Is TSC2 p.Pro91Ser (c.271C>T) pathogenic?

TSC2 p.Pro91Ser (c.271C>T) is classified Uncertain significance in TSC2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-07-07). AlphaMissense: likely benign (0.1499); Very rare (popmax 6.95e-05%); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Pro91Ser (c.271C>T)?

TSC2 p.Pro91Ser (c.271C>T) is associated with hereditary neoplastic syndrome, isolated focal cortical dysplasia type II, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Pro91Ser (c.271C>T) in the general population?

TSC2 p.Pro91Ser (c.271C>T) is very rare (popmax 6.95e-05%) (gnomAD).

What do computational predictors say about TSC2 p.Pro91Ser (c.271C>T)?

AlphaMissense predicts likely benign (score 0.1499) — an in-silico prediction, not a clinical call.

TSC2 p.Pro91Ser

c.271C>T · rs1555496979 · VCV535967

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1499 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.95e-05%)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1499	likely benign
REVEL	0.374	indeterminate
SaProt	LLR -8.87	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 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.95e-05%

Overall 6.95e-05% 1/1,439,442 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.Pro91Ser
Coding: c.271C>T
MANE Select: NM_000548
dbSNP: rs1555496979
Type: single nucleotide variant
Location: chr16:2053387 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 91: the 'required for interaction with tsc1' region

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: isolated focal cortical dysplasia type II tuberous sclerosis 2

Similar variants

TSC2 p.Pro91Thr Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro91= Benign/Likely benign ★★ same residue
TSC2 p.Pro91Leu Benign/Likely benign ★★ 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
TSC2 c.1362-1G>A 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-pro91ser (accessed [today's date]).

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