# NM_005373.3(MPL):c.1025del (p.Pro342fs)

https://sugi.bio/variant/mpl-p-pro342fs

## Summary

**MPL p.Pro342fs (c.1025del)** is classified **Pathogenic** in MPL (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-20). Very rare (popmax 0.00891%, eas); Associated with essential thrombocythemia.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1286303912 · 1 submitter · 2 linked conditions · very rare (popmax 0.00891%, eas)

## For patients & families {#patients}

This is a change in the MPL gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to essential thrombocythemia.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Multigenic/multifactorial, Not applicable |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-5 / 10 000 (United States) |
| Clinical trials | 104 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | MPL is a diagnostic-grade gene on 5 Genomics England panels |

**Commonly reported features of Essential thrombocythemia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Myocardial infarction — Very frequent (99-80%)
- Abnormality of thrombocytes — Very frequent (99-80%)
- Thrombocytosis — Very frequent (99-80%)
- Prolonged bleeding time — Very frequent (99-80%)
- Paresthesia — Very frequent (99-80%)
- Arterial thrombosis — Very frequent (99-80%)
- Venous thrombosis — Very frequent (99-80%)
- Increased megakaryocyte count — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006594/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MPL](https://sugi.bio/atlas/gene/MPL/) |
| Protein change (HGVS p.) | p.Pro342fs |
| Coding change (HGVS c.) | c.1025del |
| MANE Select transcript | [NM_005373](https://www.ncbi.nlm.nih.gov/nuccore/NM_005373) |
| dbSNP | [rs1286303912](https://www.ncbi.nlm.nih.gov/snp/rs1286303912/) |
| Variant type | Deletion |
| Location | chr1:43346488-43346488 (GRCh38) |
| ClinVar | [VCV1074655](https://www.ncbi.nlm.nih.gov/clinvar/variation/1074655/) |

**All HGVS expressions:** `LRG_510:g.13686del`, `NC_000001.10:g.43812160del`, `NC_000001.11:g.43346489del`, `NG_007525.1:g.13686del`, `NM_005373.3:c.1025del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -0.977, GERP -4.01 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.022, pLI 3.3405e-21. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 of 12**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00891%** (eas) · FAF95 0.00298% · FAF99 0.0018% · 4/44,876 in the highest group · 4/1,461,892 alleles overall — very rare (popmax 0.00891%, eas).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**MPL** population constraint: LOEUF 1.022, pLI 3.3405e-21, missense-Z 1.7057. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **thrombocythemia 2** — Definitive (AD)
- **congenital amegakaryocytic thrombocytopenia 1** — Definitive (AR)

## Protein context {#protein}

Residue **342** lies in a disulfide bond.

AlphaFold model confidence (whole protein): pLDDT 73.44, 33% of residues very-high.

**1 experimental structure(s)** (PDB): [8G04](https://www.rcsb.org/structure/8G04).

## What this gene does {#gene-function}

*Describes the biological roles of MPL (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** MPL's established molecular role includes thrombopoietin receptor activity.


### Pathways affected {#pathways}

MPL participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Platelet Aggregation (Plug Formation)](https://reactome.org/content/detail/R-HSA-76009) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** thrombopoietin receptor activity.

**Biological process:** thrombopoietin-mediated signaling pathway, regulation of hemopoiesis.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-01-20.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-20 |

## Associated conditions {#conditions}

[essential thrombocythemia](https://sugi.bio/atlas/disease/essential-thrombocythemia/), [congenital amegakaryocytic thrombocytopenia](https://sugi.bio/atlas/disease/congenital-amegakaryocytic-thrombocytopenia/).

**Reported phenotype names (ClinVar):** Essential thrombocythemia, Congenital amegakaryocytic thrombocytopenia, essential thrombocytemia, Suspected essential thromboythemia.

## Similar variants {#similar}

Related MPL variant pages (same residue, condition, or type): [MPL p.Pro342Gln](/variant/mpl-p-pro342gln), [MPL p.Pro342=](/variant/mpl-p-pro342), [MPL c.1653+1del](/variant/mpl-c-1653-plus-1del), [MPL p.Arg325fs](/variant/mpl-p-arg325fs), [MPL p.Cys422fs](/variant/mpl-p-cys422fs), [MPL p.Cys77fs](/variant/mpl-p-cys77fs), [MPL p.Glu439fs](/variant/mpl-p-glu439fs), [MPL p.Ile138fs](/variant/mpl-p-ile138fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1074655). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*