# NM_000548.5(TSC2):c.5313G>A (p.Pro1771=)

https://sugi.bio/variant/tsc2-p-pro1771

## Summary

**TSC2 p.Pro1771= (c.5313G>A)** is classified **Benign/Likely benign** in TSC2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-11-18). Ultra-rare (popmax 0.0165%, mid); Associated with hereditary neoplastic syndrome.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs765607686 · 9 submitters · 3 linked conditions · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the TSC2 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 9 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.Pro1771= |
| Coding change (HGVS c.) | c.5313G>A |
| MANE Select transcript | [NM_000548](https://www.ncbi.nlm.nih.gov/nuccore/NM_000548) |
| dbSNP | [rs765607686](https://www.ncbi.nlm.nih.gov/snp/rs765607686/) |
| Variant type | single nucleotide variant |
| Location | chr16:2088499-2088499 (GRCh38) |
| ClinVar | [VCV413716](https://www.ncbi.nlm.nih.gov/clinvar/variation/413716/) |

**All HGVS expressions:** `LRG_487:g.44194G>A`, `LRG_487t1:c.5313G>A`, `NC_000016.10:g.2088499G>A`, `NC_000016.9:g.2138500G>A`, `NG_005895.1:g.44194G>A`, `NG_008617.1:g.54722C>T`, `NM_000548.4:c.5313G>A`, `NM_000548.5:c.5313G>A`, `NM_001077183.3:c.5112G>A`, `NM_001114382.3:c.5244G>A`, `NM_001318827.2:c.5004G>A`, `NM_001318829.2:c.4968G>A`, `NM_001318831.2:c.4581G>A`, `NM_001318832.2:c.5145G>A`, `NM_001363528.2:c.5115G>A`, `NM_001370404.1:c.5181G>A`, `NM_001370405.1:c.5172G>A`, `NM_021055.3:c.5184G>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 (below), not from a missing predictor score.
- Conservation: phyloP -4.498, GERP -3.14 — fast-evolving / accelerated position
- CADD: **PHRED 0.188**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.34 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0165%** (mid) · FAF95 0.00223% · FAF99 0.00198% · 1/6,062 in the highest group · 47/1,612,740 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,062 |
| East Asian | 0.00446% | 22,437 |
| Admixed American | 0.00333% | 30,003 |
| South Asian | 0.00329% | 30,359 |
| European (non-Finnish) | 0.00305% | 32,777 |
| African / African-American | 0.00267% | 37,501 |
| Finnish (not grpmax-eligible) | 0.00159% | 62,738 |

*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 **1771** lies in the 'disordered' region.

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.Pro1771= falls in the disordered region. 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-11-18.

**Submitter consensus:** conflicting (5 Likely benign, 3 Benign, 1 Likely Benign).

**Submission history:** 9 submissions (2019–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2020-01-08 |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-11-07 |
| Genetic Services Laboratory, University of Chicago | Likely benign | criteria provided, single submitter | clinical testing | 2021-12-17 |
| All of Us Research Program, National Institutes of Health | Likely Benign | criteria provided, single submitter | clinical testing | 2023-12-01 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2019-11-13 |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2025-06-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-11-18 |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2022-11-06 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2024-12-01 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related TSC2 variant pages (same residue, condition, or type): [TSC2 p.Pro1771Ser](/variant/tsc2-p-pro1771ser), [TSC2 p.Pro1771Ala](/variant/tsc2-p-pro1771ala), [TSC2 p.Pro1771Gln](/variant/tsc2-p-pro1771gln), [TSC2 p.Pro1771Thr](/variant/tsc2-p-pro1771thr), [TSC2 p.Pro1771fs](/variant/tsc2-p-pro1771fs), [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 2026-10-06); 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 413716). 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.*