# Platform to support clinical variant interpretation through probabilistic assessment of functional evidence

> **NIH NIH R44** · CONSTANTIAM BIOSCIENCES INC. · 2024 · $1,016,400

## Abstract

PROJECT SUMMARY
Advances in DNA sequencing technology have revolutionized the diagnosis and treatment of disease,
including cancer, cardiovascular disease, and neurodegeneration. Accurate clinical interpretation of genetic
variants can enable early detection, inform precision treatment plans, and improve patient outcomes. However,
the majority of unique variants uncovered by clinical genetic tests have insufficient evidence for confident
classification and are therefore categorized as “variants of uncertain significance” (VUS). The uncertainty
introduced by VUS impedes diagnosis, delays care, and increases unnecessary medical treatment.
Constantiam Biosciences has developed Varify, an innovative platform that addresses the VUS problem at
scale by leveraging the recent advent and rapid proliferation of Multiplexed Assays of Variant Effect, or MAVEs,
for variant classification. MAVEs generate functional data for thousands of variants in a single experiment and
have been shown to enable reclassification of 44% of VUS within each assayed gene. Leveraging these large
and complex datasets, however, is challenging and time-consuming for variant scientists at genetic testing
companies and diagnostic laboratories, who spend hours manually searching the literature and evaluating
MAVE datasets in an ad hoc and error-prone process. There are no commercial platforms that curate the
growing body of MAVEs and perform the rigorous analyses required to responsibly apply the data as evidence
within classification guidelines established by the American College of Medical Genetics (ACMG) and the
Association for Molecular Pathology (AMP).
Constantiam’s technology reduces the time spent searching and evaluating MAVE data by 90%, removing a
critical barrier by comprehensively curating MAVE data and transforming it into evidence that can be applied
towards classification in minutes. During Phase I, Constantiam Biosciences successfully built a prototype of
Varify, leveraging breakthroughs in Bayesian inference and probabilistic programming to analyze raw MAVE
data for use as evidence. In parallel, we developed a user-facing application, MAVEvidence, for presenting
data and generating evidence reports. The progress made in Phase I has laid a strong foundation for the
Phase II project, which includes the following aims: 1) Expand Varify to include all MAVEs for cancer genes,
and evaluate performance against clinically annotated variants; 2) Evaluate the functional evidence generated
by Varify using population data from UK Biobank; and 3) Integrate Varify-derived evidence into MAVEvidence
and develop automation capabilities for scalability. This proposed Phase II plan will enable Constantiam to
complete development of a first-to-market, commercial-ready functional evidence platform. At the end of Phase
II, genetic testing companies and diagnostic labs will be able to purchase Varify + MAVEvidence to reduce the
time spent searching and evaluating functional data by 90%, addr...

## Key facts

- **NIH application ID:** 10919315
- **Project number:** 2R44HG012535-02
- **Recipient organization:** CONSTANTIAM BIOSCIENCES INC.
- **Principal Investigator:** Nicholas Schafer
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,016,400
- **Award type:** 2
- **Project period:** 2023-01-23 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10919315

## Citation

> US National Institutes of Health, RePORTER application 10919315, Platform to support clinical variant interpretation through probabilistic assessment of functional evidence (2R44HG012535-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10919315. Licensed CC0.

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