MRPL12

protein-coding

mitochondrial ribosomal protein L12, the group of Large 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 39S subunit protein which forms homodimers. In prokaryotic ribosomes, two L7/L12 dimers and one L10 protein form the L8 protein complex. [provided by RefSeq, Jul 2008]

Previous symbols:

RPML12

MANE transcript

NM_002949.4

Inheritance

ClinVar variants

P:1U:53B:33

Top phenotype

Combined oxidative phosphorylation deficiency 45

gnomAD constraint

pLI —, LoF o/e 0.57

Max pathogenic AF

—

Genomic locus

chr17:81,703,367-81,707,517

External References & Databases

Ensembl (ENSG00000262814)

Transcript & Mutation Effects

hg38 • Region Span ~4.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

combined oxidative phosphorylation deficiency 45LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0033533

Submitter: PanelApp Australia

mitochondrial diseaseLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *MRPL12* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of October 27, 2025. The *MRPL1*2 gene encodes the mitochondrial ribosomal protein L12. The first and only report of *MRPL12* in relation to autosomal recessive primary mitochondrial disease was in 2013 (PMID: 23603806). *MRPL12* has been associated with a single disease entity to date; combined oxidative phosphorylation deficiency 45 [OMIM# 618951]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and is considered a primary mitochondrial disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included one homozygous missense variant identified in one case from one publication (PMID: 23603806). This child had Leigh syndrome spectrum disorder (psychomotor delay, changes on brain MRI noted in the white matter and basal ganglia, elevated blood lactate, reduced activities of complexes I and IV in fibroblasts). The mechanism of disease is suspected to be 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). In summary, there is limited evidence to support this gene-disease relationship. 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 October 27, 2025 (SOP Version 11).

combined oxidative phosphorylation deficiency 45LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0033533

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Combined oxidative phosphorylation deficiency 45AR

Manifestation: Biochemical; Craniofacial; 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

Refs: 23603806

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MRPL12 variants in ClinVar

4 Conditions Cataloged

not providedTotal: 84

not specifiedTotal: 43

MRPL12-related disorderTotal: 1

Combined oxidative phosphorylation deficiency 45Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002949.4. 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			2 clinvar	28 clinvar		30
missense	1 clinvar		49 clinvar	3 clinvar	2 clinvar	55
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	1	0	53	31	2	87

Highest pathogenic variant AF is 0.000011157186

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002949.4	RefSeq	NP_002940.2	5	MANE Select
ENST00000333676.8	Ensembl	ENSP00000333837.3	5	MANE Select
ENST00000853971.1	Ensembl	ENSP00000524030.1	5	Standard
ENST00000853971.2	Ensembl	ENSP00000524030.1	5	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 transcription
positive regulation of transcription, DNA-templated
mitochondrial translational elongation
mitochondrial translational termination

Molecular Function

RNA binding
structural constituent of ribosome
protein binding

Cellular Component

mitochondrion
mitochondrial inner membrane
mitochondrial large ribosomal subunit

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000333676
Coding exons: 5
Length: 4170
Individuals with no LoFs: 125719
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125727
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.279	111	120	0.928	0.00000732	1255
Missense (PolyPhen)		47	50.699	0.92704		566
Synonymous	-0.555	62	56.7	1.09	0.00000409	423
Loss of Function	1.17	5	8.73	0.573	4.91e-7	97

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0.000034	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Associates with mitochondrial RNA polymerase to activate transcription. {ECO:0000269|PubMed:22003127}.;

Recessive Scores

pRec: 0.132

Intolerance Scores

LoFtool: 0.465
RVIS EVS: 0.04
RVIS percentile EVS: 56.92

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.961

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium