# Understanding ABCA4 Variants of Unknown Significance Through Computational and Functional Approaches

> **NIH NIH R01** · UNIVERSITY OF DELAWARE · 2024 · $460,197

## Abstract

ABSTRACT
Variants in the ABCA4 gene are a fundamental cause of several inherited retinal degenerations (IRDs),
including Stargardt macular dystrophy, fundus flavimaculatus, and cone-rod dystrophy; these three ABCA4-
driven diseases cause blindness in 1.4 million people worldwide. As a result, genetic testing of ABCA4 is
increasingly common in clinical settings. Of the 1,485 identified missense variants in ABCA4, 50% are of
unknown pathogenicity (variants of unknown significance, VUS). This genetic uncertainty leads to three key
problems: (i) for IRD patients who have multiple unclassified ABCA4 mutations, it is impossible to predict
which variant will cause disease in relatives who have not yet developed the disease; (ii) development of
variant-specific therapies will remain limited; and (iii) these variants cannot be used to predict disease
prospectively, which facilitates important life-planning decisions for patients and which is critical to direct
patients to new clinical trials. Our proposed study aims to unravel the clinical significance of ABCA4 genetic
variants of unknown significance (VUS) using in silico and in vitro functional analyses in combination. In this
proposal, we have assembled a team of investigators with extensive expertise in complementary fields: protein
biochemistry, computational biology, bioimaging, and biostatistics to create a “sequence-structure-function”
workflow, whereby in silico 3D protein structural analysis of ABCA4 sequence variants will be used as a tool to
predict disease severity/clinical pathogenicity in combination with high throughput functional analysis. The
combined expertise of the investigators and our unique biochemical resources allow us to carry out this project.
Successful completion of this study will be a significant and critical step forward in understanding the biology
of ABCA4-mediated IRDs and the characterization of variants for pathogenicity risk prediction.
The proposal incorporates interrelated initiatives focused on DEIA (Diversity, Equity, Inclusion, and
Accessibility), which will include training opportunities for students at different stages of their careers,
interdisciplinary research training, fostering inclusive and collaborative team science, and engaging with
community stakeholders to raise awareness and generate interest in vision research. Together, these efforts will
contribute to the creation of a transformative framework that promotes diversity within the biomedical
research community while aligning with our scientific objectives.

## Key facts

- **NIH application ID:** 10853161
- **Project number:** 1R01EY036065-01
- **Recipient organization:** UNIVERSITY OF DELAWARE
- **Principal Investigator:** ESTHER Elissa BISWAS-FISS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $460,197
- **Award type:** 1
- **Project period:** 2024-06-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10853161

## Citation

> US National Institutes of Health, RePORTER application 10853161, Understanding ABCA4 Variants of Unknown Significance Through Computational and Functional Approaches (1R01EY036065-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10853161. Licensed CC0.

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