SMAD6

Chr 15

SMAD family member 6

SMAD6 encodes an inhibitory SMAD protein that negatively regulates BMP and TGF-beta signaling pathways, which are critical for bone, cartilage, and cardiovascular development. Mutations cause autosomal dominant craniosynostosis, radioulnar synostosis, and aortic valve disease. The gene is not highly constrained against loss-of-function variants, consistent with its role in developmental disorders affecting specific tissue types rather than causing severe multisystem disease.

ResearchSummary from RefSeq, OMIM, UniProt

Acts as an inhibitory regulator of signaling mediated by the TGF-beta superfamily, with strong selectivity toward BMP-dependent pathways (PubMed:10647776, PubMed:10708948, PubMed:10708949, PubMed:16951688, PubMed:22275001, PubMed:30848080, PubMed:9436979, PubMed:9759503). Suppresses IL1R-TLR signaling through its direct interaction with PEL1, preventing NF-kappa-B activation, nuclear translocation and NF-kappa-B-mediated expression of pro-inflammatory genes (PubMed:16951688). Blocks the BMP-SMAD1 signaling pathway by competing with SMAD4 for receptor-activated SMAD1-binding (PubMed:30848080, PubMed:9436979). Associates with regulatory elements in target promoter regions (PubMed:16491121). Functions as an adapter protein that recruits ubiquitin ligases, including SMURF1 and, in some contexts, SMURF2, promoting proteasomal degradation of signaling components and transcription factors such as RUNX2, TBX6, BMPR1A and MYD88 (PubMed:16299379, PubMed:19561075, PubMed:28847510)

ResearchGenerating clinical summary…

LOFmechanismLOEUF 1.98

Clinical Summary— SMAD6

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Gene-Disease Validity (ClinGen)

SMAD6-related disease · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

34 unique Pathogenic / Likely Pathogenic· 334 VUS of 493 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (2)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.98LOEUF

pLI 0.000

Z-score -3.07

OE 1.97 (1.31–1.98)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.59Z-score

OE missense 1.11 (1.00–1.23)

249 obs / 224.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.97 (1.31–1.98)

0≤0.351.4

Missense OE?1.11 (1.00–1.23)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 23 / 11.7Missense obs/exp: 249 / 224.1Syn Z: 0.37

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedSMAD6-related non-syndromic craniosynostosisLOFAD

This gene — mechanism propensity

0.3693th %ile

GOF

0.3888th %ile

LOF

0.66top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 88% of P/LP variants are LoF

Literature Evidence

LOFIn addition, none of the 18 family members who carried only the rs1884302 risk allele, including 2 homozygotes, had craniosynostosis. Segregation analysis in a parametric 2-locus linkage model yielded a 7.37 maximum lod score. Of the 13 SMAD6 variants, 8 were frameshift or premature termination muta1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 27606499 ↗

ClinVar Variant Classifications

493 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13

Likely Pathogenic21

VUS334

Likely Benign101

Conflicting19

Pathogenic

Likely Pathogenic

334

VUS

101

Likely Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	11	2	0	0	13
Likely Pathogenic	19	2	0	0	21
VUS	54	274	6	0	334
Likely Benign	0	3	12	86	101
Benign	0	0	0	0	0
Conflicting	—				19
Total	84	281	18	86	488

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

4 pathogenic / likely-pathogenic (of 5) ClinVar copy-number / structural variants overlap SMAD6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →