# NM_005359.6(SMAD4):c.457C>T (p.Pro153Ser)

https://sugi.bio/variant/smad4-p-pro153ser

## Summary

**SMAD4 p.Pro153Ser (c.457C>T)** is classified **Conflicting classifications of pathogenicity** in SMAD4 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-09-22). AlphaMissense: likely benign (0.0589); Very rare (popmax 0.00167%, amr); Associated with juvenile polyposis syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs751763157 · 5 submitters · 4 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the SMAD4 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 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.Pro153Ser |
| Coding change (HGVS c.) | c.457C>T |
| MANE Select transcript | [NM_005359](https://www.ncbi.nlm.nih.gov/nuccore/NM_005359) |
| dbSNP | [rs751763157](https://www.ncbi.nlm.nih.gov/snp/rs751763157/) |
| Variant type | single nucleotide variant |
| Location | chr18:51054783-51054783 (GRCh38) |
| ClinVar | [VCV649107](https://www.ncbi.nlm.nih.gov/clinvar/variation/649107/) |

**All HGVS expressions:** `LRG_318:g.91744C>T`, `LRG_318t1:c.457C>T`, `NC_000018.10:g.51054783C>T`, `NC_000018.9:g.48581153C>T`, `NG_013013.2:g.91744C>T`, `NM_005359.6:c.457C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.0589)
- REVEL 0.423 (indeterminate)
- SaProt LLR -7.485 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 5.703, GERP 2.93, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.1**. 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 0.80** across the covering region of the MANE Select transcript (51,049,310–51,059,901), spanning 10,591 bp. Chi-square p 0.0038. 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 **0.00167%** (amr) · 1/59,978 in the highest group · 4/1,606,512 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00167% | 59,978 |
| Remaining individuals (not grpmax-eligible) | 0.00161% | 62,224 |
| African / African-American | 0.00134% | 74,722 |
| European (non-Finnish) | 8.52e-05% | 1,173,290 |

*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 **153** lies in the 'mediates interaction with zbtb7a' region.

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.Pro153Ser falls in the mediates interaction with zbtb7a region. 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-09-22.

**Submitter consensus:** conflicting (4 Uncertain significance, 1 Likely benign).

**Submission history:** 5 submissions (2023–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-07-21 |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-06-14 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-15 |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-22 |

## 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, Familial thoracic aortic aneurysm and aortic dissection, Hereditary cancer-predisposing syndrome, not specified, Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, not provided, Hereditary neoplastic syndrome, Neoplastic Syndromes, Hereditary, Tumor predisposition, Hereditary Cancer Syndrome.

## Similar variants {#similar}

Related SMAD4 variant pages (same residue, condition, or type): [SMAD4 p.Pro153=](/variant/smad4-p-pro153), [SMAD4 p.Pro153Ala](/variant/smad4-p-pro153ala), [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 2026-10-06); 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 649107). 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.*