Is TSC2 p.Ser1653Phe (c.4958C>T) pathogenic?

TSC2 p.Ser1653Phe (c.4958C>T) is classified Conflicting classifications of pathogenicity in TSC2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-10-14). AlphaMissense: likely pathogenic (0.9626); Absent from gnomAD v4.1; Associated with TSC2-related disorder.

What condition is associated with TSC2 p.Ser1653Phe (c.4958C>T)?

TSC2 p.Ser1653Phe (c.4958C>T) is associated with TSC2-related disorder, tuberous sclerosis, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Ser1653Phe (c.4958C>T) in the general population?

TSC2 p.Ser1653Phe (c.4958C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TSC2 p.Ser1653Phe (c.4958C>T)?

AlphaMissense predicts likely pathogenic (score 0.9626) — an in-silico prediction, not a clinical call.

TSC2 p.Ser1653Phe

c.4958C>T · rs45517383 · VCV49336

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9626 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TSC2-related disorder

Computational evidence

Protein change
AlphaMissense	0.9626	likely pathogenic
REVEL	0.906	moderately pathogenic-leaning
SaProt	LLR -16.43	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 1,785 bp · p 3.9e-05 · regional, not allelic
Overall
CADD	24.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TSC2
Protein: p.Ser1653Phe
Coding: c.4958C>T
MANE Select: NM_000548
dbSNP: rs45517383
Type: single nucleotide variant
Location: chr16:2086840 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 1653: the rap-gap domain; a UniProt-annotated variant site (in tsc2); a β-strand

Full TSC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

TSC2-related disorder

Also linked: tuberous sclerosis tuberous sclerosis 2

Similar variants

TSC2 p.Ser1653= Likely benign ★★ same residue
TSC2 p.Ser1653Pro 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
TSC2 c.1361+1G>T Pathogenic/Likely pathogenic ★★ same condition
TSC2 c.1362-1G>A Pathogenic ★★ same condition
TSC2 c.138+2T>C 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-ser1653phe (accessed [today's date]).

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