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…

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

11 unique Pathogenic / Likely Pathogenic· 68 VUS of 123 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 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

This gene — mechanism propensity

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.1

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

References

1.PMID 27931036 ↗

ClinVar Variant Classifications

123 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic5

VUS68

Likely Benign31

Benign6

Conflicting7

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	2	0	0	6
Likely Pathogenic	4	1	0	0	5
VUS	3	64	1	0	68
Likely Benign	0	7	2	22	31
Benign	0	1	2	3	6
Conflicting	—				7
Total	11	75	5	25	123

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

View in ClinVar →

309 pathogenic / likely-pathogenic (of 316) ClinVar copy-number / structural variants overlap MKRN3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →