Is TSC2 p.Pro1098= (c.3294C>T) pathogenic?

TSC2 p.Pro1098= (c.3294C>T) is classified Conflicting classifications of pathogenicity in TSC2 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-01-13). Very rare (popmax 0.00503%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Pro1098= (c.3294C>T)?

TSC2 p.Pro1098= (c.3294C>T) is associated with hereditary neoplastic syndrome, tuberous sclerosis, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Pro1098= (c.3294C>T) in the general population?

TSC2 p.Pro1098= (c.3294C>T) is very rare (popmax 0.00503%, amr) (gnomAD).

TSC2 p.Pro1098=

c.3294C>T · rs150126331 · VCV468000

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00503%, amr)

Conditions

hereditary neoplastic syndrome

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 -2.8	GERP -3.9
Overall
CADD	1.153	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00503% Admixed American · 3/59,686 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00067%

Overall 0.00106% 17/1,610,476 alleles · very rare exomes 16/1,458,274 · genomes 1/152,202 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00503%	19,895
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,528
African / African-American	0.00267%	37,455
European (non-Finnish)	0.000933%	107,192

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.Pro1098=
Coding: c.3294C>T
MANE Select: NM_000548
dbSNP: rs150126331
Type: single nucleotide variant
Location: chr16:2079566 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 1098: the 'disordered' region

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: tuberous sclerosis tuberous sclerosis 2

Similar variants

TSC2 p.Pro1098Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Pro1098Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Pro1098Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Pro1098Ser Conflicting classifications of pathogenicity ★ ⚠ 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

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-pro1098 (accessed [today's date]).

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