# NM_000368.5(TSC1):c.1236C>T (p.Pro412=)

https://sugi.bio/variant/tsc1-p-pro412

## Summary

**TSC1 p.Pro412= (c.1236C>T)** is classified **Benign/Likely benign** in TSC1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-09). Absent from gnomAD v4.1; Associated with tuberous sclerosis 1.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs1588321355 · 3 submitters · 2 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the TSC1 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 3 submitters, 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.Pro412= |
| Coding change (HGVS c.) | c.1236C>T |
| MANE Select transcript | [NM_000368](https://www.ncbi.nlm.nih.gov/nuccore/NM_000368) |
| dbSNP | [rs1588321355](https://www.ncbi.nlm.nih.gov/snp/rs1588321355/) |
| Variant type | single nucleotide variant |
| Location | chr9:132910598-132910598 (GRCh38) |
| ClinVar | [VCV766681](https://www.ncbi.nlm.nih.gov/clinvar/variation/766681/) |

**All HGVS expressions:** `LRG_486:g.39036C>T`, `LRG_486t1:c.1236C>T`, `NC_000009.11:g.135785985G>A`, `NC_000009.12:g.132910598G>A`, `NG_012386.1:g.39036C>T`, `NM_000368.5:c.1236C>T`, `NM_001162426.2:c.1233C>T`, `NM_001162427.2:c.1083C>T`, `NM_001362177.2:c.873C>T`

## 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 -0.326, GERP -3.88, phastCons 0.029 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 5.882**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **412** lies in the 'mediates interaction with wdr45b' region; 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. p.Pro412= falls in the mediates interaction with wdr45b region.


### 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-04-09.

**Submitter consensus:** conflicting (2 Likely benign, 1 Benign).

**Submission history:** 3 submissions (2020–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-05-01 |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2025-04-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2020-01-29 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Tuberous sclerosis 1, Hereditary cancer-predisposing syndrome, Neoplastic Syndromes, Hereditary, Hereditary neoplastic syndrome, Tumor predisposition, Hereditary Cancer Syndrome.

## Similar variants {#similar}

Related TSC1 variant pages (same residue, condition, or type): [TSC1 p.Pro412Leu](/variant/tsc1-p-pro412leu), [TSC1 p.Pro412Ser](/variant/tsc1-p-pro412ser), [TSC1 p.Pro412Thr](/variant/tsc1-p-pro412thr), [TSC1 c.1029+1G>A](/variant/tsc1-c-1029-plus-1g-a), [TSC1 c.1029+1G>C](/variant/tsc1-c-1029-plus-1g-c), [TSC1 c.107-1G>A](/variant/tsc1-c-107-minus-1g-a), [TSC1 c.1141+1G>A](/variant/tsc1-c-1141-plus-1g-a), [TSC1 c.1264-1G>A](/variant/tsc1-c-1264-minus-1g-a).

### 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 766681). 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.*