# NM_005359.6(SMAD4):c.1533G>A (p.Pro511=)

https://sugi.bio/variant/smad4-p-pro511

## Summary

**SMAD4 p.Pro511= (c.1533G>A)** is classified **Benign/Likely benign** in SMAD4 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-10-14). Very rare (popmax 0.00445%, eas); Associated with juvenile polyposis syndrome.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs1057523968 · 8 submitters · 4 linked conditions · very rare (popmax 0.00445%, eas)

## For patients & families {#patients}

This is a change in the SMAD4 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 8 submitters, and is linked to juvenile polyposis 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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Infancy |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 11 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | SMAD4 is a diagnostic-grade gene on 22 Genomics England panels |

**Commonly reported features of Juvenile polyposis syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Juvenile colonic polyposis — Obligate (100%)
- Rectal polyposis — Obligate (100%)
- Juvenile gastrointestinal polyposis — Obligate (100%)
- Intestinal polyp — Very frequent (99-80%)
- Anemia — Frequent (79-30%)
- Abdominal pain — Frequent (79-30%)
- Hamartomatous polyposis — Frequent (79-30%)
- Small intestinal polyposis — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003065/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SMAD4](https://sugi.bio/atlas/gene/SMAD4/) |
| Protein change (HGVS p.) | p.Pro511= |
| Coding change (HGVS c.) | c.1533G>A |
| MANE Select transcript | [NM_005359](https://www.ncbi.nlm.nih.gov/nuccore/NM_005359) |
| dbSNP | [rs1057523968](https://www.ncbi.nlm.nih.gov/snp/rs1057523968/) |
| Variant type | single nucleotide variant |
| Location | chr18:51078341-51078341 (GRCh38) |
| ClinVar | [VCV391101](https://www.ncbi.nlm.nih.gov/clinvar/variation/391101/) |

**All HGVS expressions:** `LRG_318:g.115302G>A`, `LRG_318t1:c.1533G>A`, `NC_000018.10:g.51078341G>A`, `NC_000018.9:g.48604711G>A`, `NG_013013.2:g.115302G>A`, `NM_005359.6:c.1533G>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 -3.874, GERP -3.98 — fast-evolving / accelerated position
- CADD: **PHRED 8.132**. 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: **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 **0.00445%** (eas) · FAF95 0.000738% · FAF99 0.000276% · 2/44,898 in the highest group · 5/1,614,002 alleles overall — very rare (popmax 0.00445%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00445% | 22,449 |
| South Asian | 0.0022% | 45,544 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,486 |

*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}

**SMAD4** population constraint: LOEUF 0.227, pLI 1, missense-Z 4.9422; 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.*

Curated gene–disease validity (ClinGen):

- **pulmonary arterial hypertension** — Disputed (AD)
- **Myhre syndrome** — Definitive (AD)
- **juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **511** lies in the mh2 domain.

AlphaFold model confidence (whole protein): pLDDT 74.56, 53% of residues very-high.

**14 experimental structure(s)** (PDB): [1DD1](https://www.rcsb.org/structure/1DD1), [1G88](https://www.rcsb.org/structure/1G88), [1MR1](https://www.rcsb.org/structure/1MR1), [1U7F](https://www.rcsb.org/structure/1U7F), [1U7V](https://www.rcsb.org/structure/1U7V), [1YGS](https://www.rcsb.org/structure/1YGS) — incl. mutant structure 1G88.

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

*Describes the biological roles of SMAD4 (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:** SMAD4's established molecular role includes transcription cis-regulatory region binding. p.Pro511= falls in the mh2 domain. In Reactome, SMAD4 is annotated in disease pathway(s) including **SARS-CoV-1 targets host intracellular signalling and regulatory pathways**, **SMAD2/3 MH2 Domain Mutants in Cancer**.

**Disease mechanism (Reactome):** SMAD4 loss or alteration is curated in [SARS-CoV-1 targets host intracellular signalling and regulatory pathways](https://reactome.org/content/detail/R-HSA-9735871), [SMAD2/3 MH2 Domain Mutants in Cancer](https://reactome.org/content/detail/R-HSA-3315487), [SMAD4 MH2 Domain Mutants in Cancer](https://reactome.org/content/detail/R-HSA-3311021).

### Pathways affected {#pathways}

SMAD4 participates in **21 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [SARS-CoV-1 targets host intracellular signalling and regulatory pathways](https://reactome.org/content/detail/R-HSA-9735871) | curated |
| ⚕ [SMAD2/3 MH2 Domain Mutants in Cancer](https://reactome.org/content/detail/R-HSA-3315487) | curated |
| ⚕ [SMAD4 MH2 Domain Mutants in Cancer](https://reactome.org/content/detail/R-HSA-3311021) | curated |
| [RUNX2 regulates bone development](https://reactome.org/content/detail/R-HSA-8941326) | curated |
| [RUNX3 regulates BCL2L11 (BIM) transcription](https://reactome.org/content/detail/R-HSA-8952158) | curated |
| [RUNX3 regulates CDKN1A transcription](https://reactome.org/content/detail/R-HSA-8941855) | curated |
| [SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription](https://reactome.org/content/detail/R-HSA-2173796) | curated |
| [Signaling by BMP](https://reactome.org/content/detail/R-HSA-201451) | curated |
| [TGF-beta receptor signaling activates SMADs](https://reactome.org/content/detail/R-HSA-2173789) | curated |
| [TGFBR3 expression](https://reactome.org/content/detail/R-HSA-9839394) | curated |
| [Transcriptional regulation of pluripotent stem cells](https://reactome.org/content/detail/R-HSA-452723) | curated |
| [Ub-specific processing proteases](https://reactome.org/content/detail/R-HSA-5689880) | curated |
| [Cardiogenesis](https://reactome.org/content/detail/R-HSA-9733709) | electronic |
| [Downregulation of SMAD2/3:SMAD4 transcriptional activity](https://reactome.org/content/detail/R-HSA-2173795) | electronic |
| [FOXO-mediated transcription of cell cycle genes](https://reactome.org/content/detail/R-HSA-9617828) | electronic |
| [FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes](https://reactome.org/content/detail/R-HSA-9615017) | electronic |
| [Formation of definitive endoderm](https://reactome.org/content/detail/R-HSA-9823730) | electronic |
| [Germ layer formation at gastrulation](https://reactome.org/content/detail/R-HSA-9754189) | electronic |
| [Signaling by Activin](https://reactome.org/content/detail/R-HSA-1502540) | electronic |
| [Signaling by NODAL](https://reactome.org/content/detail/R-HSA-1181150) | electronic |
| [Transcriptional regulation of brown and beige adipocyte differentiation by EBF2](https://reactome.org/content/detail/R-HSA-9844594) | electronic |

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

**Molecular function:** transcription cis-regulatory region binding, RNA polymerase II cis-regulatory region sequence-specific DNA binding, transcription corepressor binding, transcription coactivator binding, DNA-binding transcription activator activity, RNA polymerase II-specific, DNA-binding transcription factor activity.

**Biological process:** response to hypoxia, epithelial to mesenchymal transition, DNA-templated transcription, transforming growth factor beta receptor signaling pathway, positive regulation of gene expression, epithelial cell migration.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-14.

**Submitter consensus:** conflicting (6 Likely benign, 1 Likely Benign, 1 Benign).

**Submission history:** 8 submissions (2016–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2016-11-21 |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2017-05-09 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-02-25 |
| All of Us Research Program, National Institutes of Health | Likely Benign | criteria provided, single submitter | clinical testing | 2024-01-11 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2016-07-28 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2024-08-30 |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2025-03-24 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-10-14 |

## Associated conditions {#conditions}

[juvenile polyposis syndrome](https://sugi.bio/atlas/disease/juvenile-polyposis-syndrome/), [juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome](https://sugi.bio/atlas/disease/juvenile-polyposis-hereditary-hemorrhagic-telangiectasia-syndrome/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [familial thoracic aortic aneurysm and aortic dissection](https://sugi.bio/atlas/disease/familial-thoracic-aortic-aneurysm-and-aortic-dissection/).

**Reported phenotype names (ClinVar):** Juvenile polyposis syndrome, not specified, Hereditary cancer-predisposing syndrome, Familial thoracic aortic aneurysm and aortic dissection, Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, SMAD4-related disorder, SMAD4-related condition, SMAD4-Related disorders, Neoplastic Syndromes, Hereditary, Hereditary Cancer Syndrome.

## Same-residue context {#hotspot}

Residue **511** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [SMAD4 p.Pro511fs](/variant/smad4-p-pro511fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related SMAD4 variant pages (same residue, condition, or type): [SMAD4 p.Pro511Leu](/variant/smad4-p-pro511leu), [SMAD4 p.Pro511Ser](/variant/smad4-p-pro511ser), [SMAD4 c.1140-1G>A](/variant/smad4-c-1140-minus-1g-a), [SMAD4 c.1308+1G>A](/variant/smad4-c-1308-plus-1g-a), [SMAD4 c.1308+2T>G](/variant/smad4-c-1308-plus-2t-g), [SMAD4 c.1309-1G>A](/variant/smad4-c-1309-minus-1g-a), [SMAD4 c.1447+2T>C](/variant/smad4-c-1447-plus-2t-c), [SMAD4 c.249+1G>T](/variant/smad4-c-249-plus-1g-t).

### 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 391101). 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.*