This track shows MPC v4.1.1 ("Missense deleteriousness Prediction by Constraint"), a machine-learning score that predicts which missense variants are likely to be deleterious. It was computed by the Broad Institute gnomAD team from the gnomAD v4.1.1 release of 730,947 exomes aligned to GRCh38/hg38. Scores are provided for every possible single-nucleotide -missense variant in 17,841 MANE Select or canonical protein-coding -transcripts that passed gnomAD QC, as well as for an additional 1,534 -transcripts that failed QC (the authors note that scores may be less -accurate in these 1,534 transcripts). +missense variant across 18,245 MANE Select or canonical protein-coding +transcripts.
Missense variants change a single amino acid in a protein and are a common source of variants of uncertain significance (VUS): about 90% of missense variants in ClinVar are VUS. MPC predicts which missense variants are likely deleterious by combining three lines of evidence: (i) regional missense constraint (how depleted the surrounding sub-genic region is of rare missense variation in the general population), (ii) the biochemical severity of the specific amino-acid substitution and additional protein-structure and homology information from PolyPhen-2, and (iii) cross-species conservation (phyloP). Higher scores indicate greater predicted deleteriousness.
This data is available as two separate tracks:
The MPC track on hg19 is an older release of the MPC score, calculated on gnomAD v2 (125,748 exomes) rather than gnomAD v4 (730,947 exomes).
| Color | Max MPC range |
|---|---|
| < 1 | |
| 1 – 2 | |
| 2 – 3 | |
| ≥ 3 |
For each of 17,841 QC-passing MANE Select or canonical coding transcripts, the authors tallied the observed rare missense variants (allele count > 0, allele frequency < 0.1%, %AN ≥ 20, QC PASS) in gnomAD v4.1.1 against the expected count under a position- and coverage-adjusted mutational model. A recursive likelihood-ratio test (Poisson model, p-value threshold 0.001, minimum 16 expected missense variants per sub-region) identifies change-points at which the transcript-wide observed/expected (OE) ratio deviates significantly; each resulting segment is a missense constraint region (MCR). 36% of transcripts (6,361/17,841) harbor two or more MCRs. MCR missense OE was calibrated against ClinVar P/LP vs. B/LB missense variants following ClinGen recommendations for the ACMG/AMP guidelines: OE ≤ 0.36 meets moderate evidence for pathogenicity, OE ≤ 0.59 meets supporting evidence for pathogenicity, OE > 0.97 and OE > 1.23 meet supporting and moderate evidence for benignity, respectively.
MPC is an XGBoost gradient-boosted-tree classifier that takes as input (1) MCR missense OE, (2) gene-level constraint, (3) a per-substitution amino-acid severity feature, (4) the PolyPhen-2 pathogenicity score, and (5) phyloP conservation. The model is trained to distinguish pathogenic missense variants under strong heterozygous selection from benign missense variants under neutral to near-neutral selection. Training: 20,931 "pathogenic" variants (high-quality ClinVar P/LP in 2,987 haploinsufficient genes with pHaplo ≥ 0.86 or in 359 non-LoF DD genes from Gene2Phenotype) vs. 93,638 "benign" variants (high-quality ClinVar B/LB or gnomAD variants with AF > 0.1% in the same gene set). The model is applied to all 70,313,598 possible exome-wide missense variants in the Ensembl VEP table. For a variant i, MPC is di = log10(M / mi), where M is the number of benign training variants and mi is the number of those with a fitted pathogenicity probability lower than variant i's; when mi is 0 the score is capped at 6. Restricted to genes already known to cause developmental disorders, the authors report that de novo variants with MPC ≥ 2.5 are strongly enriched in affected individuals relative to their unaffected siblings, with MPC 2–2.5 showing intermediate enrichment and MPC < 2 little enrichment. The authors caution that MPC is best suited to modelling strong fitness effects (as expected given its training set) and that naively taking the maximum of MPC and AlphaMissense decreases case/control discrimination for de novo variants relative to either score alone. Code for calculating the MPC scores and MCRs is available at the broadinstitute/regional_missense_constraint GitHub repository.
The precomputed MPC score table was downloaded from the gnomAD Broad public bucket at gs://gcp-public-data--gnomad/papers/2026-rmc/gnomad_v4.1.1_mpc.tsv.bgz, companion to the Hail-table release gnomad_v4.1.1_mpc.ht in the same directory. The input TSV contains one row per (locus, alleles, transcript) combination, for 70M rows. Two Python scripts convert to bigWig/bigBed formats, available on GitHub. Build commands are documented in the gnomadMpc.txt makeDoc file.
The raw data can be explored interactively with the Table Browser or the Data Integrator. For automated access, this track is available via our API. The underlying bigWig and bigBed files are at our download server as a.bw, c.bw, g.bw, t.bw, and mpcOverlaps.bb. Individual positions or whole chromosomes can be extracted with bigWigToBedGraph / bigWigToWig (for the bigWigs) or bigBedToBed (for the bigBed), for example:
bigWigToBedGraph -chrom=chr1 -start=100000 -end=100500 \
http://hgdownload.soe.ucsc.edu/gbdb/hg38/gnomAD/mpc/a.bw stdout
The original MPC table and the accompanying missense constraint regions can be downloaded from the gnomAD downloads page.
Thanks to the gnomAD production team and the Samocha and MacArthur laboratories for generating and releasing the MPC scores.
Wang L, Chao KR, Panchal R, Liao C, Abderrazzaq H, Ye R, Schultz P, Compitello J, Grant RH, Kosmicki JA, Weisburd B, Phu W, Wilson MW, Laricchia KM, Goodrich JK, Goldstein D, Goldstein JI, Vittal C, Poterba T, Baxter S, Watts NA, Solomonson M, gnomAD consortium, Tiao G, Rehm HL, Neale BM, Talkowski ME, MacArthur DG, O'Donnell-Luria A, Karczewski KJ, Radivojac P, Daly MJ, Samocha KE. The landscape of regional missense mutational intolerance quantified from 730,947 exomes. bioRxiv April 23, 2026; doi: 10.1101/2024.04.11.588920.