MRAP2

Chr 6AD

melanocortin 2 receptor accessory protein 2

Also known as: C6orf117, bA51G5.2

NCBI Gene: 112609ENSG00000135324UniProt: Q96G30

This gene encodes a protein that modulates melanocortin receptor signaling. The encoded protein has been shown to interact with all known melanocortin receptors and may regulate both receptor trafficking and activation in response to ligands. Mice lacking a functional copy of this gene exhibit severe obesity and a mutation in this gene may be associated with severe obesity in human patients. [provided by RefSeq, Oct 2016]

Primary Disease Associations & Inheritance

{?Obesity, susceptibility to, BMIQ18}MIM #615457
AD
153
ClinVar variants
13
Pathogenic / LP
0.00
pLI score
4
Active trials
Clinical Summary— MRAP2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
13 Pathogenic / Likely Pathogenic· 105 VUS of 153 total submissions
💊
Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available

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.
1.88LOEUF
pLI 0.000
Z-score -0.67
OE 1.27 (0.75–1.88)
Tolerant

Highly tolerant — LoF variants common in population

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.
0.31Z-score
OE missense 0.92 (0.78–1.08)
99 obs / 108.0 exp
Tolerant

Mild missense constraint

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.1.27 (0.75–1.88)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.92 (0.78–1.08)
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.1.05
0≤1.21.6
LoF obs/exp: 9 / 7.1Missense obs/exp: 99 / 108.0Syn Z: -0.25

ClinVar Variant Classifications

153 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13
VUS105
Likely Benign28
Benign6
Conflicting1
13
Pathogenic
105
VUS
28
Likely Benign
6
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
13
0
13
Likely Pathogenic
0
0
0
0
0
VUS
7
71
25
2
105
Likely Benign
0
3
6
19
28
Benign
0
1
3
2
6
Conflicting
—1
Total7754723153

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

View in ClinVar →

Protein Context — Lollipop Plot

MRAP2 · 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

{?Obesity, susceptibility to, BMIQ18}

MIM #615457

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Promiscuity among the MRAPs.
Clark AJ et al.·J Mol Endocrinol
2017Review
Emerging roles of melanocortin receptor accessory proteins (MRAP and MRAP2) in physiology and pathophysiology.
Berruien NNA et al.·Gene
2020Review
A novel pathogenic variant in MRAP2 in an obese patient with successful outcome of bariatric surgery.
Gatta-Cherifi B et al.·Eur J Endocrinol
2023Case report
Medical semiology of patients with monogenic obesity: A systematic review.
Renard E et al.·Obes Rev
2024Review
Association of Mutations in the Melanocortin-2 Receptor Accessory Protein 2 Gene (MRAP2) and Obesity: A Systematic Review and Meta-Analysis.
Ji RL et al.·Int J Mol Sci
2026Review
Obesity-associated MRAP2 variants impair multiple MC4R-mediated signaling pathways.
Wyatt RA et al.·Hum Mol Genet
2025
Loss-of-function mutations in MRAP2 are pathogenic in hyperphagic obesity with hyperglycemia and hypertension.
Baron M et al.·Nat Med
2019
Variant reclassification over time decreases the level of diagnostic uncertainty in monogenic obesity: Experience from two centres.
Morandi A et al.·Pediatr Obes
2024
Functional characterisation of obesity-associated MRAP2 variants on MC4R and GHSR signalling.
Rodríguez Rondón AV et al.·Hum Mol Genet
2026Functional
Monogenic etiologies in a cohort of early onset obesity: a real-world experience from Belgium.
Harvengt J et al.·Front Endocrinol (Lausanne)
2025Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Obesity

Intensive Weight Loss Intervention Versus Usual Care for Adults With Severe and Complex Obesity

RECRUITING
NCT06321458Phase NACarsten DirksenStarted 2024-04-29
Intensive weight loss interventionUsual care
Morbid ObesityBariatric SurgeryTelerehabilitation

Exercise to Fight Obesity

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

Intensive Weight Loss Intervention Versus Usual Care for Adults With Obesity

ACTIVE NOT RECRUITING
NCT06321432Phase NACarsten DirksenStarted 2024-06-05
Intensive weight loss interventionUsual care
Obesity

Intensive Weight Loss Intervention Versus Bariatric Surgery for Adults With Severe and Complex Obesity: the LightBAR Randomised Trial

RECRUITING
NCT06309238Phase NACarsten DirksenStarted 2024-05-08
Intensive weight loss interventionBariatric surgery

External Resources

Links to major genomics databases and tools