Is TSC2 p.Cys253= (c.759C>T) pathogenic?

TSC2 p.Cys253= (c.759C>T) is classified Conflicting classifications of pathogenicity in TSC2 (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-01-21). Very rare (popmax 0.00533%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Cys253= (c.759C>T)?

TSC2 p.Cys253= (c.759C>T) is associated with hereditary neoplastic syndrome, tuberous sclerosis, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Cys253= (c.759C>T) in the general population?

TSC2 p.Cys253= (c.759C>T) is very rare (popmax 0.00533%, afr) (gnomAD).

TSC2 p.Cys253=

c.759C>T · rs45517125 · VCV389500

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 0.00533%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.83	donor gain · deltas
Pangolin	Δ0.27	gain · loss 0.15 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -5	GERP -3.4
Overall
CADD	18.98	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00533% African / African-American · 4/75,046 alleles

Filtering AF 0.00223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.0028% 45/1,609,938 alleles · very rare exomes 39/1,457,630 · genomes 6/152,308 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00533%	18,762
Admixed American	0.005%	20,008
European (non-Finnish)	0.00305%	32,777
East Asian	0.00223%	44,874
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Cys253=
Coding: c.759C>T
MANE Select: NM_000548
dbSNP: rs45517125
Type: single nucleotide variant
Location: chr16:2056754 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 253: 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 tuberous sclerosis 2

Similar variants

TSC2 p.Cys253Ter Pathogenic ★★ same residue
TSC2 p.Cys253Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Cys253Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Cys253fs 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
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-cys253 (accessed [today's date]).

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