# NM_000368.5(TSC1):c.1196del (p.Pro399fs)

https://sugi.bio/variant/tsc1-p-pro399fs

## Summary

**TSC1 p.Pro399fs (c.1196del)** is classified **Pathogenic** in TSC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-02). Associated with tuberous sclerosis 1.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the TSC1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to tuberous sclerosis 1.

*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 | TSC1 is a diagnostic-grade gene on 20 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/0015121/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TSC1](https://sugi.bio/atlas/gene/TSC1/) |
| Protein change (HGVS p.) | p.Pro399fs |
| Coding change (HGVS c.) | c.1196del |
| MANE Select transcript | [NM_000368](https://www.ncbi.nlm.nih.gov/nuccore/NM_000368) |
| Variant type | Deletion |
| Location | chr9:132910638-132910638 (GRCh38) |
| ClinVar | [VCV3643111](https://www.ncbi.nlm.nih.gov/clinvar/variation/3643111/) |

**All HGVS expressions:** `LRG_486:g.38996del`, `LRG_486t1:c.1193del`, `NC_000009.11:g.135786028del`, `NC_000009.12:g.132910641del`, `NG_012386.1:g.38996del`, `NM_000368.5:c.1196del`, `NM_001162426.2:c.1193del`, `NM_001162427.2:c.1043del`, `NM_001362177.2:c.833del`, `NM_001406592.1:c.1196del`, `NM_001406593.1:c.1196del`, `NM_001406594.1:c.1196del`, `NM_001406595.1:c.1196del`, `NM_001406596.1:c.1196del`, `NM_001406597.1:c.1193del`, `NM_001406598.1:c.1193del`, `NM_001406599.1:c.1193del`, `NM_001406600.1:c.1193del`, `NM_001406601.1:c.1196del`, `NM_001406602.1:c.1196del`, `NM_001406603.1:c.1193del`, `NM_001406604.1:c.1193del`, `NM_001406605.1:c.1196del`, `NM_001406606.1:c.1196del`, `NM_001406607.1:c.1196del`, `NM_001406608.1:c.1193del`, `NM_001406609.1:c.1193del`, `NM_001406610.1:c.1043del`, `NM_001406611.1:c.1040del`, `NM_001406612.1:c.1040del`, `NM_001406613.1:c.1040del`, `NM_001406614.1:c.833del`, `NM_001406615.1:c.833del`, `NM_001406616.1:c.833del`, `NM_001406617.1:c.833del`, `NM_001406618.1:c.833del`, `NM_001406619.1:c.833del`, `NM_001406620.1:c.830del`, `NM_001406621.1:c.830del`, `NM_001406622.1:c.830del`, `NM_001406623.1:c.830del`, `NM_001406624.1:c.833del`, `NM_001406625.1:c.830del`, `NM_001406626.1:c.245del`, `NM_001406627.1:c.242del`, `NM_001406628.1:c.242del`, `NM_001406629.1:c.143del`, `NM_001406630.1:c.143del`, `NR_176214.1:n.1413del`, `NR_176215.1:n.1413del`, `NR_176216.1:n.1280del`, `NR_176217.1:n.1410del`, `NR_176218.1:n.1413del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 -12.699, GERP -3.88 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.227, 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 12 of 23**, 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.

*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}

**TSC1** population constraint: LOEUF 0.227, pLI 1, missense-Z 3.7116; 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}

Residue **399** lies in a UniProt-annotated variant site (in tsc1).

AlphaFold model confidence (whole protein): pLDDT 63.55, 26% of residues very-high.

**5 experimental structure(s)** (PDB): [4Z6Y](https://www.rcsb.org/structure/4Z6Y), [5EJC](https://www.rcsb.org/structure/5EJC), [7DL2](https://www.rcsb.org/structure/7DL2), [9C9I](https://www.rcsb.org/structure/9C9I), [9CE3](https://www.rcsb.org/structure/9CE3).

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

*Describes the biological roles of TSC1 (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:** TSC1's established molecular role includes Hsp70 protein binding.


### Pathways affected {#pathways}

TSC1 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [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:** Hsp70 protein binding, ATPase inhibitor activity, protein folding chaperone, protein-folding chaperone binding, Hsp90 protein binding.

**Biological process:** regulation of cell-matrix adhesion, cell-matrix adhesion, negative regulation of cell population proliferation, cellular response to starvation, negative regulation of TOR signaling, negative regulation of ATP-dependent activity.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-05-02.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-05-02 |

## Associated conditions {#conditions}

[tuberous sclerosis 1](https://sugi.bio/atlas/disease/tuberous-sclerosis-1/).

**Reported phenotype names (ClinVar):** Tuberous sclerosis 1.

## Same-residue context {#hotspot}

Residue **399** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [TSC1 p.Pro399Ter](/variant/tsc1-p-pro399ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related TSC1 variant pages (same residue, condition, or type): [TSC1 p.Pro399Ala](/variant/tsc1-p-pro399ala), [TSC1 p.Pro399Ser](/variant/tsc1-p-pro399ser), [TSC1 p.Pro399=](/variant/tsc1-p-pro399), [TSC1 p.Pro399Leu](/variant/tsc1-p-pro399leu), [TSC1 p.Ala283fs](/variant/tsc1-p-ala283fs), [TSC1 p.Ala398fs](/variant/tsc1-p-ala398fs), [TSC1 p.Arg429fs](/variant/tsc1-p-arg429fs), [TSC1 p.Arg570fs](/variant/tsc1-p-arg570fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 3643111). 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.*