Is TSC2 p.Pro1092= (c.3276G>A) pathogenic?

TSC2 p.Pro1092= (c.3276G>A) is classified Conflicting classifications of pathogenicity in TSC2 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-20). Ultra-rare (popmax 0.0141%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Pro1092= (c.3276G>A)?

TSC2 p.Pro1092= (c.3276G>A) is associated with hereditary neoplastic syndrome, tuberous sclerosis, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Pro1092= (c.3276G>A) in the general population?

TSC2 p.Pro1092= (c.3276G>A) is ultra-rare (popmax 0.0141%, nfe) (gnomAD).

TSC2 p.Pro1092=

c.3276G>A · rs368923127 · VCV238016

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0141%, nfe)

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 -7.4	GERP -3.9
Overall
CADD	0.172	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0141% European (non-Finnish) · 165/1,167,766 alleles

Filtering AF 0.0124% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0117%

Overall 0.0109% 174/1,591,526 alleles · ultra-rare exomes 164/1,440,312 · genomes 10/151,214 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0141%	7,077
Remaining individualsnot grpmax-eligible	0.00822%	12,164
African / African-American	0.00406%	24,617
South Asian	0.0011%	90,706

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.Pro1092=
Coding: c.3276G>A
MANE Select: NM_000548
dbSNP: rs368923127
Type: single nucleotide variant
Location: chr16:2079420 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 1092: 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.Pro1092Arg Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro1092Gln Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro1092Ser Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro1092Leu Benign/Likely benign ★★ same residue
TSC2 p.Pro1092Thr Uncertain significance ★ ⚠ 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

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-pro1092 (accessed [today's date]).

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