MC4R

melanocortin 4 receptor, the group of Melanocortin receptors

Basic information

Region (hg38): 18:60371061-60372775

Links

ENSG00000166603 ∙ NCBI:4160 ∙ OMIM:155541 ∙ HGNC:6932 ∙ Uniprot:P32245 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• obesity due to melanocortin 4 receptor deficiency (Supportive), mode of inheritance: AD
• inherited obesity (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Obesity, autosomal dominant	AD	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Endocrine	9771698; 9771699; 10199800; 10577903; 11487744; 12646665; 12499395; 12646666; 14764818; 16507637; 16492696; 20957447; 20966905; 21047921; 21921657; 22463805
Biallelic variants have been described

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MC4R gene.

• not provided (62 variants)
• Obesity (61 variants)
• BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 (53 variants)
• MC4R-related condition (23 variants)
• not specified (16 variants)
• Monogenic diabetes (9 variants)
• Obesity, autosomal dominant (4 variants)
• Inherited obesity (2 variants)
• Inborn genetic diseases (2 variants)
• MELANOCORTIN 4 RECEPTOR POLYMORPHISM (1 variants)
• Schizophrenia (1 variants)
• OBESITY, RESISTANCE TO (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MC4R gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			5	6	1	12
missense	5	14	49	2	1	71
nonsense	2	2	1			5
start loss						0
frameshift	3	2	3			8
inframe indel			1			1
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding			15		3	18
Total	10	18	74	8	5

Highest pathogenic variant AF is 0.000118

Variants in MC4R

This is a list of pathogenic ClinVar variants found in the MC4R region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
18-60371099-T-C			Benign (Jun 20, 2021)
18-60371367-A-T		MC4R-related disorder	Uncertain significance (Oct 20, 2023)
18-60371377-G-T		BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20	Uncertain significance (Apr 15, 2022)
18-60371378-G-A		not specified • Obesity • MC4R-related disorder	Conflicting classifications of pathogenicity (Apr 29, 2023)
18-60371401-T-A		Obesity	Uncertain significance (Apr 27, 2017)
18-60371403-A-C		Obesity • Obesity due to melanocortin 4 receptor deficiency • BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20	Pathogenic/Likely pathogenic (Feb 24, 2022)
18-60371415-G-C			Uncertain significance (Jun 18, 2022)
18-60371421-C-T		Obesity	Uncertain significance (Apr 28, 2017)
18-60371435-C-T			Likely benign (Feb 25, 2018)
18-60371436-C-T		Obesity • BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20	Uncertain significance (Jan 25, 2022)
18-60371437-G-A		Obesity • Obesity due to melanocortin 4 receptor deficiency	Conflicting classifications of pathogenicity (Dec 30, 2022)
18-60371440-G-A		MC4R-related disorder	Uncertain significance (Dec 31, 2023)
18-60371444-A-C		Obesity due to melanocortin 4 receptor deficiency	Likely pathogenic (Sep 19, 2018)
18-60371445-T-A		MC4R-related disorder	Uncertain significance (Nov 16, 2023)
18-60371448-A-G			Pathogenic (Jul 03, 2023)
18-60371451-A-G		BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 • MC4R-related disorder	Uncertain significance (Mar 03, 2023)
18-60371454-G-T		Obesity • BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 • MC4R-related disorder • Obesity due to melanocortin 4 receptor deficiency	Conflicting classifications of pathogenicity (Feb 13, 2024)
18-60371455-G-A		BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20	Uncertain significance (Jan 05, 2021)
18-60371459-G-A		MC4R-related disorder	Likely benign (Feb 03, 2021)
18-60371460-A-T		not specified	Uncertain significance (May 19, 2016)
18-60371467-A-G		Monogenic diabetes • BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20	Uncertain significance (Sep 21, 2021)
18-60371470-T-G		not specified	Uncertain significance (May 19, 2016)
18-60371474-CATG-C			Uncertain significance (Apr 27, 2023)
18-60371488-G-A			Uncertain significance (Mar 23, 2023)
18-60371489-A-T		Obesity due to melanocortin 4 receptor deficiency • BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20	Pathogenic (Sep 20, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MC4R	protein_coding	protein_coding	ENST00000299766	1	1438

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000917	0.589	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-1.01	218	180	1.21	0.00000960	2195
Missense in Polyphen		106	93.454	1.1343		1177
Synonymous	-0.852	78	69.0	1.13	0.00000384	664
Loss of Function	0.484	5	6.31	0.792	2.73e-7	97

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Receptor specific to the heptapeptide core common to adrenocorticotropic hormone and alpha-, beta-, and gamma-MSH. Plays a central role in energy homeostasis and somatic growth. This receptor is mediated by G proteins that stimulate adenylate cyclase (cAMP). {ECO:0000269|PubMed:12646665, ECO:0000269|PubMed:25163632}.
• Pathway: Neuroactive ligand-receptor interaction - Homo sapiens (human);Peptide GPCRs;GPCRs, Class A Rhodopsin-like;Signaling by GPCR;Signal Transduction;G alpha (s) signalling events;Peptide ligand-binding receptors;Class A/1 (Rhodopsin-like receptors);GPCR ligand binding;GPCR downstream signalling;Syndecan-3-mediated signaling events (Consensus)

Recessive Scores

• pRec: 0.561

Intolerance Scores

• loftool: 0.771
• rvis_EVS: -0.18
• rvis_percentile_EVS: 40.36

Haploinsufficiency Scores

• pHI: 0.229
• hipred: N
• hipred_score: 0.466
• ghis: 0.503

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.403

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Mc4r
• Phenotype: growth/size/body region phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); homeostasis/metabolism phenotype; normal phenotype; reproductive system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; neoplasm; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; immune system phenotype; skeleton phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: mc4r
• Affected structure: whole organism
• Phenotype tag: abnormal
• Phenotype quality: increased length

Gene ontology

• Biological process: diet induced thermogenesis;energy reserve metabolic process;G protein-coupled receptor signaling pathway;adenylate cyclase-modulating G protein-coupled receptor signaling pathway;adenylate cyclase-activating G protein-coupled receptor signaling pathway;feeding behavior;regulation of metabolic process;insulin secretion;response to insulin;positive regulation of bone resorption;negative regulation of feeding behavior;regulation of grooming behavior
• Cellular component: nucleus;plasma membrane;integral component of membrane
• Molecular function: melanocortin receptor activity;melanocyte-stimulating hormone receptor activity;protein binding;peptide hormone binding;ubiquitin protein ligase binding;neuropeptide binding