# NM_000548.5(TSC2):c.4988A>C (p.Lys1663Thr)

https://sugi.bio/variant/tsc2-p-lys1663thr

## Summary

**TSC2 p.Lys1663Thr (c.4988A>C)** is classified **Uncertain significance** in TSC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-05). AlphaMissense: likely pathogenic (0.7472); Very rare (popmax 0.00135%, afr); Associated with tuberous sclerosis 2.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2544409309 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00135%, afr)

## 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 1 submitter, 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.Lys1663Thr |
| Coding change (HGVS c.) | c.4988A>C |
| MANE Select transcript | [NM_000548](https://www.ncbi.nlm.nih.gov/nuccore/NM_000548) |
| dbSNP | [rs2544409309](https://www.ncbi.nlm.nih.gov/snp/rs2544409309/) |
| Variant type | single nucleotide variant |
| Location | chr16:2086870-2086870 (GRCh38) |
| ClinVar | [VCV2769647](https://www.ncbi.nlm.nih.gov/clinvar/variation/2769647/) |

**All HGVS expressions:** `LRG_487:g.42565A>C`, `LRG_487t1:c.4988A>C`, `NC_000016.10:g.2086870A>C`, `NC_000016.9:g.2136871A>C`, `NG_005895.1:g.42565A>C`, `NG_008617.1:g.56351T>G`, `NM_000548.5:c.4988A>C`, `NM_001077183.3:c.4787A>C`, `NM_001114382.3:c.4919A>C`, `NM_001318827.2:c.4679A>C`, `NM_001318829.2:c.4643A>C`, `NM_001318831.2:c.4256A>C`, `NM_001318832.2:c.4820A>C`, `NM_001363528.2:c.4790A>C`, `NM_001370404.1:c.4856A>C`, `NM_001370405.1:c.4859A>C`, `NM_001406663.1:c.4985A>C`, `NM_001406664.1:c.4916A>C`, `NM_001406665.1:c.4910A>C`, `NM_001406667.1:c.4880A>C`, `NM_001406668.1:c.4877A>C`, `NM_001406670.1:c.4808A>C`, `NM_001406671.1:c.4778A>C`, `NM_001406673.1:c.4775A>C`, `NM_001406675.1:c.4772A>C`, `NM_001406676.1:c.4769A>C`, `NM_001406677.1:c.4730A>C`, `NM_001406678.1:c.4676A>C`, `NM_001406679.1:c.4640A>C`, `NM_001406680.1:c.4388A>C`, `NM_001406681.1:c.4328A>C`, `NM_001406682.1:c.4319A>C`, `NM_001406683.1:c.4319A>C`, `NM_001406684.1:c.4316A>C`, `NM_001406685.1:c.4190A>C`, `NM_001406686.1:c.4190A>C`, `NM_001406687.1:c.4187A>C`, `NM_001406688.1:c.4187A>C`, `NM_001406689.1:c.3575A>C`, `NM_001406690.1:c.3515A>C`, `NM_001406691.1:c.3512A>C`, `NM_001406692.1:c.3446A>C`, `NM_001406693.1:c.3446A>C`, `NM_001406694.1:c.3446A>C`, `NM_001406695.1:c.3443A>C`, `NM_001406696.1:c.3443A>C`, `NM_001406697.1:c.3443A>C`, `NM_001406698.1:c.3185A>C`, `NM_021055.3:c.4859A>C`, `NR_176225.1:n.4940A>C`, `NR_176226.1:n.5188A>C`, `NR_176227.1:n.5116A>C`, `NR_176228.1:n.4937A>C`, `NR_176229.1:n.4862A>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.7472)
- REVEL 0.778 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -6.31 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- SpliceAI predicts **donor gain** (Δ 0.22) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 2.18, GERP 1.91, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 23.5**. 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.*
- Regional missense constraint: **o/e 1.27** across the covering region of the MANE Select transcript (2,086,822–2,088,607), spanning 1,785 bp. Chi-square p 3.9e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.22**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.22**.
- Population frequency (gnomAD v4.1): grpmax **0.00135%** (afr) · 1/74,280 in the highest group · 2/1,584,414 alleles overall — very rare (popmax 0.00135%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00135% | 74,280 |
| South Asian | 0.00114% | 87,556 |

*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.Lys1663Thr 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 Single submitter *(criteria provided, single submitter)*, last evaluated 2023-06-05.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-06-05 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Tuberous sclerosis 2.

## 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.Lys1663=](/variant/tsc2-p-lys1663), [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 2026-10-15); 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 2769647). 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.*