MKRN3

Chr 15AD

makorin ring finger protein 3

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

NCBI Gene: 7681ENSG00000179455UniProt: Q13064OMIM: 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.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
GOFmechanismADLOEUF 0.631 OMIM phenotype
Clinical Summary— MKRN3
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Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.
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ClinVar Variants
319 unique Pathogenic / Likely Pathogenic· 74 VUS of 437 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 — 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 OE0.25 (0.11–0.63)
0≤0.351.4
Missense OE1.07 (0.97–1.17)
0≤0.61.4
Synonymous OE1.25
0≤1.21.6
LoF obs/exp: 3 / 12.2Missense obs/exp: 329 / 308.1Syn Z: -2.13
DN
0.5772th %ile
GOF
0.6442th %ile
LOF
0.3842th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction above median · 1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFUp to now, just gain-of-function mutations of KISS1/KISS1R and loss-of-function mutations of the maternally imprinted gene MKRN3 are the known genetic causes of ICPP.PMID:27931036

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

ClinVar Variant Classifications

437 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic303
Likely Pathogenic16
VUS74
Likely Benign31
Benign6
Conflicting7
303
Pathogenic
16
Likely Pathogenic
74
VUS
31
Likely Benign
6
Benign
7
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
4
2
297
0
303
Likely Pathogenic
4
1
11
0
16
VUS
3
64
7
0
74
Likely Benign
0
7
2
22
31
Benign
0
1
2
3
6
Conflicting
—7
Total117531925437

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

View in ClinVar →

Protein Context — Lollipop Plot

MKRN3 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Central precocious puberty: From genetics to treatment.
Aguirre RS et al.·Best Pract Res Clin Endocrinol Metab
2018Review
Causes, diagnosis, and treatment of central precocious puberty.
Latronico AC et al.·Lancet Diabetes Endocrinol
2016Review
Diagnosis and management of precocious sexual maturation: an updated review.
Cheuiche AV et al.·Eur J Pediatr
2021Review
Central precocious puberty: Recent advances in understanding the aetiology and in the clinical approach.
Maione L et al.·Clin Endocrinol (Oxf)
2021Review
MKRN3 and KISS1R mutations in precocious and early puberty.
Pagani S et al.·Ital J Pediatr
2020
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
MKRN3 variants in central precocious puberty as an example of the complexity to classify missense variants in imprinted genes as pathogenic.
Delcour C et al.·Horm Res Paediatr
2026
Use of serum MKRN3 and DLK1 levels in precocious puberty: association with an MKRN3 pathogenic variant.
Karakilic-Ozturan E et al.·Ther Adv Endocrinol Metab
2026Open Access
Divergent epigenetic profile underlie pubertal disorders in MKRN3-associated central precocious puberty and Prader-Willi syndrome: insights from a frameshift variant.
Jin YY et al.·World J Pediatr
2026
Outcomes of Patients With Familial Central Precocious Puberty due to Mutations of MKRN3 Gene After Treatment With Gonadotropin-Releasing Hormone Agonist.
Chen Z et al.·Int J Endocrinol
2025Open AccessCohort
Phenotypic Variability of Males with Loss-of-Function Mutations of MKRN3: A Case Report and Literature Review.
Yamanaka MYM et al.·Horm Res Paediatr
2025Review
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients