Is TSC2 p.Pro1109Gln (c.3326C>A) pathogenic?

TSC2 p.Pro1109Gln (c.3326C>A) is classified Uncertain significance in TSC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-28). AlphaMissense: ambiguous (0.5214); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Pro1109Gln (c.3326C>A)?

TSC2 p.Pro1109Gln (c.3326C>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is TSC2 p.Pro1109Gln (c.3326C>A) in the general population?

TSC2 p.Pro1109Gln (c.3326C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TSC2 p.Pro1109Gln (c.3326C>A)?

AlphaMissense predicts ambiguous (score 0.5214) — an in-silico prediction, not a clinical call.

TSC2 p.Pro1109Gln

c.3326C>A · rs796053474 · VCV1730247

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5214 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.5214	ambiguous
REVEL	0.55	indeterminate
SaProt	LLR -6.39	tolerated
Splicing
SpliceAI	Δ0.20	acceptor loss, 41 bp away · masked 0 · deltas
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	25.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TSC2
Protein: p.Pro1109Gln
Coding: c.3326C>A
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

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

Similar variants

TSC2 p.Pro1109Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Pro1109Arg Uncertain significance ★ same residue
TSC2 p.Pro1109Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Pro1109= Likely benign ★ same residue
TSC2 p.Pro1109Ser Uncertain significance ★ same residue
TSC2 c.1443+2T>C Pathogenic/Likely pathogenic ★★ same condition
TSC2 c.1443+5G>C Pathogenic/Likely pathogenic ★★ same condition
TSC2 c.1599+1G>A 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-pro1109gln (accessed [today's date]).

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