Is TSC2 p.Pro1450Arg (c.4349C>G) pathogenic?

TSC2 p.Pro1450Arg (c.4349C>G) is classified Conflicting classifications of pathogenicity in TSC2 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-01-13). AlphaMissense: likely benign (0.169); Ultra-rare (popmax 0.0134%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Pro1450Arg (c.4349C>G)?

TSC2 p.Pro1450Arg (c.4349C>G) is associated with hereditary neoplastic syndrome, tuberous sclerosis, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Pro1450Arg (c.4349C>G) in the general population?

TSC2 p.Pro1450Arg (c.4349C>G) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about TSC2 p.Pro1450Arg (c.4349C>G)?

AlphaMissense predicts likely benign (score 0.169) — an in-silico prediction, not a clinical call.

TSC2 p.Pro1450Arg

c.4349C>G · rs45517338 · VCV49293

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.169 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.169	likely benign
REVEL	0.525	indeterminate
SaProt	LLR -6.92	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
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 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	25.8	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

Grpmax group 0.0134% East Asian · 6/44,846 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.000373% 6/1,607,612 alleles · ultra-rare exomes 6/1,455,268 · genomes 0/152,344 · 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.Pro1450Arg
Coding: c.4349C>G
MANE Select: NM_000548
dbSNP: rs45517338
Type: single nucleotide variant
Location: chr16:2084571 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 1450: a UniProt-annotated variant site (in); the 'disordered' region

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: tuberous sclerosis tuberous sclerosis 2

Similar variants

TSC2 p.Pro1450His Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro1450Leu Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro1450= Benign/Likely benign ★★ same residue
TSC2 p.Pro1450Ala Benign/Likely benign ★★ same residue
TSC2 p.Pro1450Ser Conflicting classifications of pathogenicity ★ ⚠ 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-pro1450arg (accessed [today's date]).

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