SMAD6

Chr 15

SMAD family member 6

Also known as: AOVD2, HsT17432, MADH6, MADH7

NCBI Gene: 4091 ENSG00000137834 UniProt: O43541

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

The protein encoded by this gene belongs to the SMAD family of proteins, which are related to Drosophila 'mothers against decapentaplegic' (Mad) and C. elegans Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways. This protein functions in the negative regulation of BMP and TGF-beta/activin-signalling. Multiple transcript variants have been found for this gene.[provided by RefSeq, Sep 2014]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtAortic valve disease 2

UniProtCraniosynostosis 7

UniProtRadioulnar synostosis, non-syndromic

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · SMAD6-related disease · AD · ClinGen 2023

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.98

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

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

Background carrier burden — how many people carry a rare variant somewhere in SMAD6?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 59

1,208 rare PASS variants

Rare truncating (LoF)

1 in 640

398 rare PASS variants

Rare synonymous (reference)

1 in 95

482 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SMAD6. 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 84	1 in 680
South Asian	~43k	1 in 50	1 in 510
Remaining (unassigned)	~30k	1 in 57	1 in 750
European (Finnish)	~27k	1 in 130	1 in 520
Admixed American	~22k	1 in 57	1 in 470
African / African American	~21k	1 in 48	1 in 1,200
East Asian	~20k	1 in 67	1 in 630
Ashkenazi Jewish	~13k	1 in 330	1 in 480
Middle Eastern	~2,884	1 in 50	≈ 1 in 660

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): 3 of 4 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 4.? see exons ↓