GENE REFERENCE / HGNC:6770

SMAD4

SMAD family member 4

protein-coding gene18q21.2Gene information

What does this gene do?

The SMAD4 gene provides instructions for making a protein involved in transmitting chemical signals from the cell surface to the nucleus. The SMAD4 protein is part of a signaling pathway, called the transforming growth factor beta (TGF-β) pathway, that allows the environment outside the cell to affect gene activity and protein production within the cell. The signaling process begins when a TGF-β protein attaches (binds) to a receptor protein on the cell surface, which turns on (activates) a group of related SMAD proteins. The SMAD proteins bind to the SMAD4 protein and form a protein complex, which then moves to the cell nucleus. In the nucleus, the SMAD protein complex binds to specific areas of DNA where it controls the activity of particular genes and regulates cell growth and division (proliferation). By controlling these cellular processes, the SMAD4 protein is involved in the development of many body systems.

The SMAD4 protein serves both as a transcription factor and as a tumor suppressor. Transcription factors help control the activity of particular genes, and tumor suppressors keep cells from growing and dividing too fast or in an uncontrolled way.

Source: MedlinePlus, National Library of Medicine. Source publication: 2023-05-02. Source review: 2020-02.

ClinGen reviews

ClinGen reviews the evidence linking a particular gene to a condition. Each rating below describes the strength of that link. It does not classify a variant in your DNA file.

Condition	Inheritance	Evidence
pulmonary arterial hypertensionMONDO:0015924 · Evaluated 2022-11-21	Autosomal dominant	DisputedPulmonary Hypertension Gene Curation Expert Panel
Myhre syndromeMONDO:0007688 · Evaluated 2025-10-29	Autosomal dominant	DefinitiveIntellectual Disability and Autism Gene Curation Expert Panel
juvenile polyposis/hereditary hemorrhagic telangiectasia syndromeMONDO:0008278 · Evaluated 2023-04-18	Autosomal dominant	DefinitiveHemostasis/Thrombosis Gene Curation Expert Panel

ClinVar records

These numbers show what has been submitted to ClinVar. They cannot tell you how likely you are to have a condition.

Submitted alleles: 2,698
Submissions for variants in or overlapping this gene: 6,220
Submissions explicitly reporting this gene: 6,149
Alleles reported pathogenic / likely pathogenic: 331
VariationIDs with uncertain significance: 1,145
VariationIDs with conflicting classifications: 169

The rows count different things: alleles, submissions or VariationIDs. Their categories can overlap, so do not add them together. Pathogenic/likely pathogenic counts exclude structural variants that merely overlap a gene. A dash in the source means “not reported,” not zero.

NCBI produces the gene-summary file each week using counts recorded at the start of the month. The numbers may differ from those on the live ClinVar website. Read the field definitions ↗

View this gene in ClinVar ↗

YOUR DNA FILE

Can your DNA file tell you about SMAD4?

From a DNA test kit (such as 23andMe, AncestryDNA or MyHeritage). These kits check a fixed list of about 600,000 to 700,000 positions across your whole genome. ClinVar lists 331 alleles in SMAD4 reported as pathogenic or likely pathogenic. A kit checks only some of these positions, and often none of them.

From whole genome sequencing (a VCF file). Sequencing reads most of your genome. Your file lists the places where your DNA differs from the reference genome. Some regions are hard to sequence, including parts of some genes that have near-identical copies elsewhere, and a VCF file does not record which positions were read well.

If a variant is not in your file, that does not mean you don’t have it.

What BioDecode checks

BioDecode compares every variant in your file with ClinVar, on your own computer. For each match, it shows the ClinVar classification, the review status and the condition it was reported for. Your file is not uploaded.

A ClinVar classification applies to one particular variant and the condition it was reported for. It does not tell you about other variants in SMAD4.

BioDecode cannot fill gaps in your test, diagnose a condition or replace clinical testing.

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