# NM_003238.6(TGFB2):c.864C>G (p.Ser288=)

https://sugi.bio/variant/tgfb2-p-ser288

## Summary

**TGFB2 p.Ser288= (c.864C>G)** is classified **Likely benign** in TGFB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-05). Very rare (popmax 8.47e-05%, nfe); Associated with Loeys-Dietz syndrome 4.

**At a glance:** Likely benign · review: Single submitter · rsID rs373646036 · 1 submitter · 1 linked condition · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the TGFB2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Loeys-Dietz syndrome 4.

*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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010588/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TGFB2](https://sugi.bio/atlas/gene/TGFB2/) |
| Protein change (HGVS p.) | p.Ser288= |
| Coding change (HGVS c.) | c.864C>G |
| MANE Select transcript | [NM_003238](https://www.ncbi.nlm.nih.gov/nuccore/NM_003238) |
| dbSNP | [rs373646036](https://www.ncbi.nlm.nih.gov/snp/rs373646036/) |
| Variant type | single nucleotide variant |
| Location | chr1:218436079-218436079 (GRCh38) |
| ClinVar | [VCV1597126](https://www.ncbi.nlm.nih.gov/clinvar/variation/1597126/) |

**All HGVS expressions:** `NC_000001.10:g.218609421C>G`, `NC_000001.11:g.218436079C>G`, `NG_027721.2:g.95746C>G`, `NM_001135599.4:c.948C>G`, `NM_003238.6:c.864C>G`

## 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 **acceptor loss** (Δ 0.38) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 7.694, GERP 2.04, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 14.2**. 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 **0.38**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 6 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,179,984 in the highest group · 1/1,614,136 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}

**TGFB2** population constraint: LOEUF 0.463, pLI 0.99612, missense-Z 2.3626. *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):

- **familial thoracic aortic aneurysm and aortic dissection** — Definitive (AD)

## Protein context {#protein}

Residue **288** lies in a UniProt-annotated variant site (in lds4); an α-helix.

AlphaFold model confidence (whole protein): pLDDT 80.41, 39% of residues very-high.

**11 experimental structure(s)** (PDB): [1TFG](https://www.rcsb.org/structure/1TFG), [2TGI](https://www.rcsb.org/structure/2TGI), [4KXZ](https://www.rcsb.org/structure/4KXZ), [5TX4](https://www.rcsb.org/structure/5TX4), [5TY4](https://www.rcsb.org/structure/5TY4), [6I9J](https://www.rcsb.org/structure/6I9J).

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

*Describes the biological roles of TGFB2 (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:** TGFB2's established molecular role includes amyloid-beta binding.


### Pathways affected {#pathways}

TGFB2 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Molecules associated with elastic fibres](https://reactome.org/content/detail/R-HSA-2129379) | curated |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | 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 |
| [ECM proteoglycans](https://reactome.org/content/detail/R-HSA-3000178) | electronic |

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

**Molecular function:** amyloid-beta binding, signaling receptor binding, type II transforming growth factor beta receptor binding, transforming growth factor beta receptor binding, type III transforming growth factor beta receptor binding, protein homodimerization activity.

**Biological process:** cell morphogenesis, eye development, response to hypoxia, epithelial to mesenchymal transition, hair follicle development, heart morphogenesis.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-06-05.

**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 | 2021-06-05 |

## Associated conditions {#conditions}

[Loeys-Dietz syndrome 4](https://sugi.bio/atlas/disease/loeys-dietz-syndrome-4/).

**Reported phenotype names (ClinVar):** Loeys-Dietz syndrome 4, ANEURYSM, AORTIC AND CEREBRAL, WITH ARTERIAL TORTUOSITY AND SKELETAL MANIFESTATIONS, TGFB2-Related Loeys-Dietz Syndrome.

## Similar variants {#similar}

Related TGFB2 variant pages (same residue, condition, or type): [TGFB2 p.Ser288Cys](/variant/tgfb2-p-ser288cys), [TGFB2 c.346+1G>A](/variant/tgfb2-c-346-plus-1g-a), [TGFB2 c.346+1G>T](/variant/tgfb2-c-346-plus-1g-t), [TGFB2 c.510+1G>A](/variant/tgfb2-c-510-plus-1g-a), [TGFB2 c.932+1G>A](/variant/tgfb2-c-932-plus-1g-a), [TGFB2 c.933-1G>A](/variant/tgfb2-c-933-minus-1g-a), [TGFB2 p.Arg131Ter](/variant/tgfb2-p-arg131ter), [TGFB2 p.Arg299Gln](/variant/tgfb2-p-arg299gln).

### 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 1597126). 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.*