Is TSC2 p.Arg718Pro (c.2153G>C) pathogenic?

TSC2 p.Arg718Pro (c.2153G>C) is classified Conflicting classifications of pathogenicity in TSC2 (ClinVar, Conflicting submitters, 15 submitters; last evaluated 2026-03-02). AlphaMissense: likely pathogenic (0.8441); Very rare (popmax 0.0028%, nfe); Associated with lymphangioleiomyomatosis.

What condition is associated with TSC2 p.Arg718Pro (c.2153G>C)?

TSC2 p.Arg718Pro (c.2153G>C) is associated with lymphangioleiomyomatosis, tuberous sclerosis, isolated focal cortical dysplasia type II (ClinVar).

How common is TSC2 p.Arg718Pro (c.2153G>C) in the general population?

TSC2 p.Arg718Pro (c.2153G>C) is very rare (popmax 0.0028%, nfe) (gnomAD).

What do computational predictors say about TSC2 p.Arg718Pro (c.2153G>C)?

AlphaMissense predicts likely pathogenic (score 0.8441) — an in-silico prediction, not a clinical call.

TSC2 p.Arg718Pro

c.2153G>C · rs45517215 · VCV49597

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 15 submitters

AlphaMissense

likely pathogenic

0.8441 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0028%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lymphangioleiomyomatosis

Computational evidence

Protein change
AlphaMissense	0.8441	likely pathogenic
REVEL	0.767	pathogenic-leaning
SaProt	LLR -5.76	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 9.8	GERP 0.81, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	25.9	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 0.0028% European (non-Finnish) · 33/1,180,046 alleles

Filtering AF 0.00199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00175%

Overall 0.00985% 159/1,613,990 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.375%	267
Remaining individualsnot grpmax-eligible	0.0224%	4,463
European (non-Finnish)grpmax	0.0028%	35,759
Admixed American	0.00167%	60,004

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg718Pro
Coding: c.2153G>C
MANE Select: NM_000548
dbSNP: rs45517215
Type: single nucleotide variant
Location: chr16:2072296 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB

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

Disease context

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

Also linked: tuberous sclerosis isolated focal cortical dysplasia type II tuberous sclerosis 2 hereditary neoplastic syndrome

For Perivascular epithelioid cell neoplasm (Orphanet):

Onset: Adolescent, Adult, Childhood, Elderly

Similar variants

TSC2 p.Arg718Leu Uncertain significance ★★ ⚠ same residue
TSC2 p.Arg718= Benign/Likely benign ★★ same residue
TSC2 p.Arg718Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Arg718His Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Arg718Ser 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-arg718pro (accessed [today's date]).

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