ABCA1

Chr 9ADAR

ATP binding cassette subfamily A member 1

Also known as: ABC-1, ABC1, CERP, HDLCQTL13, HDLDT1, HPALP1, TGD

NCBI Gene: 19 ENSG00000165029 UniProt: O95477

The membrane-associated 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 intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. With cholesterol as its substrate, this protein functions as a cholesteral efflux pump in the cellular lipid removal pathway. Mutations in both alleles of this gene cause Tangier disease and familial high-density lipoprotein (HDL) deficiency. [provided by RefSeq, Sep 2019]

Primary Disease Associations & Inheritance

HDL deficiency, familial, 1MIM #604091

Tangier diseaseMIM #205400

UniProtHypoalphalipoproteinemia, primary, 1

Active trials

Pathogenic / LP

443

ClinVar variants

Pubs (1 yr)

1.8

Missense Z

0.49

LOEUF

Clinical Summary— ABCA1

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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

24 Pathogenic / Likely Pathogenic· 203 VUS of 443 total submissions

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Clinical Trials

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

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GeneReview available — ABCA1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.49LOEUF

pLI 0.000

Z-score 6.23

OE 0.38 (0.30–0.49)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

1.75Z-score

OE missense 0.86 (0.81–0.90)

1029 obs / 1200.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.38 (0.30–0.49)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.86 (0.81–0.90)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.08

0≤1.21.6

LoF obs/exp: 44 / 116.5Missense obs/exp: 1029 / 1200.0Syn Z: -1.39

0.74top 25%

GOF

0.74top 25%

LOF

0.2288th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative, gain-of-function and loss-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports dominant-negative. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median

LOF63% of P/LP variants are LoF · LOEUF 0.49

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

DNOur results suggest that the severe reduction of HDL-C in patients with truncation mutations may be at least partly explained by dominant negative suppression of expression and activity of the remaining full-length ABCA1 allele.PMID:12401893

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