SMAD9

Chr 13

SMAD family member 9

Also known as: MADH6, MADH9, PPH2, SMAD8, SMAD8/9, SMAD8A, SMAD8B

NCBI Gene: 4093 ENSG00000120693 UniProt: O15198

The encoded protein is a transcriptional modulator that transduces signals from bone morphogenetic proteins (BMPs) and interacts with SMAD4 in the TGF-beta signaling pathway. Mutations cause primary pulmonary hypertension type 2 with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants, indicating intolerance to haploinsufficiency.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a member of the SMAD family, which transduces signals from TGF-beta family members. The encoded protein is activated by bone morphogenetic proteins and interacts with SMAD4. Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2010]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtPulmonary hypertension, primary, 2

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · pulmonary arterial hypertension · AD · ClinGen 2021

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.85

LOEUF

Multiple*

Mechanism· predicted

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GeneReview available — SMAD9

Authoritative clinical overview · Recommended first read

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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?

0.85LOEUF

pLI 0.000

Z-score 2.06

OE 0.50 (0.31–0.85)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.52Z-score

OE missense 0.91 (0.82–1.01)

248 obs / 272.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.50 (0.31–0.85)

0≤0.351.4

Missense OE?0.91 (0.82–1.01)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 10 / 19.9Missense obs/exp: 248 / 272.2Syn Z: -1.03

Background carrier burden — how many people carry a rare variant somewhere in SMAD9?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 110

611 rare PASS variants

Rare truncating (LoF)

1 in 1,000

102 rare PASS variants

Rare synonymous (reference)

1 in 120

260 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SMAD9. 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 100	1 in 970
South Asian	~43k	1 in 120	1 in 1,100
Remaining (unassigned)	~30k	1 in 130	1 in 1,500
European (Finnish)	~27k	1 in 320	1 in 1,900
Admixed American	~22k	1 in 120	1 in 1,400
African / African American	~21k	1 in 83	1 in 1,500
East Asian	~20k	1 in 130	1 in 1,100
Ashkenazi Jewish	~13k	1 in 790	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 180	none seen

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 6 coding exons well covered in gnomAD exomes and genomes.? see exons ↓