MRPS2
protein-codingmitochondrial ribosomal protein S2, the group of Small subunit mitochondrial ribosomal proteins|Mitochondrial ribosomal proteins
Gene summary
Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 28S subunit protein that belongs to the ribosomal protein S2 family. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, May 2012]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~4.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0054781
Submitter: Ambry Genetics
Inheritance Pattern: Unknown
Disease ID:MONDO:0054781
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0054781
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0054781
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0044970
Submitter: ClinGen
The relationship between *MRPS2* and *MRPS2*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of January 27, 2025. The *MRPS2* gene encodes the mitochondrial ribosomal protein S2. The *MRPS2* gene was first reported in relation to autosomal recessive *MRPS2*-related primary mitochondrial disease in 2018 (PMID: 29576219). *MRPS2* has been associated with a single disease entity to date; combined oxidative phosphorylation deficiency 36 [OMIM# 617950]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *MRPS2*-related primary mitochondrial disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included four missense variants identified in four unrelated cases from three publications (PMIDs: 29576219, 34991560, 38029925). Affected individuals had developmental delay, sensorineural hearing loss, feeding difficulty, hypoglycemia, failure to thrive, muscle weakness, elevated blood lactate, metabolic acidosis, and increased excretion of Krebs cycle intermediates. Brain imaging was normal. There were variable respiratory chain enzyme deficiencies in skeletal muscle, skin fibroblasts, and liver. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416) and rescue in patient cells (PMID: 29576219). In summary, there is limited evidence to support the relationship between *MRPS2* and autosomal recessive *MRPS2*-related primary mitochondrial disease. However, given the consistent clinical and biochemical phenotype seen in the four reported cases, and since it is likely homozygous or compound heterozygous nonsense variants are not compatible with life, this Expert Panel elected to upgrade the classification to moderate. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on January 27, 2025 (SOP Version 11).
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Biochemical; Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MRPS2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_016034.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 27 | 1 | 29 | ||
| missense | 1 | 4 | 77 | 7 | 6 | 95 |
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 2 | 3 | |||
| Total | 1 | 6 | 81 | 34 | 7 | 129 |
Highest pathogenic variant AF is 0.000061972765
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_057118.1 | 4 | MANE Select | |
| Ensembl | ENSP00000241600.5 | 4 | MANE Select | |
| RefSeq | NP_001358330.1 | 4 | Standard | |
| Ensembl | ENSP00000360850.1 | 4 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Ribosome - Homo sapiens (human)
- Mitochondrial translation initiation
- Translation
- Metabolism of proteins
- Mitochondrial translation elongation
Biological Process
- mitochondrial translation
- mitochondrial ribosome assembly
- mitochondrial translational elongation
- mitochondrial translational termination
Molecular Function
- structural constituent of ribosome
Cellular Component
- mitochondrion
- mitochondrial inner membrane
- mitochondrial small ribosomal subunit
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000371785
- Coding exons
- 4
- Length
- 4690
- Individuals with no LoFs
- 125717
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 23
- Defined
- 125740
- p
- 0.0000915
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.0738 | 197 | 200 | 0.985 | 0.0000129 | 1925 |
| Missense (PolyPhen) | 61 | 73.6 | 0.82881 | 650 | ||
| Synonymous | -0.805 | 99 | 89.3 | 1.11 | 0.00000610 | 618 |
| Loss of Function | -0.579 | 9 | 7.31 | 1.23 | 3.95e-7 | 82 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00039 | 0.00038 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000099 | 0.000097 | rare |
| South Asian | 0.000099 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Required for mitoribosome formation and stability, and mitochondrial translation. {ECO:0000269|PubMed:29576219}.;
- Disease
- DISEASE: Combined oxidative phosphorylation deficiency 36 (COXPD36) [MIM:617950]: An autosomal recessive, multisystem disease resulting from deficiencies of mitochondrial respiratory enzyme complexes and mitochondrial dysfunction. Clinical manifestations include sensorineural hearing impairment, mild developmental delay, hypoglycemia, and intellectual disability. {ECO:0000269|PubMed:29576219}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.158
Intolerance Scores
- LoFtool
- 0.588
- RVIS EVS
- 0.6
- RVIS percentile EVS
- 82.74
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.849
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |