MGRN1

Chr 16

mahogunin ring finger 1

Also known as: RNF156

NCBI Gene: 23295 ENSG00000102858 UniProt: O60291

MGRN1 encodes an E3 ubiquitin-protein ligase that mediates protein monoubiquitination and regulates endosome-to-lysosome trafficking, while also inhibiting melanocortin receptor signaling and hedgehog pathway activity. Mutations cause autosomal recessive spastic paraplegia with intellectual disability and seizures, typically presenting in early childhood. The gene is highly constrained against loss-of-function variants, indicating that complete loss of MGRN1 function has significant developmental consequences.

ResearchSummary from RefSeq, UniProt

Enables ubiquitin-protein transferase activity. Involved in endosome to lysosome transport; negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway; and protein monoubiquitination. Located in several cellular components, including early endosome; endoplasmic reticulum; and nucleus. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

DNmechanismLOEUF 0.47

Clinical Summary— MGRN1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.

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ClinVar Variants

115 VUS of 165 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.47LOEUF

pLI 0.104

Z-score 3.83

OE 0.26 (0.15–0.47)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

-1.55Z-score

OE missense 1.23 (1.14–1.32)

457 obs / 372.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.26 (0.15–0.47)

0≤0.351.4

Missense OE?1.23 (1.14–1.32)

0≤0.61.4

Synonymous OE?1.44

0≤1.21.6

LoF obs/exp: 8 / 31.1Missense obs/exp: 457 / 372.8Syn Z: -4.63

This gene — mechanism propensity

0.6356th %ile

GOF

0.5857th %ile

LOF

0.4331th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

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.

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

ClinVar Variant Classifications

165 submitted variants in ClinVar

ClinVar

Classification Summary

VUS115

Likely Benign12

Benign1

115

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	115	0	0	115
Likely Benign	6	2	4	12
Benign	0	0	1	1
Total	121	2	5	128

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

View in ClinVar →

30 pathogenic / likely-pathogenic (of 44) ClinVar copy-number / structural variants overlap MGRN1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →