Is TSC2 p.Ser664Phe (c.1991C>T) pathogenic?

TSC2 p.Ser664Phe (c.1991C>T) is classified Conflicting classifications of pathogenicity in TSC2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-18). AlphaMissense: ambiguous (0.4643); Very rare (popmax 0.00134%, afr); Associated with tuberous sclerosis 2.

What condition is associated with TSC2 p.Ser664Phe (c.1991C>T)?

TSC2 p.Ser664Phe (c.1991C>T) is associated with tuberous sclerosis 2, hereditary neoplastic syndrome (ClinVar).

How common is TSC2 p.Ser664Phe (c.1991C>T) in the general population?

TSC2 p.Ser664Phe (c.1991C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

How is Tuberous sclerosis complex inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TSC2 p.Ser664Phe (c.1991C>T)?

AlphaMissense predicts ambiguous (score 0.4643) — an in-silico prediction, not a clinical call.

TSC2 p.Ser664Phe

c.1991C>T · rs991714565 · VCV647861

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4643 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

tuberous sclerosis 2

Computational evidence

Protein change
AlphaMissense	0.4643	ambiguous
REVEL	0.684	pathogenic-leaning
SaProt	LLR -9.45	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,662 alleles

Overall 6.26e-05% 1/1,598,084 alleles · very rare exomes 1/1,445,894 · genomes 0/152,190 · joint denominator

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.Ser664Phe
Coding: c.1991C>T
MANE Select: NM_000548
dbSNP: rs991714565
Type: single nucleotide variant
Location: chr16:2071828 (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

tuberous sclerosis 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Tuberous sclerosis complex (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-9 / 100 000 (Taiwan, Province of China)

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.Ser664= Likely benign ★★ 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-ser664phe (accessed [today's date]).

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