ABCA7

Chr 19AD

ATP binding cassette subfamily A member 7

Also known as: ABCA-SSN, ABCX, AD9

NCBI Gene: 10347 ENSG00000064687 UniProt: Q8IZY2 OMIM: 605414

The ABCA7 protein is an ATP-binding cassette transporter that catalyzes phospholipid translocation across cell membranes and plays important roles in lipid homeostasis, macrophage-mediated phagocytosis, and clearance of amyloid-beta by microglial cells. Mutations cause autosomal dominant susceptibility to Alzheimer disease. The gene shows tolerance to loss-of-function variants (LOEUF 1.067), suggesting that complete loss of function may not be the primary disease mechanism in affected individuals.

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 ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. This full transporter has been detected predominantly in myelo-lymphatic tissues with the highest expression in peripheral leukocytes, thymus, spleen, and bone marrow. The function of this protein is not yet known; however, the expression pattern suggests a role in lipid homeostasis in cells of the immune system. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 1.071 OMIM phenotype

Clinical Summary— ABCA7

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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 unique Pathogenic / Likely Pathogenic· 369 VUS of 566 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.07LOEUF

pLI 0.000

Z-score 0.97

OE 0.90 (0.75–1.07)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.47Z-score

OE missense 1.11 (1.06–1.16)

1516 obs / 1363.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.90 (0.75–1.07)

0≤0.351.4

Missense OE?1.11 (1.06–1.16)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 90 / 100.5Missense obs/exp: 1516 / 1363.2Syn Z: -1.07

This gene — mechanism propensity

0.6259th %ile

GOF

0.72top 25%

LOF

0.3066th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, loss-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

LOF1 literature citation · 100% of P/LP variants are LoF

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

LOFIn a patient with late-onset Alzheimer disease-9 (AD9; 608907), Cuyvers et al. (2015) identified a heterozygous c.3641G-A transition (c.3641G-A, NM_019112.3) in exon 27 of the ABCA7 gene, resulting in a trp1214-to-ter (W1214X) substitution. The variant was not found in 757 controls. Patient brain ti1

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

References

1.PMID 26141617 ↗

ClinVar Variant Classifications

566 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic21

VUS369

Likely Benign81

Benign34

Conflicting12

Pathogenic

Likely Pathogenic

369

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	0	0	0	3
Likely Pathogenic	21	0	0	0	21
VUS	13	352	3	1	369
Likely Benign	0	33	12	36	81
Benign	1	14	9	10	34
Conflicting	—				12
Total	38	399	24	47	520

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

32 pathogenic / likely-pathogenic (of 43) ClinVar copy-number / structural variants overlap ABCA7 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →