Is TSC1 p.Pro311Arg (c.932C>G) pathogenic?

TSC1 p.Pro311Arg (c.932C>G) is classified Conflicting classifications of pathogenicity in TSC1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-11-28). AlphaMissense: likely benign (0.1303); Ultra-rare (popmax 0.0125%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC1 p.Pro311Arg (c.932C>G)?

TSC1 p.Pro311Arg (c.932C>G) is associated with hereditary neoplastic syndrome, tuberous sclerosis, tuberous sclerosis 1 (ClinVar).

How common is TSC1 p.Pro311Arg (c.932C>G) in the general population?

TSC1 p.Pro311Arg (c.932C>G) is ultra-rare (popmax 0.0125%, afr) (gnomAD).

What do computational predictors say about TSC1 p.Pro311Arg (c.932C>G)?

AlphaMissense predicts likely benign (score 0.1303) — an in-silico prediction, not a clinical call.

TSC1 p.Pro311Arg

c.932C>G · rs776158460 · VCV231741

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1303 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0125%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1303	likely benign
REVEL	0.805	moderately pathogenic-leaning
SaProt	LLR -8.82	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 23 kb · p 5.3e-09 · regional, not allelic
Overall
CADD	26.5	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 0.0125% African / African-American · 9/72,102 alleles

Filtering AF 0.00645% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.00127% 20/1,579,402 alleles · ultra-rare exomes 16/1,435,298 · genomes 4/144,104 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0125%	8,011
Admixed American	0.00174%	57,380
European (non-Finnish)	0.000861%	116,138

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: TSC1
Protein: p.Pro311Arg
Coding: c.932C>G
MANE Select: NM_000368
dbSNP: rs776158460
Type: single nucleotide variant
Location: chr9:132911550 (GRCh38)
Gene constraint: LOEUF 0.227 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.55 · 5 PDB
Residue 311: a UniProt-annotated variant site (in tsc1)

Full TSC1 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 tuberous sclerosis 1

Similar variants

TSC1 p.Pro311His Uncertain significance ★★ ⚠ same residue
TSC1 p.Pro311Leu Uncertain significance ★★ ⚠ same residue
TSC1 p.Pro311Ser Uncertain significance ★★ ⚠ same residue
TSC1 p.Pro311Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC1 p.Pro311Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC1 p.Pro311fs Pathogenic ★ same residue
TSC1 c.1029+1G>A Pathogenic/Likely pathogenic ★★ same condition
TSC1 c.1029+1G>C 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/tsc1-p-pro311arg (accessed [today's date]).

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