Clinical Report: 44,000 Protein Forms Mapped in Plasma

Overview

A bioRxiv preprint describes a draft atlas identifying 44,083 high-confidence plasma proteoforms across 2,089 protein groups, with a median of 11 proteoforms per protein. The findings document substantial molecular diversity and report that proteoform diversity may contribute to differences between Olink and SomaScan measurements.

Background

Proteins in plasma can occur in multiple forms, or proteoforms, arising from processes such as alternative splicing, cleavage, and post-translational modification. These forms may have different biological functions, while many proteomic assays report a single measurement for each protein. This distinction is relevant to biomarker research because assays targeting the same protein may recognize different proteoforms. The preprint presents an initial reference atlas, while noting that many detected forms were not fully identified at the molecular level.

Data Highlights

Key Findings

• The workflow combined depletion of 14 highly abundant plasma proteins, separation of intact proteins by physical properties, DIA mass spectrometry, and computational reconstruction of peptide-signal positions across fractions.
• The complete dataset contained 179,049 potential proteoforms representing 5,077 protein groups; 44,083 proteoforms from 2,089 groups met the study’s high-confidence criterion.
• The greatest proteoform diversity was observed among abundant proteins and proteins involved in nutrient transport, blood clotting, and the complement immune system.
• For each protein, the most abundant form accounted for less than half of the total measured peptide signal, indicating that other forms contributed substantially to the measured signal.
• Olink and SomaScan measurements generally agreed more closely for relatively abundant proteins with low or moderate proteoform diversity. Poor agreement was most often associated with low-concentration proteins, while high proteoform diversity may explain some discrepancies for more abundant proteins.
• The authors describe the atlas as an initial reference: most forms were not fully identified, and low-abundance or disease-associated forms may be underrepresented; some signals may represent related proteoform groups or proteins introduced through cellular contamination.

Clinical Implications

The authors note that assays designed to measure the same protein may recognize different proteoforms, potentially affecting comparisons between technologies and interpretation of biomarker results. The preprint identifies further work using top-down mass spectrometry, clinical cohorts, and samples from different populations as necessary to assess proteoform associations with normal biology and disease.

Conclusion

This draft atlas maps extensive proteoform diversity in human plasma and identifies a potential source of variation in affinity-based protein measurements. Its findings remain preliminary because many forms were not molecularly resolved and disease-specific relevance was not established.

Related Resources & Content

1. Authors not specified, bioRxiv, 2026 -- A draft atlas of the human plasma proteome at isoform resolution
2. Clinical and Laboratory Standards Institute, CLSI -- C62: Liquid Chromatography-Mass Spectrometry Methods
3. Nature Communications, 2025 -- Cross-ancestry comparison of aptamer and antibody protein measures
4. The Pathologist, 2014 -- Human Proteome Maps
5. The Analytical Scientist, 2025 -- Protein Mapping at Subcellular Resolution
6. The ASCO Post, 2014 -- Proteome-Scale Map of the Human Interactome Network Created
7. the pathologist — Deep Profiles
8. A draft atlas of the human plasma proteome at isoform resolution
9. C62: Liquid Chromatography-Mass Spectrometry Methods
10. Cross-ancestry comparison of aptamer and antibody protein measures
11. A draft atlas of the human plasma proteome at isoform resolution | bioRxiv
12. C62 | Liquid Chromatography-Mass Spectrometry Methods
13. Cross-ancestry comparison of aptamer and antibody protein measures | Nature Communications