Is TSC2 p.Pro1227= (c.3681C>A) pathogenic?

TSC2 p.Pro1227= (c.3681C>A) is classified Benign/Likely benign in TSC2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-04-01). Ultra-rare (popmax 0.0366%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Pro1227= (c.3681C>A)?

TSC2 p.Pro1227= (c.3681C>A) is associated with hereditary neoplastic syndrome, tuberous sclerosis, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Pro1227= (c.3681C>A) in the general population?

TSC2 p.Pro1227= (c.3681C>A) is ultra-rare (popmax 0.0366%, amr) (gnomAD).

TSC2 p.Pro1227=

c.3681C>A · rs181279399 · VCV379631

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0366%, amr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.32 · evaluated, not missing
Constraint at this position
Conservation	phyloP -11	GERP -3.2
Overall
CADD	0.17	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0366% Admixed American · 22/60,032 alleles

Filtering AF 0.0248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0209%

Overall 0.00539% 87/1,612,982 alleles · ultra-rare exomes 76/1,460,616 · genomes 11/152,366 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0366%	2,729
Remaining individualsnot grpmax-eligible	0.008%	12,498
European (non-Finnish)	0.00508%	19,667

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.Pro1227=
Coding: c.3681C>A
MANE Select: NM_000548
dbSNP: rs181279399
Type: single nucleotide variant
Location: chr16:2081665 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 1227: a UniProt-annotated variant site (in tsc2)

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.Pro1227Leu Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro1227Ser Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro1227His Uncertain significance ★ ⚠ same residue
TSC2 p.Pro1227_Leu1228del Uncertain significance ★★ 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-pro1227 (accessed [today's date]).

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