MKRN3

Chr 15AD

makorin ring finger protein 3

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

NCBI Gene: 7681ENSG00000179455UniProt: Q13064

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]

Primary Disease Associations & Inheritance

Precocious puberty, central, 2MIM #615346
AD
299
ClinVar variants
186
Pathogenic / LP
0.28
pLI score
1
Active trials
Clinical Summary— MKRN3
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.
📋
ClinVar Variants
186 Pathogenic / Likely Pathogenic· 74 VUS of 299 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Some data sources returned errors (1)

pubmed: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

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.
0.63LOEUF
pLI 0.278
Z-score 2.45
OE 0.25 (0.11–0.63)
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.
-0.42Z-score
OE missense 1.07 (0.97–1.17)
329 obs / 308.1 exp
Tolerant

Tolerant to missense variation

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.0.25 (0.11–0.63)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.07 (0.97–1.17)
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.1.25
0≤1.21.6
LoF obs/exp: 3 / 12.2Missense obs/exp: 329 / 308.1Syn Z: -2.13

ClinVar Variant Classifications

299 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic171
Likely Pathogenic15
VUS74
Likely Benign27
Benign7
Conflicting5
171
Pathogenic
15
Likely Pathogenic
74
VUS
27
Likely Benign
7
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
1
168
0
171
Likely Pathogenic
3
1
11
0
15
VUS
2
65
7
0
74
Likely Benign
0
6
2
19
27
Benign
0
1
2
4
7
Conflicting
—5
Total77419023299

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.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
MAKORIN 3; MKRN3
MIM #603856 · *

Precocious puberty, central, 2

MIM #615346

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — MKRN3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
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
2026🔓 Open 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
2025🔓 Open 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
Zearalenone induces GnRH neurons activation related to central precocious puberty by triggering MKRN3 auto-ubiquitination and down-regulation.
Sun Y.·Toxicol Res (Camb)
2025
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Morbid ObesityBariatric SurgeryTelerehabilitation

Exercise to Fight Obesity

RECRUITING
NCT06934681Phase NAInstituto de Investigacion Sanitaria La FeStarted 2025-05-19
Usual Care GroupControlled exercise with telerehabilitation

External Resources

Links to major genomics databases and tools