Is TSC1 p.Pro583Ser (c.1747C>T) pathogenic?

TSC1 p.Pro583Ser (c.1747C>T) is classified Uncertain significance in TSC1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-25). AlphaMissense: likely benign (0.2686); Very rare (popmax 0.000254%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC1 p.Pro583Ser (c.1747C>T)?

TSC1 p.Pro583Ser (c.1747C>T) is associated with hereditary neoplastic syndrome, tuberous sclerosis 1 (ClinVar).

How common is TSC1 p.Pro583Ser (c.1747C>T) in the general population?

TSC1 p.Pro583Ser (c.1747C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about TSC1 p.Pro583Ser (c.1747C>T)?

AlphaMissense predicts likely benign (score 0.2686) — an in-silico prediction, not a clinical call.

TSC1 p.Pro583Ser

c.1747C>T · rs2131827202 · VCV1779321

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2686 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2686	likely benign
REVEL	0.613	indeterminate
SaProt	LLR -6.51	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 4,448 bp · p 0.00013 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,956 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,146 alleles · very rare exomes 3/1,461,782 · genomes 0/152,364 · 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: TSC1
Protein: p.Pro583Ser
Coding: c.1747C>T
MANE Select: NM_000368
dbSNP: rs2131827202
Type: single nucleotide variant
Location: chr9:132905831 (GRCh38)
Gene constraint: LOEUF 0.227 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.55 · 5 PDB
Residue 583: the 'mediates interaction with wdr45b' region; a UniProt-annotated variant site (in tsc1)

Full TSC1 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

Also linked: tuberous sclerosis 1

Similar variants

TSC1 p.Pro583Ala Uncertain significance ★★ ⚠ same residue
TSC1 p.Pro583= Benign/Likely benign ★★ same residue
TSC1 p.Pro583Arg Uncertain significance ★ ⚠ same residue
TSC1 p.Pro583Leu Uncertain significance ★ ⚠ same residue
TSC1 p.Pro583Thr Uncertain significance ★ ⚠ same residue
TSC1 c.1029+1G>A Pathogenic/Likely pathogenic ★★ same condition
TSC1 c.1029+1G>C Pathogenic/Likely pathogenic ★★ same condition
TSC1 c.107-1G>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/tsc1-p-pro583ser (accessed [today's date]).

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