# NM_000548.5(TSC2):c.2261del (p.Pro754fs)

https://sugi.bio/variant/tsc2-p-pro754fs

## Summary

**TSC2 p.Pro754fs (c.2261del)** is classified **Pathogenic** in TSC2 (ClinVar, Single submitter, 2 submitters; last evaluated 2020-04-15). No gnomAD frequency available for this variant; Associated with tuberous sclerosis 2.

**At a glance:** Pathogenic · review: Single submitter · rsID rs137854021 · 2 submitters · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the TSC2 gene that is reported as disease-causing, but on limited review, submitted by 2 submitters, and is linked to tuberous sclerosis 2.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 100 000 (Taiwan, Province of China) |
| Clinical trials | 4 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | TSC2 is a diagnostic-grade gene on 21 Genomics England panels |

**Commonly reported features of Tuberous sclerosis complex** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of the kidney — Very frequent (99-80%)
- Atypical behavior — Very frequent (99-80%)
- Seizure — Very frequent (99-80%)
- Cortical dysplasia — Very frequent (99-80%)
- Subependymal nodules — Very frequent (99-80%)
- Cortical tubers — Very frequent (99-80%)
- Hypomelanotic macule — Very frequent (99-80%)
- Generalized abnormality of skin — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015640/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TSC2](https://sugi.bio/atlas/gene/TSC2/) |
| Protein change (HGVS p.) | p.Pro754fs |
| Coding change (HGVS c.) | c.2261del |
| MANE Select transcript | [NM_000548](https://www.ncbi.nlm.nih.gov/nuccore/NM_000548) |
| dbSNP | [rs137854021](https://www.ncbi.nlm.nih.gov/snp/rs137854021/) |
| Variant type | Deletion |
| Location | chr16:2072886-2072886 (GRCh38) |
| ClinVar | [VCV49709](https://www.ncbi.nlm.nih.gov/clinvar/variation/49709/) |

**All HGVS expressions:** `LRG_487:g.28584del`, `LRG_487t1:c.2261del`, `NC_000016.10:g.2072889del`, `NC_000016.9:g.2122890del`, `NG_005895.1:g.28584del`, `NM_000548.5:c.2261del`, `NM_001077183.3:c.2261del`, `NM_001114382.3:c.2261del`, `NM_001318827.2:c.2150del`, `NM_001318829.2:c.2114del`, `NM_001318831.2:c.1661del`, `NM_001318832.2:c.2294del`, `NM_001363528.2:c.2261del`, `NM_001370404.1:c.2261del`, `NM_001370405.1:c.2261del`, `NM_021055.3:c.2261del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 5.347, GERP 1.23, phastCons 0.997 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.203, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 21 of 42**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**TSC2** population constraint: LOEUF 0.203, pLI 1, missense-Z 0.17171; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 68.81, 13% of residues very-high.

**2 experimental structure(s)** (PDB): [7DL2](https://www.rcsb.org/structure/7DL2), [9CE3](https://www.rcsb.org/structure/9CE3).

## What this gene does {#gene-function}

*Describes the biological roles of TSC2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** TSC2's established molecular role includes GTPase activator activity. In Reactome, TSC2 is annotated in disease pathway(s) including **Constitutive Signaling by AKT1 E17K in Cancer**.

**Disease mechanism (Reactome):** TSC2 loss or alteration is curated in [Constitutive Signaling by AKT1 E17K in Cancer](https://reactome.org/content/detail/R-HSA-5674400).

### Pathways affected {#pathways}

TSC2 participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by AKT1 E17K in Cancer](https://reactome.org/content/detail/R-HSA-5674400) | curated |
| [AKT phosphorylates targets in the cytosol](https://reactome.org/content/detail/R-HSA-198323) | curated |
| [Energy dependent regulation of mTOR by LKB1-AMPK](https://reactome.org/content/detail/R-HSA-380972) | curated |
| [Inhibition of TSC complex formation by AKT (PKB)](https://reactome.org/content/detail/R-HSA-165181) | curated |
| [Macroautophagy](https://reactome.org/content/detail/R-HSA-1632852) | curated |
| [TBC/RABGAPs](https://reactome.org/content/detail/R-HSA-8854214) | curated |
| [TP53 Regulates Metabolic Genes](https://reactome.org/content/detail/R-HSA-5628897) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** GTPase activator activity, phosphatase binding, small GTPase binding, protein homodimerization activity, Hsp90 protein binding.

**Biological process:** cellular response to starvation, positive regulation of macroautophagy, negative regulation of TOR signaling, anoikis, negative regulation of TORC1 signaling.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-04-15.

**Submitter consensus:** conflicting (1 not provided, 1 Pathogenic).

**Submission history:** 2 submissions (2020); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Tuberous sclerosis database (TSC2) | not provided | no classification provided | curation |  |
| Revvity Omics, Revvity | Pathogenic | criteria provided, single submitter | clinical testing | 2020-04-15 |

## Associated conditions {#conditions}

[tuberous sclerosis 2](https://sugi.bio/atlas/disease/tuberous-sclerosis-2/), [tuberous sclerosis](https://sugi.bio/atlas/disease/tuberous-sclerosis/).

**Reported phenotype names (ClinVar):** Tuberous sclerosis 2, Tuberous sclerosis syndrome, Tuberous Sclerosis Complex, Tuberous sclerosis.

## Similar variants {#similar}

Related TSC2 variant pages (same residue, condition, or type): [TSC2 p.Pro754Ala](/variant/tsc2-p-pro754ala), [TSC2 p.Pro754Arg](/variant/tsc2-p-pro754arg), [TSC2 p.Pro754=](/variant/tsc2-p-pro754), [TSC2 p.Pro754Leu](/variant/tsc2-p-pro754leu), [TSC2 p.Pro754Ser](/variant/tsc2-p-pro754ser), [TSC2 c.1945_1946+4del](/variant/tsc2-c-1945-1946-plus-4del), [TSC2 c.2355+2_2355+5del](/variant/tsc2-c-2355-plus-2-2355-plus-5del), [TSC2 c.5252_5259+19del](/variant/tsc2-c-5252-5259-plus-19del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 49709). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*