ABCC8

Chr 11ADAR

ATP binding cassette subfamily C member 8

Also known as: ABC36, HHF1, HI, HRINS, MODY12, MRP8, PHHI, PNDM3

NCBI Gene: 6833 ENSG00000006071 UniProt: Q09428 OMIM: 600509

The ABCC8 protein is a regulatory subunit of pancreatic ATP-sensitive potassium channels that controls insulin release by forming KATP channels with KCNJ11. Mutations cause a spectrum of glucose homeostasis disorders including neonatal hyperinsulinemic hypoglycemia, transient and permanent neonatal diabetes, and maturity-onset diabetes of the young type 12. Inheritance can be either autosomal dominant or autosomal recessive depending on the specific condition and mutation.

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 functions as a modulator of ATP-sensitive potassium channels and insulin release. Mutations in the ABCC8 gene and deficiencies in the encoded protein have been observed in patients with hyperinsulinemic hypoglycemia of infancy, an autosomal recessive disorder of unregulated and high insulin secretion. Mutations have also been associated with non-insulin-dependent diabetes mellitus type II, an autosomal dominant disease of defective insulin secretion. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2020]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.776 OMIM phenotypes

Clinical Summary— ABCC8

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Gene-Disease Validity (ClinGen)

monogenic diabetes · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

4 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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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.77LOEUF

pLI 0.000

Z-score 3.35

OE 0.61 (0.48–0.77)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.91Z-score

OE missense 0.82 (0.77–0.87)

752 obs / 914.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.61 (0.48–0.77)

0≤0.351.4

Missense OE?0.82 (0.77–0.87)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 51 / 84.2Missense obs/exp: 752 / 914.9Syn Z: -0.85

This gene — mechanism propensity

0.78top 25%

GOF

0.80top 10%

LOF

0.2288th %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

GOFHeterogeneous nature of diabetes in a family with a gain-of-function mutation in the ATP-binding cassette subfamily C member 8 (ABCC8) gene1

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

References