# NM_005373.3(MPL):c.305G>C (p.Arg102Pro)

https://sugi.bio/variant/mpl-p-arg102pro

## Summary

**MPL p.Arg102Pro (c.305G>C)** is classified **Pathogenic** in MPL (ClinVar, Multiple submitters, 25 submitters; last evaluated 2026-01-22). AlphaMissense: likely pathogenic (0.8371); Ultra-rare (popmax 0.0586%, nfe); Associated with thrombocythemia 2.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs28928907 · 25 submitters · 7 linked conditions · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0586%, nfe)

## For patients & families {#patients}

This is a change in the MPL gene that is considered disease-causing, submitted by 25 submitters, and is linked to thrombocythemia 2.

*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) | Autosomal dominant, X-linked recessive |
| Age of onset (of this condition) | Childhood |
| Prevalence | <1 / 1 000 000 (Worldwide) |
| Diagnostic panels | MPL is a diagnostic-grade gene on 5 Genomics England panels |

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

- Abnormal bleeding — Very frequent (99-80%)
- Thrombocytosis — Very frequent (99-80%)
- Arterial thrombosis — Very frequent (99-80%)
- Venous thrombosis — Very frequent (99-80%)
- Hyperhidrosis — Frequent (79-30%)
- Pruritus — Frequent (79-30%)
- Splenomegaly — Frequent (79-30%)
- Headache — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024778/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.Arg102Pro |
| Coding change (HGVS c.) | c.305G>C |
| MANE Select transcript | [NM_005373](https://www.ncbi.nlm.nih.gov/nuccore/NM_005373) |
| dbSNP | [rs28928907](https://www.ncbi.nlm.nih.gov/snp/rs28928907/) |
| Variant type | single nucleotide variant |
| Location | chr1:43338634-43338634 (GRCh38) |
| ClinVar | [VCV14158](https://www.ncbi.nlm.nih.gov/clinvar/variation/14158/) |

**All HGVS expressions:** `LRG_510:g.5831G>C`, `LRG_510t1:c.305G>C`, `NC_000001.10:g.43804305G>C`, `NC_000001.11:g.43338634G>C`, `NG_007525.1:g.5831G>C`, `NM_005373.3:c.305G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8371) — concordant with the pathogenic call
- REVEL 0.517 (indeterminate)
- SaProt LLR -8.789 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- Conservation: phyloP 11.876, GERP 1.91, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 6%** most-pathogenic-predicted substitutions in MPL (of 3,675 modeled).
- CADD: **PHRED 27.5**. 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.*
- Regional missense constraint: **o/e 0.80** across the covering region of the MANE Select transcript (43,337,849–43,346,796), spanning 8,947 bp. Chi-square p 8.9e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0586%** (nfe) · FAF95 0.0549% · FAF99 0.0535% · 691/1,180,008 in the highest group · 734/1,614,132 alleles overall — ultra-rare (popmax 0.0586%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0586% | 1,708 |
| Remaining individuals (not grpmax-eligible) | 0.032% | 3,125 |
| Finnish (not grpmax-eligible) | 0.0141% | 7,115 |
| African / African-American | 0.0107% | 9,378 |
| Admixed American | 0.00833% | 12,006 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,608 |

*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 **102** lies in a UniProt-annotated variant site (in camt1); a UniProt-annotated variant site (in camt1; loss of function; loss of membrane localization, impaired glycosylation).

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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-22.

**Submitter consensus:** conflicting (24 Pathogenic, 1 not provided, 1 Likely pathogenic).

**Submission history:** 26 submissions (2008–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Pathogenic | criteria provided, single submitter | clinical testing | 2021-10-14 |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-04-09 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Pathogenic | criteria provided, single submitter | research | 2022-11-25 |
| Revvity Omics, Revvity | Pathogenic | criteria provided, single submitter | clinical testing | 2024-02-12 |
| Natera, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-10-06 |
| ITMI | not provided | no classification provided | reference population | 2013-09-19 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2017-04-17 |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Pathogenic | no assertion criteria provided | clinical testing |  |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2008-06-01 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Pathogenic | criteria provided, single submitter | clinical testing | 2023-12-13 |
| Johns Hopkins Genomics, Johns Hopkins University | Pathogenic | criteria provided, single submitter | clinical testing | 2024-08-05 |
| OLLIN Analises Genomicas, OLLIN | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-09 |
| Dasa | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-14 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2024-11-01 |
| NIHR Bioresource Rare Diseases, University of Cambridge | Pathogenic | criteria provided, single submitter | research | 2019-02-01 |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Pathogenic | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Pathogenic | no assertion criteria provided | clinical testing |  |
| Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Pathogenic | criteria provided, single submitter | clinical testing | 2024-08-22 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2021-05-06 |
| Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-04 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-27 |
| NIHR Bioresource Rare Diseases, University of Cambridge | Likely pathogenic | no assertion criteria provided | research |  |
| Mayo Clinic Laboratories, Mayo Clinic | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-22 |
| First Genomix Gene Laboratory, Genetic Diagnostics Department | Pathogenic | criteria provided, single submitter | clinical testing | 2025-06-17 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-10-18 |

## Associated conditions {#conditions}

[thrombocythemia 2](https://sugi.bio/atlas/disease/thrombocythemia-2/), [thrombocytopenia](https://sugi.bio/atlas/disease/thrombocytopenia/), [essential thrombocythemia](https://sugi.bio/atlas/disease/essential-thrombocythemia/), [primary myelofibrosis](https://sugi.bio/atlas/disease/primary-myelofibrosis/), [long QT syndrome 2](https://sugi.bio/atlas/disease/long-qt-syndrome-2/), [congenital amegakaryocytic thrombocytopenia](https://sugi.bio/atlas/disease/congenital-amegakaryocytic-thrombocytopenia/), [congenital amegakaryocytic thrombocytopenia 1](https://sugi.bio/atlas/disease/congenital-amegakaryocytic-thrombocytopenia-1/).

**Reported phenotype names (ClinVar):** Thrombocythemia 2, Congenital amegakaryocytic thrombocytopenia, not specified, Thrombocytopenia, Essential thrombocythemia, not provided, Congenital amegakaryocytic thrombocytopenia 1, Primary myelofibrosis, Long QT syndrome 2, MPL-related disorder.

## Same-residue context {#hotspot}

Residue **102** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [MPL p.Arg102Cys](/variant/mpl-p-arg102cys), [MPL p.Arg102His](/variant/mpl-p-arg102his). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MPL variant pages (same residue, condition, or type): [MPL p.Arg102Cys](/variant/mpl-p-arg102cys), [MPL p.Arg102His](/variant/mpl-p-arg102his), [MPL p.Arg102=](/variant/mpl-p-arg102), [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).

### 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 14158). 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.*