MKRN3

Chr 15AD

makorin ring finger protein 3

Also known as: CPPB2, D15S9, RNF63, ZFP127, ZNF127

NCBI Gene: 7681 ENSG00000179455 UniProt: Q13064 OMIM: 603856

MKRN3 encodes a nuclear protein containing RING and C3H zinc finger motifs that is expressed only from the paternal allele due to genomic imprinting. Gain-of-function mutations cause autosomal dominant central precocious puberty (CPP2), making this an important gene to consider in children presenting with early onset puberty. The imprinted expression pattern explains why only paternally inherited mutations result in disease phenotype.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene contains a RING (C3HC4) zinc finger motif and several C3H zinc finger motifs. This gene is intronless and imprinted, with expression only from the paternal allele. Disruption of the imprinting at this locus may contribute to Prader-Willi syndrome. An antisense RNA of unknown function has been found overlapping this gene. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Precocious puberty, central, 2MIM #615346

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Precocious puberty, central; no ClinGen or GenCC tier

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.63

LOEUF

GOF

Mechanism· predicted

📖

GeneReview available — MKRN3

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?

0.63LOEUF

pLI 0.278

Z-score 2.45

OE 0.25 (0.11–0.63)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.42Z-score

OE missense 1.07 (0.97–1.17)

329 obs / 308.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.25 (0.11–0.63)

0≤0.351.4

Missense OE?1.07 (0.97–1.17)

0≤0.61.4

Synonymous OE?1.25

0≤1.21.6

LoF obs/exp: 3 / 12.2Missense obs/exp: 329 / 308.1Syn Z: -2.13

Background carrier burden — how many people carry a rare variant somewhere in MKRN3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 74

818 rare PASS variants

Rare truncating (LoF)

1 in 2,100

74 rare PASS variants

Rare synonymous (reference)

1 in 150

325 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MKRN3. 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 97	1 in 2,300
South Asian	~43k	1 in 68	1 in 5,200
Remaining (unassigned)	~30k	1 in 64	1 in 2,300
European (Finnish)	~27k	1 in 540	1 in 2,200
Admixed American	~22k	1 in 99	≈ 1 in 8,700
African / African American	~21k	1 in 82	1 in 1,400
East Asian	~20k	1 in 70	1 in 960
Ashkenazi Jewish	~13k	1 in 320	none seen
Middle Eastern	~2,884	1 in 85	≈ 1 in 2,900

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): All 1 coding exons well covered in gnomAD exomes and genomes.? see exons ↓