Is TSC2 p.Ser526Arg (c.1578C>A) pathogenic?

TSC2 p.Ser526Arg (c.1578C>A) is classified Uncertain significance in TSC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-02). AlphaMissense: likely pathogenic (0.8866); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Ser526Arg (c.1578C>A)?

TSC2 p.Ser526Arg (c.1578C>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is TSC2 p.Ser526Arg (c.1578C>A) in the general population?

TSC2 p.Ser526Arg (c.1578C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TSC2 p.Ser526Arg (c.1578C>A)?

AlphaMissense predicts likely pathogenic (score 0.8866) — an in-silico prediction, not a clinical call.

TSC2 p.Ser526Arg

c.1578C>A · rs34012042 · VCV3232082

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8866 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.8866	likely pathogenic
REVEL	0.416	indeterminate
SaProt	LLR -6.49	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.38	GERP -4.3, phastCons 0.004
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	15.29	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TSC2
Protein: p.Ser526Arg
Coding: c.1578C>A
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

Similar variants

TSC2 p.Ser526= Benign ★★ same residue
TSC2 p.Ser526Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Ser526Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 c.1443+2T>C Pathogenic/Likely pathogenic ★★ same condition
TSC2 c.1443+5G>C Pathogenic/Likely pathogenic ★★ same condition
TSC2 c.1599+1G>A Pathogenic ★★ same condition
TSC2 c.1716+1G>A Pathogenic/Likely pathogenic ★★ same condition
TSC2 c.1947-2A>C 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-ser526arg (accessed [today's date]).

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