# NM_003242.6(TGFBR2):c.1446C>T (p.Pro482=)

https://sugi.bio/variant/tgfbr2-p-pro482

## Summary

**TGFBR2 p.Pro482= (c.1446C>T)** is classified **Likely benign** in TGFBR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-02). Absent from gnomAD v4.1; Associated with familial thoracic aortic aneurysm and aortic dissection.

**At a glance:** Likely benign · review: Single submitter · rsID rs2125451813 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the TGFBR2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to familial thoracic aortic aneurysm and aortic dissection.

*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) | Adolescent, Adult, Childhood |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | TGFBR2 is a diagnostic-grade gene on 14 Genomics England panels |

**Commonly reported features of Familial thoracic aortic aneurysm and aortic dissection** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Cutis marmorata — Very frequent (99-80%)
- Abnormality of connective tissue — Very frequent (99-80%)
- Cystic medial necrosis of the aorta — Very frequent (99-80%)
- Abnormality iris morphology — Frequent (79-30%)
- Hypertension — Frequent (79-30%)
- Cardiomegaly — Frequent (79-30%)
- Aortic regurgitation — Frequent (79-30%)
- Coronaryartery atherosclerosis — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002249/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TGFBR2](https://sugi.bio/atlas/gene/TGFBR2/) |
| Protein change (HGVS p.) | p.Pro482= |
| Coding change (HGVS c.) | c.1446C>T |
| MANE Select transcript | [NM_003242](https://www.ncbi.nlm.nih.gov/nuccore/NM_003242) |
| dbSNP | [rs2125451813](https://www.ncbi.nlm.nih.gov/snp/rs2125451813/) |
| Variant type | single nucleotide variant |
| Location | chr3:30688433-30688433 (GRCh38) |
| ClinVar | [VCV2747452](https://www.ncbi.nlm.nih.gov/clinvar/variation/2747452/) |

**All HGVS expressions:** `LRG_779:g.86932C>T`, `LRG_779t1:c.1521C>T`, `LRG_779t2:c.1446C>T`, `NC_000003.11:g.30729925C>T`, `NC_000003.12:g.30688433C>T`, `NG_007490.1:g.86932C>T`, `NM_001024847.3:c.1521C>T`, `NM_001407126.1:c.1629C>T`, `NM_001407127.1:c.1554C>T`, `NM_001407128.1:c.1473C>T`, `NM_001407129.1:c.1449C>T`, `NM_001407130.1:c.1443C>T`, `NM_001407132.1:c.1341C>T`, `NM_001407133.1:c.1341C>T`, `NM_001407134.1:c.1341C>T`, `NM_001407135.1:c.1341C>T`, `NM_001407136.1:c.1341C>T`, `NM_001407137.1:c.1161C>T`, `NM_001407138.1:c.1086C>T`, `NM_001407139.1:c.576C>T`, `NM_003242.6:c.1446C>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 (below), not from a missing predictor score.
- Conservation: phyloP -0.483, GERP 1.46, phastCons 0.034 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 9.897**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for TGFBR2 (688 scored positions, the nearest 11 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**TGFBR2** population constraint: LOEUF 0.531, pLI 0.90792, missense-Z 2.9468; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Loeys-Dietz syndrome 2** — Definitive (AD)

## Protein context {#protein}

Residue **482** lies in the protein kinase domain; the 'sufficient for interaction with clu' region.

AlphaFold model confidence (whole protein): pLDDT 81.22, 58% of residues very-high.

**22 experimental structure(s)** (PDB): [1KTZ](https://www.rcsb.org/structure/1KTZ), [1M9Z](https://www.rcsb.org/structure/1M9Z), [1PLO](https://www.rcsb.org/structure/1PLO), [2PJY](https://www.rcsb.org/structure/2PJY), [3KFD](https://www.rcsb.org/structure/3KFD), [4P7U](https://www.rcsb.org/structure/4P7U).

## What this gene does {#gene-function}

*Describes the biological roles of TGFBR2 (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:** TGFBR2's established molecular role includes transmembrane receptor protein serine/threonine kinase activity. p.Pro482= falls in the protein kinase domain. In Reactome, TGFBR2 is annotated in disease pathway(s) including **SMAD2/3 Phosphorylation Motif Mutants in Cancer**, **TGFBR1 KD Mutants in Cancer**.

**Disease mechanism (Reactome):** TGFBR2 loss or alteration is curated in [SMAD2/3 Phosphorylation Motif Mutants in Cancer](https://reactome.org/content/detail/R-HSA-3304356), [TGFBR1 KD Mutants in Cancer](https://reactome.org/content/detail/R-HSA-3656532), [TGFBR1 LBD Mutants in Cancer](https://reactome.org/content/detail/R-HSA-3656535).

### Pathways affected {#pathways}

TGFBR2 participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [SMAD2/3 Phosphorylation Motif Mutants in Cancer](https://reactome.org/content/detail/R-HSA-3304356) | curated |
| ⚕ [TGFBR1 KD Mutants in Cancer](https://reactome.org/content/detail/R-HSA-3656532) | curated |
| ⚕ [TGFBR1 LBD Mutants in Cancer](https://reactome.org/content/detail/R-HSA-3656535) | curated |
| ⚕ [TGFBR2 Kinase Domain Mutants in Cancer](https://reactome.org/content/detail/R-HSA-3645790) | curated |
| ⚕ [TGFBR2 MSI Frameshift Mutants in Cancer](https://reactome.org/content/detail/R-HSA-3642279) | curated |
| [TGF-beta receptor signaling activates SMADs](https://reactome.org/content/detail/R-HSA-2173789) | curated |
| [TGFBR3 regulates TGF-beta signaling](https://reactome.org/content/detail/R-HSA-9839389) | curated |
| [Downregulation of TGF-beta receptor signaling](https://reactome.org/content/detail/R-HSA-2173788) | electronic |
| [TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition)](https://reactome.org/content/detail/R-HSA-2173791) | electronic |
| [UCH proteinases](https://reactome.org/content/detail/R-HSA-5689603) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** transmembrane receptor protein serine/threonine kinase activity, transforming growth factor beta receptor activity, transforming growth factor beta receptor activity, type II, glycosaminoglycan binding, type I transforming growth factor beta receptor binding, type III transforming growth factor beta receptor binding.

**Biological process:** epithelial to mesenchymal transition, aortic valve morphogenesis, apoptotic process, transforming growth factor beta receptor signaling pathway, response to xenobiotic stimulus, positive regulation of epithelial to mesenchymal transition.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-08-02.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-08-02 |

## Associated conditions {#conditions}

[familial thoracic aortic aneurysm and aortic dissection](https://sugi.bio/atlas/disease/familial-thoracic-aortic-aneurysm-and-aortic-dissection/).

**Reported phenotype names (ClinVar):** Familial thoracic aortic aneurysm and aortic dissection, Thoracic aortic aneurysms and dissections.

## Similar variants {#similar}

Related TGFBR2 variant pages (same residue, condition, or type): [TGFBR2 p.Pro482His](/variant/tgfbr2-p-pro482his), [TGFBR2 p.Ala414Pro](/variant/tgfbr2-p-ala414pro), [TGFBR2 p.Ala527Thr](/variant/tgfbr2-p-ala527thr), [TGFBR2 p.Ala527Val](/variant/tgfbr2-p-ala527val), [TGFBR2 p.Arg356Pro](/variant/tgfbr2-p-arg356pro), [TGFBR2 p.Arg378Ser](/variant/tgfbr2-p-arg378ser), [TGFBR2 p.Arg460Cys](/variant/tgfbr2-p-arg460cys), [TGFBR2 p.Arg460Gly](/variant/tgfbr2-p-arg460gly).

### 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 2747452). 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.*