Is TSC2 p.Pro541Arg (c.1622C>G) pathogenic?

TSC2 p.Pro541Arg (c.1622C>G) is classified Conflicting classifications of pathogenicity in TSC2 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-24). AlphaMissense: likely benign (0.136); Ultra-rare (popmax 0.0445%, eas); Associated with lymphangioleiomyomatosis.

What condition is associated with TSC2 p.Pro541Arg (c.1622C>G)?

TSC2 p.Pro541Arg (c.1622C>G) is associated with lymphangioleiomyomatosis, tuberous sclerosis, isolated focal cortical dysplasia type II (ClinVar).

How common is TSC2 p.Pro541Arg (c.1622C>G) in the general population?

TSC2 p.Pro541Arg (c.1622C>G) is ultra-rare (popmax 0.0445%, eas) (gnomAD).

What do computational predictors say about TSC2 p.Pro541Arg (c.1622C>G)?

AlphaMissense predicts likely benign (score 0.136) — an in-silico prediction, not a clinical call.

TSC2 p.Pro541Arg

c.1622C>G · rs752953762 · VCV318313

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.136 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0445%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

lymphangioleiomyomatosis

Computational evidence

Protein change
AlphaMissense	0.136	likely benign
REVEL	0.3	indeterminate
SaProt	LLR -9.07	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.005	GERP -4.2
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	12.03	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 0.0445% East Asian · 20/44,894 alleles

Filtering AF 0.0295% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0246%

Overall 0.00136% 22/1,613,652 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0445%	2,245
European (non-Finnish)	0.000169%	589,998

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.Pro541Arg
Coding: c.1622C>G
MANE Select: NM_000548
dbSNP: rs752953762
Type: single nucleotide variant
Location: chr16:2065541 (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.Pro541Ala Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro541Gln Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro541Leu Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro541Ser Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro541Thr Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro541= 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-pro541arg (accessed [today's date]).

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