Is TSC2 p.Ser664= (c.1992T>C) pathogenic?

TSC2 p.Ser664= (c.1992T>C) is classified Likely benign in TSC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-05). Ultra-rare (popmax 0.0971%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Ser664= (c.1992T>C)?

TSC2 p.Ser664= (c.1992T>C) is associated with hereditary neoplastic syndrome, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Ser664= (c.1992T>C) in the general population?

TSC2 p.Ser664= (c.1992T>C) is ultra-rare (popmax 0.0971%, sas) (gnomAD).

TSC2 p.Ser664=

c.1992T>C · rs1459545137 · VCV702268

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0971%, sas)

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 · T>A here scores Δ0.37 · evaluated, not missing
Constraint at this position
Conservation	phyloP -6.5	GERP -4.5
Overall
CADD	0.109	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0971% South Asian · 70/72,110 alleles

Filtering AF 0.0788% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0721%

Overall 0.0279% 413/1,481,206 alleles · ultra-rare exomes 406/1,369,624 · genomes 7/111,582 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0971%	1,030
Middle Eastern	0.0944%	1,060
Finnishnot grpmax-eligible	0.067%	1,493
Remaining individualsnot grpmax-eligible	0.0384%	2,602
European (non-Finnish)	0.0234%	4,265
Admixed American	0.0161%	6,197
Ashkenazi Jewishnot grpmax-eligible	0.0148%	6,753
African / African-American	0.0102%	9,807
East Asian	0.0048%	20,843

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.Ser664=
Coding: c.1992T>C
MANE Select: NM_000548
dbSNP: rs1459545137
Type: single nucleotide variant
Location: chr16:2071829 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 664: a modified residue (phosphoserine); 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.Ser664Ala Uncertain significance ★★ ⚠ same residue
TSC2 p.Ser664Cys Uncertain significance ★★ ⚠ same residue
TSC2 p.Ser664Tyr Uncertain significance ★★ ⚠ same residue
TSC2 p.Ser664Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Ser664fs Pathogenic ★ 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

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-ser664 (accessed [today's date]).

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