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…

Primary Disease Associations & Inheritance

Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy)MIM #612075

Mitochondrial DNA depletion syndrome 8B (MNGIE type)MIM #612075

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5MIM #613077

Rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunctionMIM #268315

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · mitochondrial DNA depletion syndrome 8a · AR · G2P
Strong · progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5 · AD · Labcorp Genetics (formerly Invitae)
Supportive · Kearns-Sayre syndrome · AR · Orphanet
Supportive · mitochondrial neurogastrointestinal encephalomyopathy · AR · Orphanet

+2 more curated pairs

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.70

LOEUF

LOF

Mechanism· G2P

📖

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

Background carrier burden — how many people carry a rare variant somewhere in RRM2B?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 270

476 rare PASS variants

Rare truncating (LoF)

1 in 1,600

66 rare PASS variants

Rare synonymous (reference)

1 in 390

182 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RRM2B. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 340	1 in 2,300
South Asian	~43k	1 in 140	1 in 1,100
Remaining (unassigned)	~30k	1 in 180	1 in 710
European (Finnish)	~27k	1 in 480	≈ 1 in 18,000
Admixed American	~22k	1 in 210	1 in 1,300
African / African American	~21k	1 in 130	1 in 950
East Asian	~20k	1 in 110	1 in 770
Ashkenazi Jewish	~13k	1 in 2,200	≈ 1 in 3,300
Middle Eastern	~2,884	1 in 260	≈ 1 in 2,800

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 7 of 9 coding exons well covered in gnomAD exomes; exons 3, 8 marginal. Genomes: all 9.? see exons ↓