Is TSC2 p.Ser1096Pro (c.3286T>C) pathogenic?

TSC2 p.Ser1096Pro (c.3286T>C) is classified Conflicting classifications of pathogenicity in TSC2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-15). AlphaMissense: likely benign (0.0679); Very rare (popmax 0.00267%, afr); Associated with tuberous sclerosis.

What condition is associated with TSC2 p.Ser1096Pro (c.3286T>C)?

TSC2 p.Ser1096Pro (c.3286T>C) is associated with tuberous sclerosis, tuberous sclerosis 2, hereditary neoplastic syndrome (ClinVar).

How common is TSC2 p.Ser1096Pro (c.3286T>C) in the general population?

TSC2 p.Ser1096Pro (c.3286T>C) is very rare (popmax 0.00267%, 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.Ser1096Pro (c.3286T>C)?

AlphaMissense predicts likely benign (score 0.0679) — an in-silico prediction, not a clinical call.

TSC2 p.Ser1096Pro

c.3286T>C · rs755815612 · VCV535856

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0679 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

tuberous sclerosis

Computational evidence

Protein change
AlphaMissense	0.0679	likely benign
REVEL	0.492	indeterminate
SaProt	LLR -6.77	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.21	acceptor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -0.034	GERP -3.1, phastCons 0.26
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	19.05	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 0.00267% African / African-American · 2/74,794 alleles

Filtering AF 0.000444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,609,484 alleles · very rare exomes 1/1,457,516 · genomes 2/151,968 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,397
European (non-Finnish)	8.48e-05%	1,178,702

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.Ser1096Pro
Coding: c.3286T>C
MANE Select: NM_000548
dbSNP: rs755815612
Type: single nucleotide variant
Location: chr16:2079558 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 1096: the 'disordered' region

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

Disease context

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

Also linked: tuberous sclerosis 2 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.Ser1096Cys Uncertain significance ★★ ⚠ same residue
TSC2 p.Ser1096Thr Uncertain significance ★★ ⚠ same residue
TSC2 p.Ser1096= Conflicting classifications of pathogenicity ★ same residue
TSC2 p.Ser1096Phe 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

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-ser1096pro (accessed [today's date]).

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