Glucocorticoid deficiency 2

Summary

Glucocorticoid deficiency 2 (MONDO:0011826) is a disease caused by MRAP (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: MRAP (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 34

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	glucocorticoid deficiency 2
Mondo ID	MONDO:0011826
MeSH	C564577
OMIM	607398
DOID	DOID:0061242
NCIT	C123728
UMLS	C4049714
MedGen	891117
GARD	0015412
Is cancer (heuristic)	no

Also known as: familial glucocorticoid deficiency caused by mutation in MRAP · GCCD2 · glucocorticoid deficiency 2 · glucocorticoid deficiency type 2 · MRAP familial glucocorticoid deficiency

Data availability: 34 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › familial glucocorticoid deficiency › glucocorticoid deficiency 2

Related subtypes (5): adrenocortical unresponsiveness to ACTH with postreceptor defect, glucocorticoid deficiency 3, glucocorticoid deficiency 4, glucocorticoid deficiency 1, glucocorticoid deficiency 5

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

34 retrieved; paginated sample, class counts are floors:

16 uncertain significance, 7 pathogenic, 7 benign, 3 likely benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1836	NM_001379228.1(MRAP):c.106+1G>T	MRAP	Pathogenic	no assertion criteria provided
1837	NM_001379228.1(MRAP):c.106+1G>C	MRAP	Pathogenic	criteria provided, single submitter
1838	NM_001379228.1(MRAP):c.106+1G>A	MRAP	Pathogenic	no assertion criteria provided
1840	NM_001379228.1(MRAP):c.106+3_106+4insT	MRAP	Pathogenic	no assertion criteria provided
1841	NM_001379228.1(MRAP):c.3G>A (p.Met1Ile)	MRAP	Pathogenic	criteria provided, multiple submitters, no conflicts
1843	NM_001379228.1(MRAP):c.17_23del (p.Asn6fs)	MRAP	Pathogenic	no assertion criteria provided
444068	NM_001379228.1(MRAP):c.106+1del	MRAP	Pathogenic	criteria provided, multiple submitters, no conflicts
1842	NM_001379228.1(MRAP):c.130del (p.Trp43_Val44insTer)	LOC125418060	Uncertain significance	criteria provided, single submitter
2686050	NM_178817.4(MRAP):c.-151+125C>T	MRAP	Uncertain significance	criteria provided, single submitter
339671	NM_178817.4(MRAP):c.-157G>A	MRAP	Uncertain significance	criteria provided, single submitter
339672	NM_178817.4(MRAP):c.-156C>T	MRAP	Uncertain significance	criteria provided, single submitter
339676	NM_001379228.1(MRAP):c.106+15G>C	MRAP	Uncertain significance	criteria provided, single submitter
339685	NM_001379228.1(MRAP):c.486C>G (p.Pro162=)	MRAP	Uncertain significance	criteria provided, single submitter
339686	NM_001379228.1(MRAP):c.508T>A (p.Leu170Met)	MRAP	Uncertain significance	criteria provided, single submitter
896510	NM_001379228.1(MRAP):c.126C>T (p.Phe42=)	MRAP	Uncertain significance	criteria provided, single submitter
899241	NM_001379228.1(MRAP):c.*197T>C	MRAP	Uncertain significance	criteria provided, single submitter
339679	NM_001379228.1(MRAP):c.206+13G>C	MRAP-AS1	Uncertain significance	criteria provided, single submitter
896509	NM_001379228.1(MRAP):c.107-5C>T	MRAP-AS1	Uncertain significance	criteria provided, single submitter
339680	NM_001379228.1(MRAP):c.219G>A (p.Lys73=)	URB1	Uncertain significance	criteria provided, single submitter
898129	NM_001379228.1(MRAP):c.271C>A (p.Gln91Lys)	URB1	Uncertain significance	criteria provided, single submitter
898130	NM_001379228.1(MRAP):c.451G>A (p.Gly151Ser)	URB1	Uncertain significance	criteria provided, single submitter
899239	NM_001379228.1(MRAP):c.*14T>A	URB1	Uncertain significance	criteria provided, single submitter
899240	NM_001379228.1(MRAP):c.*181G>A	URB1	Uncertain significance	criteria provided, single submitter
339677	NM_001379228.1(MRAP):c.132G>T (p.Val44=)	LOC125418060	Benign	criteria provided, multiple submitters, no conflicts
339678	NM_001379228.1(MRAP):c.148G>A (p.Val50Met)	LOC125418060	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
339673	NM_178817.4(MRAP):c.-130A>G	MRAP	Benign	criteria provided, single submitter
339675	NM_178817.4(MRAP):c.-20G>C	MRAP	Benign	criteria provided, single submitter
339682	NM_001379228.1(MRAP):c.389C>T (p.Thr130Ile)	MRAP	Benign	criteria provided, multiple submitters, no conflicts
339683	NM_001379228.1(MRAP):c.390C>G (p.Thr130=)	MRAP	Benign	criteria provided, single submitter
339687	NM_001379228.1(MRAP):c.*108A>G	MRAP	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
MRAP	Definitive	Autosomal recessive	glucocorticoid deficiency 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MRAP	Orphanet:361	Familial glucocorticoid deficiency

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MRAP	HGNC:1304	ENSG00000170262	Q8TCY5	Melanocortin-2 receptor accessory protein	gencc,clinvar
URB1	HGNC:17344	ENSG00000142207	O60287	Nucleolar pre-ribosomal-associated protein 1	clinvar
MRAP-AS1	HGNC:40108	ENSG00000232623		MRAP antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MRAP	Melanocortin-2 receptor accessory protein	Modulator of melanocortin receptors (MC1R, MC2R, MC3R, MC4R and MC5R).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MRAP	Other/Unknown	no		MRAP
URB1	Other/Unknown	no		ARM-type_fold, URB1_N, URB1_C
MRAP-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	2
right adrenal gland	1
right adrenal gland cortex	1
Brodmann (1909) area 23	1
endothelial cell	1
stromal cell of endometrium	1
male germ line stem cell (sensu Vertebrata) in testis	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MRAP	154	tissue_specific	yes	right adrenal gland, adrenal tissue, right adrenal gland cortex
URB1	221	ubiquitous	yes	endothelial cell, stromal cell of endometrium, Brodmann (1909) area 23
MRAP-AS1	139		yes	male germ line stem cell (sensu Vertebrata) in testis, adrenal tissue, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
URB1	2,005
MRAP	357
MRAP-AS1	0

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MRAP	Q8TCY5	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
URB1	O60287	75.57

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 3 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
maturation of 5.8S rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA)	1	2106.5×	0.002	URB1
regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	1685.2×	0.002	MRAP
positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	1404.3×	0.002	MRAP
negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	842.6×	0.002	MRAP
maturation of LSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA)	1	468.1×	0.003	URB1
negative regulation of protein localization to plasma membrane	1	312.1×	0.004	MRAP
protein localization to plasma membrane	1	54.4×	0.018	MRAP

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MRAP	0	0
URB1	0	0
MRAP-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	MRAP, URB1, MRAP-AS1

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MRAP	0	—
URB1	0	—
MRAP-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.