Is TSC2 p.Pro1109Leu (c.3326C>T) pathogenic?

TSC2 p.Pro1109Leu (c.3326C>T) is classified Conflicting classifications of pathogenicity in TSC2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-04-23). AlphaMissense: likely benign (0.3261); Very rare (popmax 0.00501%, amr); Associated with lymphangioleiomyomatosis.

What condition is associated with TSC2 p.Pro1109Leu (c.3326C>T)?

TSC2 p.Pro1109Leu (c.3326C>T) is associated with lymphangioleiomyomatosis, isolated focal cortical dysplasia type II, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Pro1109Leu (c.3326C>T) in the general population?

TSC2 p.Pro1109Leu (c.3326C>T) is very rare (popmax 0.00501%, amr) (gnomAD).

What do computational predictors say about TSC2 p.Pro1109Leu (c.3326C>T)?

AlphaMissense predicts likely benign (score 0.3261) — an in-silico prediction, not a clinical call.

TSC2 p.Pro1109Leu

c.3326C>T · rs796053474 · VCV207676

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.3261 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00501%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

lymphangioleiomyomatosis

Computational evidence

Protein change
AlphaMissense	0.3261	likely benign
REVEL	0.61	indeterminate
SaProt	LLR -6.04	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	28.2	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 0.00501% Admixed American · 3/59,878 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000669%

Overall 0.000617% 9/1,459,200 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00501%	19,959
East Asian	0.00223%	44,814
European (non-Finnish)	0.000424%	235,901

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.Pro1109Leu
Coding: c.3326C>T
MANE Select: NM_000548
dbSNP: rs796053474
Type: single nucleotide variant
Location: chr16:2079598 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 1109: the 'disordered' region

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

Disease context

lymphangioleiomyomatosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: isolated focal cortical dysplasia type II tuberous sclerosis 2 hereditary neoplastic syndrome

For Perivascular epithelioid cell neoplasm (Orphanet):

Onset: Adolescent, Adult, Childhood, Elderly

Similar variants

TSC2 p.Pro1109Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Pro1109Arg Uncertain significance ★ same residue
TSC2 p.Pro1109Gln Uncertain significance ★ same residue
TSC2 p.Pro1109= Likely benign ★ same residue
TSC2 p.Pro1109Ser 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-pro1109leu (accessed [today's date]).

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