Is TSC2 p.Pro952Thr (c.2854C>A) pathogenic?

TSC2 p.Pro952Thr (c.2854C>A) is classified Uncertain significance in TSC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-23). AlphaMissense: likely benign (0.0628); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Pro952Thr (c.2854C>A)?

TSC2 p.Pro952Thr (c.2854C>A) is associated with hereditary neoplastic syndrome, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Pro952Thr (c.2854C>A) in the general population?

TSC2 p.Pro952Thr (c.2854C>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about TSC2 p.Pro952Thr (c.2854C>A)?

AlphaMissense predicts likely benign (score 0.0628) — an in-silico prediction, not a clinical call.

TSC2 p.Pro952Thr

c.2854C>A · rs745456980 · VCV486683

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0628 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0628	likely benign
REVEL	0.465	indeterminate
SaProt	LLR -6.37	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 1.7	GERP 0.65, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	14.55	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 8.47e-05% European (non-Finnish) · 1/1,179,992 alleles

Overall 6.2e-05% 1/1,613,116 alleles · very rare exomes 1/1,460,830 · genomes 0/152,286 · joint denominator

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.Pro952Thr
Coding: c.2854C>A
MANE Select: NM_000548
dbSNP: rs745456980
Type: single nucleotide variant
Location: chr16:2077614 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 952: the 'disordered' 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: tuberous sclerosis 2

Similar variants

TSC2 p.Pro952Ala Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro952Arg Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro952His Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro952Leu Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro952= Benign/Likely benign ★★ same residue
TSC2 p.Pro952Ser Conflicting classifications of pathogenicity ★ ⚠ 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-pro952thr (accessed [today's date]).

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