Is TSC2 p.Pro378Arg (c.1133C>G) pathogenic?

TSC2 p.Pro378Arg (c.1133C>G) is classified Uncertain significance in TSC2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0991); Very rare (popmax 0.000169%, nfe); Associated with isolated focal cortical dysplasia type II.

What condition is associated with TSC2 p.Pro378Arg (c.1133C>G)?

TSC2 p.Pro378Arg (c.1133C>G) is associated with isolated focal cortical dysplasia type II, lymphangioleiomyomatosis, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Pro378Arg (c.1133C>G) in the general population?

TSC2 p.Pro378Arg (c.1133C>G) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about TSC2 p.Pro378Arg (c.1133C>G)?

AlphaMissense predicts likely benign (score 0.0991) — an in-silico prediction, not a clinical call.

TSC2 p.Pro378Arg

c.1133C>G · rs45517154 · VCV237959

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0991 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

isolated focal cortical dysplasia type II

Computational evidence

Protein change
AlphaMissense	0.0991	likely benign
REVEL	0.425	indeterminate
SaProt	LLR -7.99	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 1.8	GERP 0.99, phastCons 0.93
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	17.98	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,024 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,132 alleles · very rare exomes 2/1,461,832 · genomes 0/152,300 · 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.Pro378Arg
Coding: c.1133C>G
MANE Select: NM_000548
dbSNP: rs45517154
Type: single nucleotide variant
Location: chr16:2061884 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 378: an α-helix; the 'required for interaction with tsc1' region; a UniProt-annotated variant site (in)

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

Disease context

isolated focal cortical dysplasia type II — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: lymphangioleiomyomatosis tuberous sclerosis 2 hereditary neoplastic syndrome

For Isolated focal cortical dysplasia (Orphanet):

Onset: All ages

Similar variants

TSC2 p.Pro378= Conflicting classifications of pathogenicity ★ same residue
TSC2 p.Pro378Ala Uncertain significance ★ ⚠ same residue
TSC2 p.Pro378Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Pro378Ser Uncertain significance ★ ⚠ 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
TSC2 c.1361+1G>T 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-pro378arg (accessed [today's date]).

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