RRM2B

Chr 8ARAD

ribonucleotide reductase regulatory TP53 inducible subunit M2B

Also known as: MTDPS8A, MTDPS8B, P53R2, RCDFRD

NCBI Gene: 50484 ENSG00000048392 UniProt: Q7LG56 OMIM: 604712

The protein encodes the small subunit of ribonucleotide reductase, which catalyzes the conversion of ribonucleoside diphosphates to deoxyribonucleoside diphosphates necessary for DNA synthesis. Mutations cause mitochondrial DNA depletion syndromes (encephalomyopathic type with renal tubulopathy and MNGIE type) and rod-cone dystrophy with sensorineural deafness and Fanconi-type renal dysfunction through autosomal recessive inheritance, or progressive external ophthalmoplegia with mitochondrial DNA deletions through autosomal dominant inheritance. The pathogenic mechanism involves dominant-negative effects disrupting mitochondrial DNA maintenance.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAR/ADLOEUF 0.704 OMIM phenotypes

Clinical Summary— RRM2B

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

45 unique Pathogenic / Likely Pathogenic· 195 VUS of 468 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — RRM2B

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.70LOEUF

pLI 0.002

Z-score 2.58

OE 0.39 (0.23–0.70)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.21Z-score

OE missense 0.75 (0.65–0.86)

137 obs / 182.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.39 (0.23–0.70)

0≤0.351.4

Missense OE?0.75 (0.65–0.86)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 8 / 20.7Missense obs/exp: 137 / 182.9Syn Z: 0.84

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveRRM2B-related mitochondrial depletion syndromeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.82top 10%

GOF

0.76top 25%

LOF

0.1895th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

DNWe conclude that dominant-negative or gain-of-function mutations in RRM2B are a cause of multiple mtDNA deletions and adPEO.1

GOFWe conclude that dominant-negative or gain-of-function mutations in RRM2B are a cause of multiple mtDNA deletions and adPEO.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 19664747 ↗

ClinVar Variant Classifications

468 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17

Likely Pathogenic28

VUS195

Likely Benign119

Benign54

Conflicting31

Pathogenic

Likely Pathogenic

195

VUS

119

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	13	4	0	0	17
Likely Pathogenic	16	11	0	1	28
VUS	4	134	55	2	195
Likely Benign	0	5	60	54	119
Benign	1	2	48	3	54
Conflicting	—				31
Total	34	156	163	60	444

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

View in ClinVar →

41 pathogenic / likely-pathogenic (of 48) ClinVar copy-number / structural variants overlap RRM2B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →