# NM_000548.5(TSC2):c.4989G>A (p.Lys1663=)

https://sugi.bio/variant/tsc2-p-lys1663

## Summary

**TSC2 p.Lys1663= (c.4989G>A)** is classified **Uncertain significance** in TSC2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-07-11). Very rare (popmax 0.000257%, nfe); Associated with hereditary neoplastic syndrome.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1567124948 · 5 submitters · 3 linked conditions · very rare (popmax 0.000257%, nfe)

## For patients & families {#patients}

This is a change in the TSC2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 5 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.Lys1663= |
| Coding change (HGVS c.) | c.4989G>A |
| MANE Select transcript | [NM_000548](https://www.ncbi.nlm.nih.gov/nuccore/NM_000548) |
| dbSNP | [rs1567124948](https://www.ncbi.nlm.nih.gov/snp/rs1567124948/) |
| Variant type | single nucleotide variant |
| Location | chr16:2086871-2086871 (GRCh38) |
| ClinVar | [VCV571995](https://www.ncbi.nlm.nih.gov/clinvar/variation/571995/) |

**All HGVS expressions:** `LRG_487:g.42566G>A`, `LRG_487t1:c.4989G>A`, `NC_000016.10:g.2086871G>A`, `NC_000016.9:g.2136872G>A`, `NG_005895.1:g.42566G>A`, `NG_008617.1:g.56350C>T`, `NM_000548.4:c.4989G>A`, `NM_000548.5:c.4989G>A`, `NM_001077183.3:c.4788G>A`, `NM_001114382.3:c.4920G>A`, `NM_001318827.2:c.4680G>A`, `NM_001318829.2:c.4644G>A`, `NM_001318831.2:c.4257G>A`, `NM_001318832.2:c.4821G>A`, `NM_001363528.2:c.4791G>A`, `NM_001370404.1:c.4857G>A`, `NM_001370405.1:c.4860G>A`, `NM_021055.3:c.4860G>A`

## 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 **donor gain** (Δ 0.57) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 3.201, GERP -1.91, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 17.52**. 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 **0.00**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.57**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.57**.
- Pangolin: Δ**0.37** (gain), gain 0.37 / loss 0.05. 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 **0.000257%** (nfe) · FAF95 6.9e-05% · FAF99 1.9e-05% · 3/1,165,976 in the highest group · 3/1,583,294 alleles overall — very rare (popmax 0.000257%, nfe).

*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 **1663** lies in the rap-gap domain.

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. p.Lys1663= falls in the rap-gap domain. 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-07-11.

**Submitter consensus:** unanimous (5/5 Uncertain significance).

**Submission history:** 5 submissions (2023–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-01-27 |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-11-28 |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-01-11 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-26 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-11 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [isolated focal cortical dysplasia type II](https://sugi.bio/atlas/disease/isolated-focal-cortical-dysplasia-type-ii/), [tuberous sclerosis 2](https://sugi.bio/atlas/disease/tuberous-sclerosis-2/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Tuberous sclerosis 2, Isolated focal cortical dysplasia type II, TSC2-related disorder, not provided, Hereditary neoplastic syndrome, Neoplastic Syndromes, Hereditary, Hereditary Cancer Syndrome, Tumor predisposition, none provided.

## Same-residue context {#hotspot}

Residue **1663** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [TSC2 p.Lys1663Asn](/variant/tsc2-p-lys1663asn). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related TSC2 variant pages (same residue, condition, or type): [TSC2 p.Lys1663Thr](/variant/tsc2-p-lys1663thr), [TSC2 p.Lys1663Asn](/variant/tsc2-p-lys1663asn), [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), [TSC2 c.138+2T>C](/variant/tsc2-c-138-plus-2t-c).

### 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 571995). 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.*