Is TSC2 p.Val101= (c.303G>A) pathogenic?

TSC2 p.Val101= (c.303G>A) is classified Likely benign in TSC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-08). Very rare (popmax 0.00231%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Val101= (c.303G>A)?

TSC2 p.Val101= (c.303G>A) is associated with hereditary neoplastic syndrome, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Val101= (c.303G>A) in the general population?

TSC2 p.Val101= (c.303G>A) is very rare (popmax 0.00231%, eas) (gnomAD).

TSC2 p.Val101=

c.303G>A · rs2151028329 · VCV1799138

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00231%, eas)

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 0.81	GERP -3.1, phastCons 1
Overall
CADD	7.698	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00231% East Asian · 1/43,310 alleles

Overall 6.99e-05% 1/1,431,198 alleles · very rare

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.Val101=
Coding: c.303G>A
MANE Select: NM_000548
dbSNP: rs2151028329
Type: single nucleotide variant
Location: chr16:2053419 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 101: an α-helix; 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

Also linked: tuberous sclerosis 2

Similar variants

TSC2 p.Val101Ala Uncertain significance ★★ ⚠ same residue
TSC2 p.Val101Leu Uncertain significance ★★ ⚠ same residue
TSC2 p.Val101Met Uncertain significance ★★ same residue
TSC2 p.Val101Gly Uncertain significance ★ same residue
TSC2 p.Val101_Leu102insVal Likely pathogenic ★ 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-val101 (accessed [today's date]).

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