# NM_005373.3(MPL):c.1182A>C (p.Pro394=)

https://sugi.bio/variant/mpl-p-pro394

## Summary

**MPL p.Pro394= (c.1182A>C)** is classified **Likely benign** in MPL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-17). Absent from gnomAD v4.1; Associated with congenital amegakaryocytic thrombocytopenia.

**At a glance:** Likely benign · review: Single submitter · rsID rs2545683089 · 1 submitter · 2 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the MPL gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, 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.Pro394= |
| Coding change (HGVS c.) | c.1182A>C |
| MANE Select transcript | [NM_005373](https://www.ncbi.nlm.nih.gov/nuccore/NM_005373) |
| dbSNP | [rs2545683089](https://www.ncbi.nlm.nih.gov/snp/rs2545683089/) |
| Variant type | single nucleotide variant |
| Location | chr1:43346808-43346808 (GRCh38) |
| ClinVar | [VCV2949977](https://www.ncbi.nlm.nih.gov/clinvar/variation/2949977/) |

**All HGVS expressions:** `LRG_510:g.14005A>C`, `LRG_510t1:c.1182A>C`, `NC_000001.10:g.43812479A>C`, `NC_000001.11:g.43346808A>C`, `NG_007525.1:g.14005A>C`, `NM_005373.3:c.1182A>C`

## 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 -0.04, GERP -0.499, phastCons 0.018 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 6.684**. 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: **below the reporting threshold**. This position is scored for a different substitution (A>G, Δ0.20 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **394** lies in the fibronectin type-iii 2 domain; an α-helix.

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. p.Pro394= falls in the fibronectin type-iii 2 domain.


### 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-07-17.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-07-17 |

## 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.

## Similar variants {#similar}

Related MPL variant pages (same residue, condition, or type): [MPL p.Pro394Ala](/variant/mpl-p-pro394ala), [MPL c.1165+1G>C](/variant/mpl-c-1165-plus-1g-c), [MPL c.1166-1G>C](/variant/mpl-c-1166-minus-1g-c), [MPL c.1468+2T>C](/variant/mpl-c-1468-plus-2t-c), [MPL c.1469-2A>T](/variant/mpl-c-1469-minus-2a-t), [MPL c.1566-1G>A](/variant/mpl-c-1566-minus-1g-a), [MPL c.1653+1G>C](/variant/mpl-c-1653-plus-1g-c), [MPL c.79+2T>A](/variant/mpl-c-79-plus-2t-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2949977). 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.*