Is TSC2 p.Val645= (c.1935C>T) pathogenic?

TSC2 p.Val645= (c.1935C>T) is classified Benign/Likely benign in TSC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-13). Very rare (popmax 6.2e-05%); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Val645= (c.1935C>T)?

TSC2 p.Val645= (c.1935C>T) is associated with hereditary neoplastic syndrome, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Val645= (c.1935C>T) in the general population?

TSC2 p.Val645= (c.1935C>T) is very rare (popmax 6.2e-05%) (gnomAD).

TSC2 p.Val645=

c.1935C>T · rs1596342693 · VCV767340

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.77 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.43	GERP -1.6, phastCons 0.99
Overall
CADD	6.567	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.2e-05%

Overall 6.2e-05% 1/1,613,444 alleles · very rare exomes 1/1,461,072 · genomes 0/152,372 · 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.Val645=
Coding: c.1935C>T
MANE Select: NM_000548
dbSNP: rs1596342693
Type: single nucleotide variant
Location: chr16:2071605 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 645: a β-strand

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.Val645Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Val645Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Val645Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Val645fs Pathogenic ★ same residue
TSC2 p.Val645_Cys646del 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-val645 (accessed [today's date]).

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