Is TSC2 p.Arg1032Pro (c.3095G>C) pathogenic?

TSC2 p.Arg1032Pro (c.3095G>C) is classified Pathogenic/Likely pathogenic in TSC2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-16). AlphaMissense: likely pathogenic (0.9987); Absent from gnomAD v4.1; Associated with TSC2-related disorder.

What condition is associated with TSC2 p.Arg1032Pro (c.3095G>C)?

TSC2 p.Arg1032Pro (c.3095G>C) is associated with TSC2-related disorder, tuberous sclerosis, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Arg1032Pro (c.3095G>C) in the general population?

TSC2 p.Arg1032Pro (c.3095G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TSC2 p.Arg1032Pro (c.3095G>C)?

AlphaMissense predicts likely pathogenic (score 0.9987) — an in-silico prediction, not a clinical call.

TSC2 p.Arg1032Pro

c.3095G>C · rs45491698 · VCV49241

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.9987 · 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	0.9987	likely pathogenic ✓ concordant with ClinVar · top 1% in TSC2
REVEL	0.936	strongly pathogenic-leaning
SaProt	LLR -7.34	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	29.8	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.Arg1032Pro
Coding: c.3095G>C
MANE Select: NM_000548
dbSNP: rs45491698
Type: single nucleotide variant
Location: chr16:2079160 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 1032: an α-helix

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.Arg1032Ter Pathogenic ★★ same residue
TSC2 p.Arg1032Gln Uncertain significance ★★ ⚠ same residue
TSC2 p.Arg1032Gly Uncertain significance ★★ ⚠ same residue
TSC2 p.Arg1032_Tyr1033insTer Pathogenic ★★ same residue
TSC2 p.Arg1032fs Pathogenic ★ same residue
TSC2 p.Arg1032= Likely benign ★ same residue
TSC2 c.1257+1G>A Pathogenic ★★ same condition
TSC2 c.1258-2A>G 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-arg1032pro (accessed [today's date]).

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