Glucocorticoid deficiency 5

Summary

Glucocorticoid deficiency 5 (MONDO:0040502) is a disease caused by TXNRD2 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: TXNRD2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 38

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	glucocorticoid deficiency 5
Mondo ID	MONDO:0040502
OMIM	617825
DOID	DOID:0061244
UMLS	C4540522
MedGen	1614419
GARD	0016257
Is cancer (heuristic)	no

Also known as: GCCD5 · glucocorticoid deficiency 5

Data availability: 38 ClinVar variants · 2 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 5

Related subtypes (5): adrenocortical unresponsiveness to ACTH with postreceptor defect, glucocorticoid deficiency 2, glucocorticoid deficiency 3, glucocorticoid deficiency 4, glucocorticoid deficiency 1

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

38 retrieved; paginated sample, class counts are floors:

17 uncertain significance, 10 conflicting classifications of pathogenicity, 7 benign, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
407094	NM_006440.5(TXNRD2):c.77T>G (p.Val26Gly)	LOC130066960	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1060940	NM_006440.5(TXNRD2):c.41_42delinsTT (p.Arg14Leu)	TXNRD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1211079	NM_006440.5(TXNRD2):c.1036C>T (p.Arg346Trp)	TXNRD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1318484	NM_006440.5(TXNRD2):c.529A>G (p.Ile177Val)	TXNRD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
155853	NM_006440.5(TXNRD2):c.1321C>T (p.Arg441Ter)	TXNRD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240655	NM_006440.5(TXNRD2):c.656G>C (p.Gly219Ala)	TXNRD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
264269	NM_006440.5(TXNRD2):c.1341T>G (p.Tyr447Ter)	TXNRD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
392373	NM_006440.5(TXNRD2):c.760C>T (p.Arg254Cys)	TXNRD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
454286	NM_006440.5(TXNRD2):c.650C>A (p.Ser217Tyr)	TXNRD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
647175	NM_006440.5(TXNRD2):c.1037G>A (p.Arg346Gln)	TXNRD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1000359	NM_006440.5(TXNRD2):c.2T>C (p.Met1Thr)	COMT	Uncertain significance	criteria provided, multiple submitters, no conflicts
432854	NM_006440.5(TXNRD2):c.11T>C (p.Met4Thr)	COMT	Uncertain significance	criteria provided, multiple submitters, no conflicts
263690	NM_006440.5(TXNRD2):c.46C>T (p.Arg16Trp)	LOC130066960	Uncertain significance	criteria provided, multiple submitters, no conflicts
1017858	NM_006440.5(TXNRD2):c.1348-2A>G	TXNRD2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1034740	NM_006440.5(TXNRD2):c.1370dup (p.Gln458fs)	TXNRD2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1365306	NM_006440.5(TXNRD2):c.575C>T (p.Pro192Leu)	TXNRD2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1438049	NM_006440.5(TXNRD2):c.392C>T (p.Ala131Val)	TXNRD2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1509876	NM_006440.5(TXNRD2):c.175G>A (p.Ala59Thr)	TXNRD2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3587848	NM_006440.5(TXNRD2):c.1173C>G (p.Asp391Glu)	TXNRD2	Uncertain significance	criteria provided, single submitter
3892800	NM_006440.5(TXNRD2):c.750C>A (p.Ser250Arg)	TXNRD2	Uncertain significance	criteria provided, single submitter
3892801	NM_006440.5(TXNRD2):c.768C>G (p.Phe256Leu)	TXNRD2	Uncertain significance	criteria provided, single submitter
390757	NM_006440.5(TXNRD2):c.745C>T (p.Arg249Cys)	TXNRD2	Uncertain significance	criteria provided, multiple submitters, no conflicts
451945	NM_006440.5(TXNRD2):c.417del (p.Asn140fs)	TXNRD2	Uncertain significance	criteria provided, multiple submitters, no conflicts
524921	NM_006440.5(TXNRD2):c.1030G>T (p.Asp344Tyr)	TXNRD2	Uncertain significance	criteria provided, multiple submitters, no conflicts
666196	NM_006440.5(TXNRD2):c.591+1G>C	TXNRD2	Uncertain significance	criteria provided, multiple submitters, no conflicts
965157	NM_006440.5(TXNRD2):c.139G>A (p.Gly47Arg)	TXNRD2	Uncertain significance	criteria provided, multiple submitters, no conflicts
977410	NM_006440.5(TXNRD2):c.949+222C>T	TXNRD2	Uncertain significance	criteria provided, single submitter
1246627	NM_006440.5(TXNRD2):c.949+437del	TXNRD2	Benign	criteria provided, multiple submitters, no conflicts
240653	NM_006440.5(TXNRD2):c.110A>T (p.Gln37Leu)	TXNRD2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
263343	NM_006440.5(TXNRD2):c.196G>T (p.Ala66Ser)	TXNRD2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 3 · 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
TXNRD2	Strong	Autosomal recessive	glucocorticoid deficiency 5	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TXNRD2	Orphanet:154	Familial isolated dilated cardiomyopathy
TXNRD2	Orphanet:361	Familial glucocorticoid deficiency
COMT	Orphanet:567	22q11.2 deletion syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TXNRD2	HGNC:18155	ENSG00000184470	Q9NNW7	Thioredoxin reductase 2, mitochondrial	gencc,clinvar
COMT	HGNC:2228	ENSG00000093010	P21964	Catechol O-methyltransferase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TXNRD2	Thioredoxin reductase 2, mitochondrial	Involved in the control of reactive oxygen species levels and the regulation of mitochondrial redox homeostasis.
COMT	Catechol O-methyltransferase	Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	2	12.0×	0.007

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TXNRD2	Enzyme (other)	yes	1.8.1.9	Pyr_nuc-diS_OxRdtase, Pyr_nucl-diS_OxRdtase_dimer, Thioredoxin/glutathione_Rdtase
COMT	Enzyme (other)	yes	2.1.1.6	SAM_O-MeTrfase, Catechol_O-MeTrfase_euk, SAM-dependent_MTases_sf

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right adrenal gland cortex	2
apex of heart	1
right lobe of liver	1
right adrenal gland	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TXNRD2	264	ubiquitous	marker	right lobe of liver, right adrenal gland cortex, apex of heart
COMT	296	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TXNRD2	3,712
COMT	3,362

Intra-cohort edges

A	B	Sources
COMT	TXNRD2	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COMT	P21964	12

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TXNRD2	Q9NNW7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways 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.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Enzymatic degradation of Dopamine by monoamine oxidase	1	2855.0×	0.001	COMT
Enzymatic degradation of dopamine by COMT	1	1903.3×	0.001	COMT
Methylation	1	407.9×	0.004	COMT
Detoxification of Reactive Oxygen Species	1	150.3×	0.008	TXNRD2
Potential therapeutics for SARS	1	57.1×	0.017	COMT

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
response to oxygen radical	1	8426.0×	0.002	TXNRD2
norepinephrine secretion	1	8426.0×	0.002	COMT
response to dopamine	1	8426.0×	0.002	COMT
catecholamine catabolic process	1	4213.0×	0.002	COMT
dopamine secretion	1	2808.7×	0.002	COMT
renal filtration	1	2808.7×	0.002	COMT
renin secretion into blood stream	1	2106.5×	0.002	COMT
cellular response to phosphate starvation	1	2106.5×	0.002	COMT
renal sodium excretion	1	2106.5×	0.002	COMT
habituation	1	2106.5×	0.002	COMT
mastication	1	2106.5×	0.002	COMT
renal albumin absorption	1	1685.2×	0.002	COMT
cerebellar cortex morphogenesis	1	1404.3×	0.003	COMT
synaptic transmission, dopaminergic	1	1053.2×	0.003	COMT
response to salt	1	1053.2×	0.003	COMT
response to angiotensin	1	936.2×	0.003	COMT
dopamine catabolic process	1	842.6×	0.003	COMT
norepinephrine metabolic process	1	766.0×	0.003	COMT
response to selenium ion	1	702.2×	0.003	TXNRD2
artery development	1	702.2×	0.003	COMT
glomerulus development	1	648.1×	0.003	COMT
cellular response to cocaine	1	648.1×	0.003	COMT
startle response	1	561.7×	0.003	COMT
response to corticosterone	1	561.7×	0.003	COMT
response to hyperoxia	1	561.7×	0.003	TXNRD2
dopamine metabolic process	1	495.6×	0.004	COMT
prostaglandin metabolic process	1	421.3×	0.004	COMT
detection of temperature stimulus involved in sensory perception of pain	1	421.3×	0.004	COMT
developmental process	1	337.0×	0.005	COMT
exploration behavior	1	324.1×	0.005	COMT

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
COMT	OPICAPONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TXNRD2	3	3
COMT	3	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
OPICAPONE	4	COMT
TOLCAPONE	4	COMT
ENTACAPONE	4	COMT
CURCUMIN	3	TXNRD2
ELLAGIC ACID	2	TXNRD2
ETHASELEN	1	TXNRD2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TXNRD2	91	Binding:76, Functional:15
COMT	55	Binding:47, ADMET:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TXNRD2	1.8.1.9	thioredoxin-disulfide reductase (NADPH)
COMT	2.1.1.6	catechol O-methyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
COMT	1

Chemical tractability of cohort targets

6 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.

Compound	Max phase	Cohort target (bioactivity)
OPICAPONE	4	COMT
TOLCAPONE	4	COMT
ENTACAPONE	4	COMT
CURCUMIN	3	TXNRD2
ELLAGIC ACID	2	TXNRD2
ETHASELEN	1	TXNRD2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	COMT
B	Phased (≥1) drug, not yet approved	1	TXNRD2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.