Is TSC2 p.Ile365= (c.1095C>T) pathogenic?

TSC2 p.Ile365= (c.1095C>T) is classified Conflicting classifications of pathogenicity in TSC2 (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-01-19). Very rare (popmax 0.00347%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Ile365= (c.1095C>T)?

TSC2 p.Ile365= (c.1095C>T) is associated with hereditary neoplastic syndrome, tuberous sclerosis, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Ile365= (c.1095C>T) in the general population?

TSC2 p.Ile365= (c.1095C>T) is very rare (popmax 0.00347%, nfe) (gnomAD).

TSC2 p.Ile365=

c.1095C>T · rs757135168 · VCV184699

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00347%, 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 -9.9	GERP -3.7
Overall
CADD	2.1	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00347% European (non-Finnish) · 41/1,179,900 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.00266% 43/1,613,618 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00347%	28,778
Admixed American	0.00167%	59,990
African / African-American	0.00134%	74,878

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.Ile365=
Coding: c.1095C>T
MANE Select: NM_000548
dbSNP: rs757135168
Type: single nucleotide variant
Location: chr16:2060789 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 365: an α-helix; the 'required for interaction with tsc1' region; a UniProt-annotated variant site (in tsc2)

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.Ile365Thr Uncertain significance ★★ ⚠ same residue
TSC2 p.Ile365Met Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Ile365Ser Uncertain significance ★ ⚠ same residue
TSC2 p.Ile365Val 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-ile365 (accessed [today's date]).

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