Is TSC2 p.Ile40= (c.120C>A) pathogenic?

TSC2 p.Ile40= (c.120C>A) is classified Uncertain significance in TSC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-11). Very rare (popmax 0.000169%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Ile40= (c.120C>A)?

TSC2 p.Ile40= (c.120C>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is TSC2 p.Ile40= (c.120C>A) in the general population?

TSC2 p.Ile40= (c.120C>A) is very rare (popmax 0.000169%, nfe) (gnomAD).

TSC2 p.Ile40=

c.120C>A · VCV3462636

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000169%, 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
Pangolin	Δ0.32	loss · gain 0.14 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 4.8	GERP 2, phastCons 1
Overall
CADD	14.68	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,018 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,062 alleles · very rare exomes 2/1,461,770 · genomes 0/152,292 · 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.Ile40=
Coding: c.120C>A
MANE Select: NM_000548
Type: single nucleotide variant
Location: chr16:2048735 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 40: the 'required for interaction with tsc1' 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.Ile40Thr Uncertain significance ★★ ⚠ same residue
TSC2 p.Ile40Phe Uncertain significance ★ ⚠ same residue
TSC2 p.Ile40Val 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
TSC2 c.1716+1G>A Pathogenic/Likely pathogenic ★★ same condition
TSC2 c.1947-2A>C 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-ile40 (accessed [today's date]).

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