Is TSC2 p.Pro910Arg (c.2729C>G) pathogenic?

TSC2 p.Pro910Arg (c.2729C>G) is classified Uncertain significance in TSC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-12). AlphaMissense: ambiguous (0.4874); Very rare (popmax 8.47e-05%, nfe); Associated with tuberous sclerosis 2.

What condition is associated with TSC2 p.Pro910Arg (c.2729C>G)?

TSC2 p.Pro910Arg (c.2729C>G) is associated with tuberous sclerosis 2, tuberous sclerosis, hereditary neoplastic syndrome (ClinVar).

How common is TSC2 p.Pro910Arg (c.2729C>G) in the general population?

TSC2 p.Pro910Arg (c.2729C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Tuberous sclerosis complex inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TSC2 p.Pro910Arg (c.2729C>G)?

AlphaMissense predicts ambiguous (score 0.4874) — an in-silico prediction, not a clinical call.

TSC2 p.Pro910Arg

c.2729C>G · rs2089329428 · VCV1795258

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4874 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

tuberous sclerosis 2

Computational evidence

Protein change
AlphaMissense	0.4874	ambiguous
REVEL	0.592	indeterminate
SaProt	LLR -10.28	damaging
Splicing
SpliceAI	Δ0.21	donor gain, 13 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 5.9	GERP 0.81, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	24.3	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 8.47e-05% European (non-Finnish) · 1/1,180,016 alleles

Overall 6.84e-05% 1/1,461,476 alleles · very rare

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.Pro910Arg
Coding: c.2729C>G
MANE Select: NM_000548
dbSNP: rs2089329428
Type: single nucleotide variant
Location: chr16:2076157 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 910: an α-helix

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

Disease context

tuberous sclerosis 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: tuberous sclerosis hereditary neoplastic syndrome

For Tuberous sclerosis complex (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-9 / 100 000 (Taiwan, Province of China)

Similar variants

TSC2 p.Pro910Leu Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro910Ser Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro910His Uncertain significance ★ same residue
TSC2 p.Pro910Thr Uncertain significance ★ ⚠ same residue
TSC2 p.Pro910fs Pathogenic ★ same residue
TSC2 p.Pro910Ile 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-pro910arg (accessed [today's date]).

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