-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. The MPC score ("Missense deleteriousness -Prediction by Constraint") is a machine-learning score that flags missense -variants likely to be 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 as captured by -PolyPhen-2, and (iii) cross-species conservation (phyloP). The model is -trained to separate pathogenic from benign missense variation under strong -heterozygous selection; higher scores indicate greater predicted -deleteriousness. The authors report that MPC ≥ 2.5 is strongly -enriched for de novo variants in individuals with severe developmental -disorders relative to their unaffected siblings, with MPC 2–2.5 showing -intermediate enrichment and MPC < 2 little enrichment. +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).
-This track shows MPC v4.1.1, computed by the Broad Institute gnomAD team from -the gnomAD v4.1.1 release of 730,947 exomes aligned to GRCh38. 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 the latter). Our 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). +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.
--Two views of the same underlying data are available: +This data is available as two separate tracks:
-Across the 250,000 multi-transcript variants, per-transcript MPC scores -typically agree within 0.5 units; only a few percent differ by more than -0.5. The bigBed view is the authoritative source for the full -transcript-level detail in those cases; the bigWig view collapses -transcripts by showing the maximum MPC at each position. +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 | +
-Regional missense constraint (MCR). For each of 17,841 QC-passing +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 score. MPC is an XGBoost gradient-boosted-tree classifier that +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. Training: 20,931 +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. Higher scores -indicate greater predicted deleteriousness. The authors caution that MPC is +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.
+-At UCSC. The precomputed MPC score table was downloaded from the +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, +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 in src/hg/makeDb/scripts/gnomadMpc -convert to bigWig/bigBed formats. Build commands are documented -in the +href="https://github.com/ucscGenomeBrowser/kent/tree/master/src/hg/makeDb/scripts/gnomadMpc">Two Python scripts +convert to bigWig/bigBed formats, available on GitHub. Build commands are +documented in the hg38/gnomadMpc.txt +href="https://github.com/ucscGenomeBrowser/kent/blob/master/src/hg/makeDb/doc/hg38/gnomadMpc.txt">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