Is TSC2 p.Ala583Ser (c.1747G>T) pathogenic?

TSC2 p.Ala583Ser (c.1747G>T) is classified Uncertain significance in TSC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-13). AlphaMissense: likely benign (0.2875); Very rare (popmax 8.47e-05%, nfe); Associated with tuberous sclerosis 2.

What condition is associated with TSC2 p.Ala583Ser (c.1747G>T)?

TSC2 p.Ala583Ser (c.1747G>T) is associated with tuberous sclerosis 2, hereditary neoplastic syndrome (ClinVar).

How common is TSC2 p.Ala583Ser (c.1747G>T) in the general population?

TSC2 p.Ala583Ser (c.1747G>T) is very rare (popmax 8.47e-05%, nfe) (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.Ala583Ser (c.1747G>T)?

AlphaMissense predicts likely benign (score 0.2875) — an in-silico prediction, not a clinical call.

TSC2 p.Ala583Ser

c.1747G>T · rs1800729 · VCV2564730

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2875 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tuberous sclerosis 2

Computational evidence

Protein change
AlphaMissense	0.2875	likely benign
REVEL	0.665	pathogenic-leaning
SaProt	LLR -7.19	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	23.7	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 8.47e-05% European (non-Finnish) · 1/1,180,036 alleles

Overall 6.2e-05% 1/1,613,420 alleles · very rare exomes 1/1,461,058 · genomes 0/152,362 · 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.Ala583Ser
Coding: c.1747G>T
MANE Select: NM_000548
dbSNP: rs1800729
Type: single nucleotide variant
Location: chr16:2070486 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 583: an α-helix; a UniProt-annotated variant site (in)

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.Ala583Thr Benign/Likely benign ★★ ⚠ same residue
TSC2 p.Ala583Gly Uncertain significance ★ ⚠ same residue
TSC2 p.Ala583Val Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Ala583= Likely benign ★ 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-ala583ser (accessed [today's date]).

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