Is TSC2 p.Pro605= (c.1815A>G) pathogenic?

TSC2 p.Pro605= (c.1815A>G) is classified Benign/Likely benign in TSC2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-06-22). Very rare (popmax 0.004%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Pro605= (c.1815A>G)?

TSC2 p.Pro605= (c.1815A>G) is associated with hereditary neoplastic syndrome, tuberous sclerosis, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Pro605= (c.1815A>G) in the general population?

TSC2 p.Pro605= (c.1815A>G) is very rare (popmax 0.004%, afr) (gnomAD).

TSC2 p.Pro605=

c.1815A>G · rs961687056 · VCV382665

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

very rare (popmax 0.004%, 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 0.61	GERP -0.065, phastCons 1
Overall
CADD	7.332	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,946 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000248% 4/1,613,056 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,982
Remaining individualsnot grpmax-eligible	0.0016%	62,476

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.Pro605=
Coding: c.1815A>G
MANE Select: NM_000548
dbSNP: rs961687056
Type: single nucleotide variant
Location: chr16:2070554 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 605: an α-helix

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.Pro605Ala Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro605Leu Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro605Ser Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro605Thr 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-pro605 (accessed [today's date]).

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