Is TSC2 p.Arg1745Pro (c.5234G>C) pathogenic?

TSC2 p.Arg1745Pro (c.5234G>C) is classified Likely pathogenic in TSC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-23). AlphaMissense: likely pathogenic (0.9989); Absent from gnomAD v4.1; Associated with TSC2-related disorder.

What condition is associated with TSC2 p.Arg1745Pro (c.5234G>C)?

TSC2 p.Arg1745Pro (c.5234G>C) is associated with TSC2-related disorder (ClinVar).

How common is TSC2 p.Arg1745Pro (c.5234G>C) in the general population?

TSC2 p.Arg1745Pro (c.5234G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TSC2 p.Arg1745Pro (c.5234G>C)?

AlphaMissense predicts likely pathogenic (score 0.9989) — an in-silico prediction, not a clinical call.

TSC2 p.Arg1745Pro

c.5234G>C · VCV4927482

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9989 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TSC2-related disorder

Computational evidence

Protein change
AlphaMissense	0.9989	likely pathogenic ✓ concordant with ClinVar · top 1% in TSC2
REVEL	0.922	moderately pathogenic-leaning
SaProt	LLR -9.46	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 1,785 bp · p 3.9e-05 · regional, not allelic
Overall
CADD	32.0	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.Arg1745Pro
Coding: c.5234G>C
MANE Select: NM_000548
Type: single nucleotide variant
Location: chr16:2088300 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 1745: the rap-gap domain; an α-helix

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

Disease context

TSC2-related disorder

Similar variants

TSC2 p.Arg1745Leu Uncertain significance ★★ ⚠ same residue
TSC2 p.Arg1745Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Arg1745His Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Arg1745= Likely benign ★ same residue
TSC2 c.1444-2A>G Pathogenic/Likely pathogenic ★★ same condition
TSC2 c.1946+1G>A Pathogenic ★★ same condition
TSC2 c.2356-1G>T Pathogenic/Likely pathogenic ★★ same condition
TSC2 c.2838-122G>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-arg1745pro (accessed [today's date]).

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