Is TSC2 p.Pro1305Arg (c.3914C>G) pathogenic?

TSC2 p.Pro1305Arg (c.3914C>G) is classified Conflicting classifications of pathogenicity in TSC2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-30). AlphaMissense: likely benign (0.0743); Very rare (popmax 8.52e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Pro1305Arg (c.3914C>G)?

TSC2 p.Pro1305Arg (c.3914C>G) is associated with hereditary neoplastic syndrome, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Pro1305Arg (c.3914C>G) in the general population?

TSC2 p.Pro1305Arg (c.3914C>G) is very rare (popmax 8.52e-05%, nfe) (gnomAD).

What do computational predictors say about TSC2 p.Pro1305Arg (c.3914C>G)?

AlphaMissense predicts likely benign (score 0.0743) — an in-silico prediction, not a clinical call.

TSC2 p.Pro1305Arg

c.3914C>G · rs45517320 · VCV653658

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0743 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.52e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0743	likely benign
REVEL	0.555	indeterminate
SaProt	LLR -6.87	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 -1.1	GERP -1.8
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	17.27	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 8.52e-05% European (non-Finnish) · 1/1,173,372 alleles

Overall 6.92e-05% 1/1,445,382 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.Pro1305Arg
Coding: c.3914C>G
MANE Select: NM_000548
dbSNP: rs45517320
Type: single nucleotide variant
Location: chr16:2083725 (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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: tuberous sclerosis 2

Similar variants

TSC2 p.Pro1305Gln Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro1305= Benign/Likely benign ★★ same residue
TSC2 p.Pro1305Leu Benign/Likely benign ★★ same residue
TSC2 p.Pro1305Thr 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-pro1305arg (accessed [today's date]).

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