Is TSC2 p.Pro1042= (c.3126G>A) pathogenic?

TSC2 p.Pro1042= (c.3126G>A) is classified Benign/Likely benign in TSC2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-21). Ultra-rare (popmax 0.0293%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Pro1042= (c.3126G>A)?

TSC2 p.Pro1042= (c.3126G>A) is associated with hereditary neoplastic syndrome, tuberous sclerosis, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Pro1042= (c.3126G>A) in the general population?

TSC2 p.Pro1042= (c.3126G>A) is ultra-rare (popmax 0.0293%, afr) (gnomAD).

TSC2 p.Pro1042=

c.3126G>A · rs36078782 · VCV378786

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0293%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.31	GERP -3.6, phastCons 0.11
Overall
CADD	4.325	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0293% African / African-American · 22/75,016 alleles

Filtering AF 0.0198% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0167%

Overall 0.0026% 42/1,612,872 alleles · ultra-rare exomes 25/1,460,636 · genomes 17/152,236 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0293%	3,410
Remaining individualsnot grpmax-eligible	0.0048%	20,831
East Asian	0.00446%	22,434
South Asian	0.00329%	30,360
European (non-Finnish)	0.00102%	98,334

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.Pro1042=
Coding: c.3126G>A
MANE Select: NM_000548
dbSNP: rs36078782
Type: single nucleotide variant
Location: chr16:2079191 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB

Full TSC2 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 tuberous sclerosis 2

Similar variants

TSC2 p.Pro1042Arg Uncertain significance ★ ⚠ same residue
TSC2 p.Pro1042Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Pro1042Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Pro1042Ser Uncertain significance ★ ⚠ same residue
TSC2 p.Pro1042fs Likely pathogenic ★ same residue
TSC2 p.Pro1042Thr Uncertain significance ★ ⚠ same residue
TSC2 c.1257+1G>A Pathogenic ★★ same condition
TSC2 c.1258-2A>G 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-pro1042 (accessed [today's date]).

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