SMAD3

Chr 15

SMAD family member 3

NCBI Gene: 4088 ENSG00000166949 UniProt: P84022

The SMAD3 protein is an intracellular signal transducer that transmits TGF-beta signals from the cell surface to the nucleus, where it functions as a transcriptional modulator regulating gene expression, cell proliferation, and processes including chondrogenesis and osteogenesis. Mutations cause Loeys-Dietz syndrome 3, an autosomal dominant connective tissue disorder affecting the cardiovascular system, skeletal system, and other organs. The gene is highly constrained against loss-of-function variants (pLI 0.80, LOEUF 0.4), reflecting its essential role in development and cellular signaling.

ResearchSummary from RefSeq, OMIM, UniProt

Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD3/SMAD4 complex, activates transcription. Also can form a SMAD3/SMAD4/JUN/FOS complex at the AP-1/SMAD site to regulate TGF-beta-mediated transcription. Has an inhibitory effect on wound healing probably by modulating both growth and migration of primary keratinocytes and by altering the TGF-mediated chemotaxis of monocytes. This effect on wound healing appears to be hormone-sensitive. Regulator of chondrogenesis and osteogenesis and inhibits early healing of bone fractures. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtColorectal cancer

UniProtLoeys-Dietz syndrome 3

Clinical highlights

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

1128

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.40

LOEUF

LOF

Mechanism· G2P

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.40LOEUF

pLI 0.798

Z-score 3.66

OE 0.17 (0.09–0.40)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

3.48Z-score

OE missense 0.38 (0.33–0.46)

97 obs / 252.5 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.17 (0.09–0.40)

0≤0.351.4

Missense OE?0.38 (0.33–0.46)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 4 / 22.9Missense obs/exp: 97 / 252.5Syn Z: -0.96

Background carrier burden — how many people carry a rare variant somewhere in SMAD3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 200

464 rare PASS variants

Rare truncating (LoF)

1 in 1,300

66 rare PASS variants

Rare synonymous (reference)

1 in 130

271 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SMAD3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 320	1 in 2,900
South Asian	~43k	1 in 170	1 in 3,200
Remaining (unassigned)	~30k	1 in 140	1 in 1,300
European (Finnish)	~27k	1 in 460	≈ 1 in 6,300
Admixed American	~22k	1 in 180	1 in 1,700
African / African American	~21k	1 in 170	1 in 1,500
East Asian	~20k	1 in 210	1 in 680
Ashkenazi Jewish	~13k	1 in 890	1 in 2,100
Middle Eastern	~2,884	1 in 250	≈ 1 in 1,200

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 9 coding exons well covered in gnomAD exomes and genomes.? see exons ↓