Is TSC2 p.Pro1777= (c.5331T>C) pathogenic?

TSC2 p.Pro1777= (c.5331T>C) is classified Benign/Likely benign in TSC2 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-01-27). Ultra-rare (popmax 0.02%, afr); Associated with lymphangioleiomyomatosis.

What condition is associated with TSC2 p.Pro1777= (c.5331T>C)?

TSC2 p.Pro1777= (c.5331T>C) is associated with lymphangioleiomyomatosis, tuberous sclerosis, isolated focal cortical dysplasia type II (ClinVar).

How common is TSC2 p.Pro1777= (c.5331T>C) in the general population?

TSC2 p.Pro1777= (c.5331T>C) is ultra-rare (popmax 0.02%, afr) (gnomAD).

TSC2 p.Pro1777=

c.5331T>C · rs370820622 · VCV65127

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, afr)

Conditions

lymphangioleiomyomatosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.5	GERP -2.7
Overall
CADD	0.067	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.02% African / African-American · 15/74,878 alleles

Filtering AF 0.0123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0099%

Overall 0.00242% 39/1,612,478 alleles · ultra-rare exomes 34/1,460,418 · genomes 5/152,060 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.02%	4,992
Remaining individualsnot grpmax-eligible	0.0176%	5,679
Middle Eastern	0.0164%	6,084
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869
Admixed American	0.00167%	59,986
European (non-Finnish)	0.000678%	147,492

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.Pro1777=
Coding: c.5331T>C
MANE Select: NM_000548
dbSNP: rs370820622
Type: single nucleotide variant
Location: chr16:2088517 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 1777: the 'disordered' region

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.Pro1777Ala Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro1777Arg Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro1777His Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro1777Leu Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro1777Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Pro1777fs Uncertain significance ★ 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-pro1777 (accessed [today's date]).

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