RRM2B

Chr 8ARAD

ribonucleotide reductase regulatory TP53 inducible subunit M2B

Also known as: MTDPS8A, MTDPS8B, P53R2, RCDFRD

NCBI Gene: 50484ENSG00000048392UniProt: Q7LG56

This gene encodes the small subunit of a p53-inducible ribonucleotide reductase. This heterotetrameric enzyme catalyzes the conversion of ribonucleoside diphosphates to deoxyribonucleoside diphosphates. The product of this reaction is necessary for DNA synthesis. Mutations in this gene have been associated with autosomal recessive mitochondrial DNA depletion syndrome, autosomal dominant progressive external ophthalmoplegia-5, and mitochondrial neurogastrointestinal encephalopathy. Alternatively spliced transcript variants have been described.[provided by RefSeq, Feb 2010]

Primary Disease Associations & Inheritance

Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy)MIM #612075
AR
Mitochondrial DNA depletion syndrome 8B (MNGIE type)MIM #612075
AR
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5MIM #613077
AD
Rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunctionMIM #268315
AR
489
ClinVar variants
85
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— RRM2B
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
85 Pathogenic / Likely Pathogenic· 199 VUS of 489 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.70LOEUF
pLI 0.002
Z-score 2.58
OE 0.39 (0.23–0.70)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.21Z-score
OE missense 0.75 (0.65–0.86)
137 obs / 182.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.39 (0.23–0.70)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.75 (0.65–0.86)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.86
0≤1.21.6
LoF obs/exp: 8 / 20.7Missense obs/exp: 137 / 182.9Syn Z: 0.84

ClinVar Variant Classifications

489 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic56
Likely Pathogenic29
VUS199
Likely Benign120
Benign54
Conflicting31
56
Pathogenic
29
Likely Pathogenic
199
VUS
120
Likely Benign
54
Benign
31
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
8
4
44
0
56
Likely Pathogenic
10
10
8
1
29
VUS
3
131
63
2
199
Likely Benign
0
5
61
54
120
Benign
1
2
48
3
54
Conflicting
—31
Total2215222460489

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

RRM2B · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

RRM2B-related mitochondrial depletion syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy)

MIM #612075

Molecular basis of disorder known

Autosomal recessive

Mitochondrial DNA depletion syndrome 8B (MNGIE type)

MIM #612075

Molecular basis of disorder known

Autosomal recessive

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5

MIM #613077

Molecular basis of disorder known

Autosomal dominant

Rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction

MIM #268315

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — RRM2B
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Mitochondrial DNA maintenance defects.
El-Hattab AW et al.·Biochim Biophys Acta Mol Basis Dis
2017Review
Mitochondrial Retinopathy.
Birtel J et al.·Ophthalmol Retina
2022
Phenotypic and Genotypic Heterogeneity of RRM2B Variants.
Finsterer J et al.·Neuropediatrics
2018Review
New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre.
Pronicka E et al.·J Transl Med
2016
Novel RRM2B Mutation and Severe Mitochondrial DNA Depletion: Report of 2 Cases and Review of the Literature.
Kropach N et al.·Neuropediatrics
2017Review
Mutation spectrum of hearing loss patients in Northwest China: Identification of 20 novel variants.
Ma P et al.·Mol Genet Genomic Med
2024Cohort
Gene aberrations of RRM1 and RRM2B and outcome of advanced breast cancer after treatment with docetaxel with or without gemcitabine.
Jørgensen CL et al.·BMC Cancer
2013
Genetic dissection of Huntington's disease modification by variation at RRM2B.
Lee K et al.·Hum Mol Genet
2025
Adults with RRM2B-related mitochondrial disease have distinct clinical and molecular characteristics.
Pitceathly RD et al.·Brain
2012
Deoxynucleoside supplementation ameliorates the disease associated phenotypes in a zebrafish model of RRM2B mtDNA depletion syndrome.
Munro B et al.·Hum Mol Genet
2025Functional
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Mitochondrial DiseasesMitochondrial EncephalomyopathyMitochondrial Encephalopathy

Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome

RECRUITING
NCT04802707Phase PHASE2Kenneth Myers, MDStarted 2021-10-18
deoxycytidine and deoxythymidine

External Resources

Links to major genomics databases and tools