Is TSC2 p.Ser526= (c.1578C>T) pathogenic?

TSC2 p.Ser526= (c.1578C>T) is classified Benign in TSC2 (ClinVar, Multiple submitters, 22 submitters; last evaluated 2026-02-04). Common (popmax 10.1%, mid) — too common for a highly-penetrant pathogenic allele; Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Ser526= (c.1578C>T)?

TSC2 p.Ser526= (c.1578C>T) is associated with hereditary neoplastic syndrome, tuberous sclerosis, lymphangioleiomyomatosis (ClinVar).

TSC2 p.Ser526=

Q: How common is TSC2 p.Ser526= (c.1578C>T) in the general population?

TSC2 p.Ser526= (c.1578C>T) is common (popmax 10.1%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1578C>T · rs34012042 · VCV49162

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 22 submitters

gnomAD v4.1

Common

common (popmax 10.1%, mid) — too common for a highly-penetrant pathogenic allele

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 -0.38	GERP -4.3, phastCons 0.004
Overall
CADD	3.175	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 10.1% Middle Eastern · 610/6,032 alleles

Filtering AF 9.45% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.18%

Overall 6.24% 100,685/1,613,664 alleles · common

Ancestry group	Frequency	1 in
Middle Easterngrpmax	10.1%	10
Ashkenazi Jewishnot grpmax-eligible	9.9%	10
Finnishnot grpmax-eligible	8.49%	12
South Asian	6.95%	14
European (non-Finnish)	6.65%	15
Remaining individualsnot grpmax-eligible	6%	17
Admixed American	3.78%	26
Amishnot grpmax-eligible	1.21%	83
African / African-American	1.19%	84
East Asian	0.0356%	2,806

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.Ser526=
Coding: c.1578C>T
MANE Select: NM_000548
dbSNP: rs34012042
Type: single nucleotide variant
Location: chr16:2064406 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 526: an α-helix

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 lymphangioleiomyomatosis tuberous sclerosis 2

Similar variants

TSC2 p.Ser526Arg Uncertain significance ★ ⚠ same residue
TSC2 p.Ser526Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Ser526Thr 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
TSC2 c.1362-1G>A 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-ser526 (accessed [today's date]).

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