Is TSC2 p.Ser1799Pro (c.5395T>C) pathogenic?

TSC2 p.Ser1799Pro (c.5395T>C) is classified Benign in TSC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-06). AlphaMissense: ambiguous (0.352); Very rare (popmax 0.00667%, amr); Associated with tuberous sclerosis 2.

What condition is associated with TSC2 p.Ser1799Pro (c.5395T>C)?

TSC2 p.Ser1799Pro (c.5395T>C) is associated with tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Ser1799Pro (c.5395T>C) in the general population?

TSC2 p.Ser1799Pro (c.5395T>C) is very rare (popmax 0.00667%, amr) (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.Ser1799Pro (c.5395T>C)?

AlphaMissense predicts ambiguous (score 0.352) — an in-silico prediction, not a clinical call.

TSC2 p.Ser1799Pro

c.5395T>C · rs1231583517 · VCV468167

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.352 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

tuberous sclerosis 2

Computational evidence

Protein change
AlphaMissense	0.352	ambiguous
REVEL	0.653	pathogenic-leaning
SaProt	LLR -7.38	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 0.75, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 1,785 bp · p 3.9e-05 · regional, not allelic
Overall
CADD	21.6	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 0.00667% Admixed American · 4/60,010 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000249% 4/1,608,028 alleles · very rare exomes 4/1,455,750 · genomes 0/152,278 · 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.Ser1799Pro
Coding: c.5395T>C
MANE Select: NM_000548
dbSNP: rs1231583517
Type: single nucleotide variant
Location: chr16:2088581 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 1799: a modified residue (phosphoserine)

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

For Tuberous sclerosis complex (Orphanet):

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

Similar variants

TSC2 p.Ser1799Ala Uncertain significance ★★ ⚠ same residue
TSC2 p.Ser1799= Benign/Likely benign ★★ same residue
TSC2 p.Ser1799Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Ser1799Trp Uncertain significance ★ ⚠ same residue
TSC2 p.Ser1799del 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

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-ser1799pro (accessed [today's date]).

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