Is TSC1 p.Ser1012Pro (c.3034T>C) pathogenic?

TSC1 p.Ser1012Pro (c.3034T>C) is classified Conflicting classifications of pathogenicity in TSC1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-06-04). AlphaMissense: likely benign (0.0641); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with TSC1 p.Ser1012Pro (c.3034T>C)?

TSC1 p.Ser1012Pro (c.3034T>C) is associated with hereditary neoplastic syndrome, tuberous sclerosis 1, lymphangioleiomyomatosis (ClinVar).

How common is TSC1 p.Ser1012Pro (c.3034T>C) in the general population?

TSC1 p.Ser1012Pro (c.3034T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TSC1 p.Ser1012Pro (c.3034T>C)?

AlphaMissense predicts likely benign (score 0.0641) — an in-silico prediction, not a clinical call.

TSC1 p.Ser1012Pro

c.3034T>C · rs764979889 · VCV466112

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0641 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0641	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -6.90	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 0.35	GERP -0.44
Regional constraint	o/e 0.85	unconstrained · MANE · 4,532 bp · p 0.0028 · regional, not allelic
Overall
CADD	12.31	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TSC1
Protein: p.Ser1012Pro
Coding: c.3034T>C
MANE Select: NM_000368
dbSNP: rs764979889
Type: single nucleotide variant
Location: chr9:132896696 (GRCh38)
Gene constraint: LOEUF 0.227 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.55 · 5 PDB
Residue 1012: the 'disordered' 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 lymphangioleiomyomatosis isolated focal cortical dysplasia type II

Similar variants

TSC1 p.Ser1012Cys Uncertain significance ★★ ⚠ same residue
TSC1 p.Ser1012Thr Likely benign ★★ same residue
TSC1 p.Ser1012Phe Uncertain significance ★ ⚠ same residue
TSC1 p.Ser1012fs 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
TSC1 c.1141+1G>A 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-ser1012pro (accessed [today's date]).

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