SMAD5

Chr 5

SMAD family member 5

Also known as: DWFC, JV5-1, MADH5

NCBI Gene: 4090ENSG00000113658UniProt: Q99717

The protein encoded by this gene is involved in the transforming growth factor beta signaling pathway that results in an inhibition of the proliferation of hematopoietic progenitor cells. The encoded protein is activated by bone morphogenetic proteins type 1 receptor kinase, and may be involved in cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

0
ClinVar variants
0
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— SMAD5
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.16LOEUF
pLI 0.998
Z-score 4.01
OE 0.00 (0.00–0.16)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
3.00Z-score
OE missense 0.47 (0.40–0.54)
117 obs / 250.7 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.16)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.47 (0.40–0.54)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.91
0≤1.21.6
LoF obs/exp: 0 / 18.7Missense obs/exp: 117 / 250.7Syn Z: 0.64

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

SMAD5 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
📖
GeneReview available — SMAD5
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The Rare and Atypical Diabetes Network (RADIANT) Study: Design and Early Results.
RADIANT Study Group·Diabetes Care
2023
Bone morphogenetic proteins.
Chen D et al.·Growth Factors
2004Review
Haploinsufficient variants in SMAD5 are associated with isolated congenital heart disease.
Alankarage D et al.·HGG Adv
2025
SMAD5 as a novel gene for familial pulmonary arterial hypertension.
Cao D et al.·Clin Sci (Lond)
2025
Combination of bulk RNA and single-cell sequencing unveils PANoptosis-related immunological ecology hallmarks and classification for clinical decision-making in hepatocellular carcinoma.
Liu L et al.·Sci Rep
2024
Targeting the Liver Serine Protease TMPRSS6 Ameliorates Steatosis and Attenuates Fibrosis in Experimental MASLD.
Pettinato M et al.·Liver Int
2025
BMP signaling controls muscle mass.
Sartori R et al.·Nat Genet
2013
Erythroferrone inhibits the induction of hepcidin by BMP6.
Arezes J et al.·Blood
2018
MicroRNA-93-5p alleviates uric acid-induced fibrosis in renal tubular epithelial cells by regulating the SMAD5/Id2 signaling pathway.
Lu X et al.·Cell Signal
2025
Mesenchymal stem cells secretomes' affect multiple myeloma translation initiation.
Marcus H et al.·Cell Signal
2016
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools