Is TSC2 p.Cys244Arg (c.730T>C) pathogenic?

TSC2 p.Cys244Arg (c.730T>C) is classified Pathogenic in TSC2 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-06-26). AlphaMissense: likely pathogenic (0.9981); Absent from gnomAD v4.1; Associated with tuberous sclerosis.

What condition is associated with TSC2 p.Cys244Arg (c.730T>C)?

TSC2 p.Cys244Arg (c.730T>C) is associated with tuberous sclerosis (ClinVar).

How common is TSC2 p.Cys244Arg (c.730T>C) in the general population?

TSC2 p.Cys244Arg (c.730T>C) is absent from gnomAD v4.1 (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.Cys244Arg (c.730T>C)?

AlphaMissense predicts likely pathogenic (score 0.9981) — an in-silico prediction, not a clinical call.

TSC2 p.Cys244Arg

c.730T>C · rs137854101 · VCV49896

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9981 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tuberous sclerosis

Computational evidence

Protein change
AlphaMissense	0.9981	likely pathogenic ✓ concordant with ClinVar · top 1% in TSC2
REVEL	0.902	moderately pathogenic-leaning
SaProt	LLR -14.47	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 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	24.1	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.Cys244Arg
Coding: c.730T>C
MANE Select: NM_000548
dbSNP: rs137854101
Type: single nucleotide variant
Location: chr16:2056725 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 244: an α-helix; the 'required for interaction with tsc1' region

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

Disease context

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

For Tuberous sclerosis complex (Orphanet):

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

Similar variants

TSC2 p.Cys244fs Pathogenic ★ same residue
TSC2 c.1257+1G>A Pathogenic ★★ same condition
TSC2 c.1361+1G>A Pathogenic/Likely pathogenic ★★ same condition
TSC2 c.1362-1G>A Pathogenic ★★ same condition
TSC2 c.138+2T>C Pathogenic ★★ same condition
TSC2 c.138+5G>A Pathogenic/Likely pathogenic ★★ same condition
TSC2 c.1443+5G>C Pathogenic/Likely pathogenic ★★ same condition
TSC2 c.1444-1G>A 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-cys244arg (accessed [today's date]).

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