# NM_000548.5(TSC2):c.2261C>G (p.Pro754Arg)

https://sugi.bio/variant/tsc2-p-pro754arg

## Summary

**TSC2 p.Pro754Arg (c.2261C>G)** is classified **Uncertain significance** in TSC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-22). AlphaMissense: ambiguous (0.3966); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs2088690950 · 2 submitters · 2 linked conditions · AlphaMissense ambiguous · very rare (popmax 8.47e-05%, 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 2 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.Pro754Arg |
| Coding change (HGVS c.) | c.2261C>G |
| MANE Select transcript | [NM_000548](https://www.ncbi.nlm.nih.gov/nuccore/NM_000548) |
| dbSNP | [rs2088690950](https://www.ncbi.nlm.nih.gov/snp/rs2088690950/) |
| Variant type | single nucleotide variant |
| Location | chr16:2072889-2072889 (GRCh38) |
| ClinVar | [VCV940398](https://www.ncbi.nlm.nih.gov/clinvar/variation/940398/) |

**All HGVS expressions:** `LRG_487:g.28584C>G`, `LRG_487t1:c.2261C>G`, `NC_000016.10:g.2072889C>G`, `NC_000016.9:g.2122890C>G`, `NG_005895.1:g.28584C>G`, `NM_000548.5:c.2261C>G`, `NM_001077183.3:c.2261C>G`, `NM_001114382.3:c.2261C>G`, `NM_001318827.2:c.2150C>G`, `NM_001318829.2:c.2114C>G`, `NM_001318831.2:c.1661C>G`, `NM_001318832.2:c.2294C>G`, `NM_001363528.2:c.2261C>G`, `NM_001370404.1:c.2261C>G`, `NM_001370405.1:c.2261C>G`, `NM_021055.3:c.2261C>G`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL are indeterminate here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.3966) — no call either way
- REVEL 0.64 (indeterminate)
- SaProt LLR -12.236 (damaging)
- Conservation: phyloP 7.599, GERP 0.936, phastCons 1 — highly conserved
- CADD: **PHRED 24.6**. 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 1.00** across the covering region of the MANE Select transcript (2,048,616–2,085,274), spanning 36,658 bp. Chi-square p 0.88. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,180,042 in the highest group · 1/1,613,622 alleles overall — very rare (popmax 8.47e-05%, 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}


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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-04-22.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2021–2026); 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 | 2021-07-21 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-04-22 |

## 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, Hereditary Cancer Syndrome, Neoplastic Syndromes, Hereditary, Tumor predisposition, Hereditary neoplastic syndrome.

## Same-residue context {#hotspot}

Residue **754** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [TSC2 p.Pro754fs](/variant/tsc2-p-pro754fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related TSC2 variant pages (same residue, condition, or type): [TSC2 p.Pro754Ala](/variant/tsc2-p-pro754ala), [TSC2 p.Pro754=](/variant/tsc2-p-pro754), [TSC2 p.Pro754Leu](/variant/tsc2-p-pro754leu), [TSC2 p.Pro754Ser](/variant/tsc2-p-pro754ser), [TSC2 p.Pro754fs](/variant/tsc2-p-pro754fs), [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).

### 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 940398). 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.*