# NM_000548.5(TSC2):c.1284C>T (p.Ser428=)

https://sugi.bio/variant/tsc2-p-ser428

## Summary

**TSC2 p.Ser428= (c.1284C>T)** is classified **Conflicting classifications of pathogenicity** in TSC2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-20). Very rare (popmax 0.00221%, sas); Associated with hereditary neoplastic syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1325874616 · 4 submitters · 2 linked conditions · very rare (popmax 0.00221%, sas)

## For patients & families {#patients}

This is a change in the TSC2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, and is linked to hereditary neoplastic syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 31 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019921/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.Ser428= |
| Coding change (HGVS c.) | c.1284C>T |
| MANE Select transcript | [NM_000548](https://www.ncbi.nlm.nih.gov/nuccore/NM_000548) |
| dbSNP | [rs1325874616](https://www.ncbi.nlm.nih.gov/snp/rs1325874616/) |
| Variant type | single nucleotide variant |
| Location | chr16:2062523-2062523 (GRCh38) |
| ClinVar | [VCV1080211](https://www.ncbi.nlm.nih.gov/clinvar/variation/1080211/) |

**All HGVS expressions:** `LRG_487:g.18218C>T`, `LRG_487t1:c.1284C>T`, `NC_000016.10:g.2062523C>T`, `NC_000016.9:g.2112524C>T`, `NG_005895.1:g.18218C>T`, `NM_000548.5:c.1284C>T`, `NM_001077183.3:c.1284C>T`, `NM_001114382.3:c.1284C>T`, `NM_001318827.2:c.1173C>T`, `NM_001318829.2:c.1137C>T`, `NM_001318831.2:c.684C>T`, `NM_001318832.2:c.1317C>T`, `NM_001363528.2:c.1284C>T`, `NM_001370404.1:c.1284C>T`, `NM_001370405.1:c.1284C>T`, `NM_021055.3:c.1284C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.43) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.516, GERP -3.3, phastCons 0.025 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 14.22**. 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 deltas (raw): acceptor loss **0.03**, donor loss **0.00**, acceptor gain **0.43**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.43**, donor gain **0.00**.
- Pangolin: Δ**0.40** (gain), gain 0.40 / loss 0.18. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00221%** (sas) · FAF95 0.000367% · FAF99 0.000137% · 2/90,436 in the highest group · 4/1,612,038 alleles overall — very rare (popmax 0.00221%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00221% | 45,218 |
| African / African-American | 0.00133% | 74,930 |
| European (non-Finnish) | 8.48e-05% | 1,179,156 |

*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}

Residue **428** lies in an α-helix.

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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-08-20.

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

**Submission history:** 4 submissions (2023–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-28 |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2025-05-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-08-20 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-09-11 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Tuberous sclerosis 2, not specified, Hereditary Cancer Syndrome, Neoplastic Syndromes, Hereditary, Tumor predisposition, Hereditary neoplastic syndrome, AllHighlyPenetrant.

## Same-residue context {#hotspot}

Residue **428** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [TSC2 p.Ser428fs](/variant/tsc2-p-ser428fs), [TSC2 p.Ser428del](/variant/tsc2-p-ser428del). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related TSC2 variant pages (same residue, condition, or type): [TSC2 p.Ser428Cys](/variant/tsc2-p-ser428cys), [TSC2 p.Ser428del](/variant/tsc2-p-ser428del), [TSC2 p.Ser428fs](/variant/tsc2-p-ser428fs), [TSC2 c.1257+1G>A](/variant/tsc2-c-1257-plus-1g-a), [TSC2 c.1258-2A>G](/variant/tsc2-c-1258-minus-2a-g), [TSC2 c.1361+1G>A](/variant/tsc2-c-1361-plus-1g-a), [TSC2 c.1361+1G>T](/variant/tsc2-c-1361-plus-1g-t), [TSC2 c.1362-1G>A](/variant/tsc2-c-1362-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 1080211). 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.*