Is TSC2 p.Ala675= (c.2025A>G) pathogenic?

TSC2 p.Ala675= (c.2025A>G) is classified Benign/Likely benign in TSC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-16). Very rare (popmax 0.00462%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Ala675= (c.2025A>G)?

TSC2 p.Ala675= (c.2025A>G) is associated with hereditary neoplastic syndrome, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Ala675= (c.2025A>G) in the general population?

TSC2 p.Ala675= (c.2025A>G) is very rare (popmax 0.00462%, afr) (gnomAD).

TSC2 p.Ala675=

c.2025A>G · rs766113544 · VCV1091343

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00462%, 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 -3.4	GERP -4.5
Overall
CADD	0.277	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00462% African / African-American · 3/64,984 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00064%

Overall 0.000866% 13/1,501,626 alleles · very rare exomes 10/1,369,230 · genomes 3/132,396 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00462%	21,661
Admixed American	0.00416%	24,011
Ashkenazi Jewishnot grpmax-eligible	0.0038%	26,322
European (non-Finnish)	0.000619%	161,505

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.Ala675=
Coding: c.2025A>G
MANE Select: NM_000548
dbSNP: rs766113544
Type: single nucleotide variant
Location: chr16:2071862 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 675: the 'disordered' region

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 2

Similar variants

TSC2 p.Ala675Val Uncertain significance ★★ ⚠ same residue
TSC2 p.Ala675Glu Uncertain significance ★ ⚠ same residue
TSC2 p.Ala675Pro Uncertain significance ★ ⚠ same residue
TSC2 p.Ala675Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Ala675Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Ala675Leu 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-ala675 (accessed [today's date]).

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