# NM_005373.3(MPL):c.1145del (p.Pro382fs)

https://sugi.bio/variant/mpl-p-pro382fs

## Summary

**MPL p.Pro382fs (c.1145del)** is classified **Pathogenic/Likely pathogenic** in MPL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-03-15). Very rare (popmax 0.00134%, afr); Associated with congenital amegakaryocytic thrombocytopenia.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs759135440 · 2 submitters · 2 linked conditions · very rare (popmax 0.00134%, afr)

## For patients & families {#patients}

This is a change in the MPL gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to congenital amegakaryocytic thrombocytopenia.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 6 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0026560/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.Pro382fs |
| Coding change (HGVS c.) | c.1145del |
| MANE Select transcript | [NM_005373](https://www.ncbi.nlm.nih.gov/nuccore/NM_005373) |
| dbSNP | [rs759135440](https://www.ncbi.nlm.nih.gov/snp/rs759135440/) |
| Variant type | Deletion |
| Location | chr1:43346606-43346606 (GRCh38) |
| ClinVar | [VCV2501166](https://www.ncbi.nlm.nih.gov/clinvar/variation/2501166/) |

**All HGVS expressions:** `LRG_510:g.13806del`, `LRG_510t1:c.1145del`, `NC_000001.10:g.43812280del`, `NC_000001.11:g.43346609del`, `NG_007525.1:g.13806del`, `NM_005373.3:c.1145del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 3.051, GERP 2.04, phastCons 1 — highly conserved position (PP3-type support)
- 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.
- CADD: **PHRED 33.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- 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 **0.00134%** (afr) · 1/74,870 in the highest group · 1/1,613,988 alleles overall — very rare (popmax 0.00134%, afr).

*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}


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/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-03-15.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Pathogenic).

**Submission history:** 2 submissions (2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-03-15 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-02-14 |

## Associated conditions {#conditions}

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

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

## Same-residue context {#hotspot}

Residue **382** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MPL p.Pro382_Phe383insArgMetTer](/variant/mpl-p-pro382-phe383insargmetter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MPL variant pages (same residue, condition, or type): [MPL p.Pro382_Phe383insArgMetTer](/variant/mpl-p-pro382-phe383insargmetter), [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), [MPL p.Ile152fs](/variant/mpl-p-ile152fs).

### 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 2026-10-14); 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 2501166). 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.*