44,000 Protein Forms Mapped in Plasma

DIA mass spectrometry maps extensive proteoform diversity in human plasma

October 19, 2026
3 min

The Analytical Scientist

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

Measure	Reported result
Potential proteoforms detected	179,049 across 5,077 protein groups
High-confidence proteoforms	44,083 across 2,089 protein groups
High-confidence criterion	Detected in at least three of four replicate gel experiments
Median high-confidence proteoforms per protein	11
Protein fractions generated	3,114
Most abundant proteoform	Accounted for less than half of its protein’s total measured peptide signal

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.