Is TSC2 p.Pro28Ser (c.82C>T) pathogenic?

TSC2 p.Pro28Ser (c.82C>T) is classified Benign/Likely benign in TSC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-10). AlphaMissense: likely benign (0.0728); Very rare (popmax 0.00266%, afr); Associated with tuberous sclerosis 2.

What condition is associated with TSC2 p.Pro28Ser (c.82C>T)?

TSC2 p.Pro28Ser (c.82C>T) is associated with tuberous sclerosis 2, hereditary neoplastic syndrome (ClinVar).

How common is TSC2 p.Pro28Ser (c.82C>T) in the general population?

TSC2 p.Pro28Ser (c.82C>T) is very rare (popmax 0.00266%, afr) (gnomAD).

How is Tuberous sclerosis complex inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TSC2 p.Pro28Ser (c.82C>T)?

AlphaMissense predicts likely benign (score 0.0728) — an in-silico prediction, not a clinical call.

TSC2 p.Pro28Ser

c.82C>T · rs200480606 · VCV2854426

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0728 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00266%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tuberous sclerosis 2

Computational evidence

Protein change
AlphaMissense	0.0728	likely benign
REVEL	0.014	strongly benign-leaning
SaProt	LLR -5.19	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP -0.5, phastCons 0.97
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	15.63	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

Grpmax group 0.00266% African / African-American · 2/75,052 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,614,052 alleles · very rare exomes 2/1,461,754 · genomes 0/152,298 · 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.Pro28Ser
Coding: c.82C>T
MANE Select: NM_000548
dbSNP: rs200480606
Type: single nucleotide variant
Location: chr16:2048697 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 28: the 'required for interaction with tsc1' region

Full TSC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

tuberous sclerosis 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Tuberous sclerosis complex (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-9 / 100 000 (Taiwan, Province of China)

Similar variants

TSC2 p.Pro28Leu Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro28Ala Uncertain significance ★ ⚠ same residue
TSC2 p.Pro28His Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Pro28Thr Uncertain significance ★ ⚠ same residue
TSC2 p.Pro28= Benign ★ same residue
TSC2 p.Pro28Arg Uncertain significance ★ ⚠ same residue
TSC2 c.1257+1G>A Pathogenic ★★ same condition
TSC2 c.1258-2A>G 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-pro28ser (accessed [today's date]).

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