ABCC9

Chr 12ADAR

ATP binding cassette subfamily C member 9

Also known as: ABC37, ATFB12, CANTU, CMD1O, IDMYS, SUR2

NCBI Gene: 10060 ENSG00000069431 UniProt: O60706 OMIM: 601439

This protein forms ATP-sensitive potassium channels in cardiac, skeletal, and smooth muscle by serving as the regulatory subunit that enables channel activation, while partnering with other proteins that form the channel pore. Mutations cause a spectrum of conditions including Cantu syndrome (hypertrichotic osteochondrodysplasia with intellectual disability), dilated cardiomyopathy, and familial atrial fibrillation, with inheritance patterns that can be either autosomal dominant or autosomal recessive. The gene is highly constrained against loss-of-function variants, indicating that complete loss of protein function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MRP subfamily which is involved in multi-drug resistance. This protein is thought to form ATP-sensitive potassium channels in cardiac, skeletal, and vascular and non-vascular smooth muscle. Protein structure suggests a role as the drug-binding channel-modulating subunit of the extra-pancreatic ATP-sensitive potassium channels. Mutations in this gene are associated with cardiomyopathy dilated type 1O. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2011]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.484 OMIM phenotypes

Clinical Summary— ABCC9

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Gene-Disease Validity (ClinGen)

hypertrichotic osteochondrodysplasia Cantu type · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

3 total gene-disease associations curated

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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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.48LOEUF

pLI 0.000

Z-score 5.49

OE 0.36 (0.27–0.48)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

4.97Z-score

OE missense 0.52 (0.48–0.56)

432 obs / 836.4 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.36 (0.27–0.48)

0≤0.351.4

Missense OE?0.52 (0.48–0.56)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 30 / 84.4Missense obs/exp: 432 / 836.4Syn Z: 0.01

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateABCC9-related intellectual disability, myopathy and white matter abnormalitiesLOFAR

limitedABCC9-related dilated cardiomyopathyOTHERAD

definitiveABCC9-related Cantu SyndromeGOFAD

This gene — mechanism propensity

0.75top 25%

GOF

0.78top 25%

LOF

0.2485th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFCantu syndrome (CS) is a rare developmental disorder characterized by a coarse facial appearance, macrocephaly, hypertrichosis, skeletal and cardiovascular anomalies and caused by heterozygous gain-of-function variants in ABCC9 and KCNJ8, encoding subunits of heterooctameric ATP-sensitive potassium 1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References