (gnomAD).

How is Tuberous sclerosis complex inherited?

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

TSC2 p.Glu32=

c.96G>A · rs1567380772 · VCV589718

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Conditions

tuberous sclerosis 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.77	donor gain · deltas
Pangolin	Δ0.55	gain · loss 0.14 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5	GERP 0.88, phastCons 1
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000593% European (non-Finnish) · 7/1,180,038 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,614,114 alleles · very rare exomes 7/1,461,772 · genomes 0/152,342 · joint denominator

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.Glu32=
Coding: c.96G>A
MANE Select: NM_000548
dbSNP: rs1567380772
Type: single nucleotide variant
Location: chr16:2048711 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 32: 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 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.Glu32Asp Uncertain significance ★★ ⚠ same residue
TSC2 p.Glu32Gln Uncertain significance ★★ ⚠ same residue
TSC2 p.Glu32Lys Uncertain significance ★★ ⚠ same residue
TSC2 p.Glu32Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Glu32Val Uncertain significance ★ ⚠ same residue
TSC2 p.Glu32fs 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-glu32 (accessed [today's date]).

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