H6PD

Summary

H6PD (hexose-6-phosphate dehydrogenase/glucose 1-dehydrogenase, HGNC:4795) is a protein-coding gene on chromosome 1p36.22, encoding GDH/6PGL endoplasmic bifunctional protein (O95479). Bifunctional enzyme localized in the lumen of the endoplasmic reticulum that catalyzes the first two steps of the oxidative branch of the pentose phosphate pathway/shunt, an alternative to glycolysis and a major source of reducing power and metabolic intermediates for biosynthet….

There are 2 forms of glucose-6-phosphate dehydrogenase. G form is X-linked and H form, encoded by this gene, is autosomally linked. This H form shows activity with other hexose-6-phosphates, especially galactose-6-phosphate, whereas the G form is specific for glucose-6-phosphate. Both forms are present in most tissues, but H form is not found in red cells.

Source: NCBI Gene 9563 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cortisone reductase deficiency 1 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 7
• Clinical variants (ClinVar): 327 total — 6 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 21
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_004285

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4795
Approved symbol	H6PD
Name	hexose-6-phosphate dehydrogenase/glucose 1-dehydrogenase
Location	1p36.22
Locus type	gene with protein product
Status	Approved
Aliases	H6PDH
Ensembl gene	ENSG00000049239
Ensembl biotype	protein_coding
OMIM	138090
Entrez	9563

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 13 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000377403, ENST00000495451, ENST00000602477, ENST00000891474, ENST00000891475, ENST00000891476, ENST00000919134, ENST00000948983, ENST00000948984, ENST00000948985, ENST00000948986, ENST00000948987, ENST00000948988, ENST00000948989

RefSeq mRNA: 2 — MANE Select: NM_004285 NM_001282587, NM_004285

CCDS: CCDS101, CCDS72697

Canonical transcript exons

ENST00000377403 — 5 exons

Exon	Start	End
ENSE00000386079	9246966	9247083
ENSE00000386080	9262059	9262328
ENSE00001041640	9234774	9235066
ENSE00001473796	9263509	9271337
ENSE00003647605	9244925	9245561

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 94.21.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.2915 / max 1502.3558, expressed in 1806 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
500	20.7869	1804
507	0.9757	262
499	0.9325	645
501	0.6935	448
509	0.2207	85
513	0.1553	14
512	0.1457	21
503	0.1393	70
505	0.0931	25
506	0.0664	18

Top tissues by expression

290 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	94.21	gold quality
germinal epithelium of ovary	UBERON:0001304	93.77	gold quality
right lobe of liver	UBERON:0001114	93.71	gold quality
nipple	UBERON:0002030	93.71	gold quality
stromal cell of endometrium	CL:0002255	93.65	gold quality
body of tongue	UBERON:0011876	93.43	gold quality
liver	UBERON:0002107	93.21	gold quality
synovial joint	UBERON:0002217	93.20	gold quality
pericardium	UBERON:0002407	93.12	gold quality
diaphragm	UBERON:0001103	92.36	silver quality
cardia of stomach	UBERON:0001162	92.33	gold quality
left ovary	UBERON:0002119	92.31	gold quality
lower lobe of lung	UBERON:0008949	92.12	gold quality
tongue	UBERON:0001723	91.70	gold quality
right ovary	UBERON:0002118	91.67	gold quality
left uterine tube	UBERON:0001303	91.46	gold quality
superior surface of tongue	UBERON:0007371	91.29	gold quality
decidua	UBERON:0002450	90.97	gold quality
gastrocnemius	UBERON:0001388	90.83	gold quality
muscle of leg	UBERON:0001383	90.61	gold quality
pharyngeal mucosa	UBERON:0000355	90.31	gold quality
mucosa of stomach	UBERON:0001199	90.28	gold quality
trachea	UBERON:0003126	90.22	gold quality
ovary	UBERON:0000992	90.17	gold quality
muscle organ	UBERON:0001630	89.93	gold quality
vastus lateralis	UBERON:0001379	89.91	gold quality
urethra	UBERON:0000057	89.88	gold quality
left adrenal gland cortex	UBERON:0035825	89.78	gold quality
adrenal cortex	UBERON:0001235	89.70	gold quality
upper arm skin	UBERON:0004263	89.61	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	15.47

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC, NR3C1

miRNA regulators (miRDB)

243 targeting H6PD, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-1-3P	99.93	72.35	1914

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 27)

• Mutations in the genes encoding 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency. (PMID:12858176)
• H6PDH directly determines the reaction direction of 11beta-Hydroxysteroid dehydrogenase1 in intact cells as an oxoreductase. (PMID:15280030)
• A new chemiluminescent method was applied to the determination of G6PDH in healthy and enzyme-deficient individuals. (PMID:15767211)
• Two new missense mutations in glucose-6-phosphate dehydrogenase gene associated with chronic hemolytic anemia. (PMID:16079115)
• Mutations found in beta thassemia patients complicated by liver disease. (PMID:16079116)
• The observed constant expression of H6PD suggests that HSD11B1 acts as a reductase throughout the adipogenesis process in human ADMSCs and murine 3T3-L1 cells. (PMID:18586838)
• Hepatic 11beta-HSD1 and H6PDH are closely interlinked. 11beta-HSD1 gene expression does not seem to be involved in the pathogenesis of fatty liver or nonalcoholic steatohepatitis. (PMID:18665910)
• Data show that adipose tissue 11-beta-Hydroxysteroid Dehydrogenase Type 1 and Hexose-6-Phosphate Dehydrogenase gene expressions are increased in patients with type 2 diabetes mellitus. (PMID:18963204)
• The impact of H6PDH on the modulation of 11beta-HSD1-dependent interconversion of cortisone and cortisol by inhibitors and alternative substrates, was investigated. (PMID:19010388)
• Using co-immunoprecipitation experiments with purified H6PDH and 11beta-HSD1, and with cell lysates expressing H6PDH and 11beta-HSD1, we observe direct physical interaction between the two enzymes. (PMID:19121282)
• This study corroborates the association of one locus determined by genome-wide association study and points to H6PD as a new candidate gene for multiple sclerosis. (PMID:19935835)
• findings indicate that the decrease in G6PDH activity that occurs after exposure of lung epithelial cells to chrysotile results from the carbonylation of G6PDH by TBARS (PMID:20211231)
• identified a mitochondrial matrix-associated G6PDH and also provide evidence that metabolic state/glucose availability modulate enzymatic sources of NADPH (PMID:20228249)
• the H6PD gene is very polymorphic and missense variants are common, coding variants rarely (<1.5%) are responsible for hyperandrogenemic polycystic ovary syndrome. (PMID:21050867)
• Results suggest a novel role for the H6PD gene in atherosclerosis susceptibility. (PMID:21858044)
• Polymorphisms in the H6PD gene may not be associated with type 2 diabetes and the metabolic syndrome. (PMID:21869537)
• Antioxidant supplementation was noted to increase G6PDH in the pentose phosphate cycle and 18S rRNA in the ribosome. There were no significant changes in the gene expression levels of beta-ACT (PMID:22285204)
• R453Q and D151A variants of the H6PD gene are associated with PCOS and obesity, respectively, and may contribute to the PCOS phenotype by influencing obesity, insulin resistance and hyperandrogenism. (PMID:22306327)
• GR and p300 are involved in the induction of H6PD by cortisol in human amnion fibroblasts (PMID:23125313)
• The aim of the work was to investigate the expression of HSD11B1, HSD11B2, H6PDH, and glucocorticoids receptor (GR) mRNA in subcutaneous adipose tissue (SAT) from obese women with or without polycystic ovary syndrome. (PMID:23979790)
• Cytoplasmic Mg2+ regulates glucose 6-phosphate utilization by reticular H6PD. (PMID:24631573)
• Inhibition of glucose-6-phosphate dehydrogenase sensitizes cisplatin-resistant cells to death. (PMID:26337086)
• The G allele of rs6688832 in H6PD might exert potential genetic protective role against the development of PCOS, especially in overweight women. PCOS patients with AG genotype of rs6688832 might confer risk to the phenotype of hyperandrogenemia of PCOS. (PMID:26452272)
• cortisol reduces glucose-6-phosphate (G6P) flux through H6PDH by increasing luminal NADPH, thereby allowing more G6P for hydrolysis via G6Pase (PMID:26860459)
• Data indicate the tetramer as the most active form of glucose-6-phosphate dehydrogenase (G6PDH). (PMID:28370139)
• Knockdown of H6PD resulted in an increase in ER lumen oxidation, and down-regulation of many components of the unfolded protein response, including the transcription factors activating transcription factor-4, activating transcription factor-6, split X-box binding protein-1, and CCAAT/enhancer binding protein homologous protein. (PMID:29295867)
• Tumor-suppressive microRNA-551b-3p targets H6PD to inhibit gallbladder cancer progression. (PMID:33250514)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	h6pd	ENSDARG00000060153
mus_musculus	H6pd	ENSMUSG00000028980
rattus_norvegicus	H6pd	ENSRNOG00000017523
drosophila_melanogaster	CG7140	FBGN0037147

Paralogs (1): G6PD (ENSG00000160211)

Protein

Protein identifiers

GDH/6PGL endoplasmic bifunctional protein — O95479 (reviewed: O95479)

All UniProt accessions (1): O95479

UniProt curated annotations — full annotation on UniProt →

Function. Bifunctional enzyme localized in the lumen of the endoplasmic reticulum that catalyzes the first two steps of the oxidative branch of the pentose phosphate pathway/shunt, an alternative to glycolysis and a major source of reducing power and metabolic intermediates for biosynthetic processes. Has a hexose-6-phosphate dehydrogenase activity, with broad substrate specificity compared to glucose-6-phosphate 1-dehydrogenase/G6PD, and catalyzes the first step of the pentose phosphate pathway. In addition, acts as a 6-phosphogluconolactonase and catalyzes the second step of the pentose phosphate pathway. May have a dehydrogenase activity for alternative substrates including glucosamine 6-phosphate and glucose 6-sulfate. The main function of this enzyme is to provide reducing equivalents such as NADPH to maintain the adequate levels of reductive cofactors in the oxidizing environment of the endoplasmic reticulum. By producing NADPH that is needed by reductases of the lumen of the endoplasmic reticulum like corticosteroid 11-beta-dehydrogenase isozyme 1/HSD11B1, indirectly regulates their activity.

Subunit / interactions. Homodimer.

Subcellular location. Endoplasmic reticulum lumen.

Tissue specificity. Present in most tissues examined, strongest in liver.

Disease relevance. Cortisone reductase deficiency 1 (CORTRD1) [MIM:604931] An autosomal recessive error of cortisone metabolism characterized by a failure to regenerate cortisol from cortisone, resulting in increased cortisol clearance, activation of the hypothalamic-pituitary axis and ACTH-mediated adrenal androgen excess. Clinical features include hyperandrogenism resulting in hirsutism, oligo-amenorrhea, and infertility in females and premature pseudopuberty in males. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Carbohydrate degradation; pentose phosphate pathway; D-ribulose 5-phosphate from D-glucose 6-phosphate (oxidative stage): step 1/3. Carbohydrate degradation; pentose phosphate pathway; D-ribulose 5-phosphate from D-glucose 6-phosphate (oxidative stage): step 2/3. Carbohydrate degradation; pentose phosphate pathway; D-ribulose 5-phosphate from D-glucose 6-phosphate (oxidative stage).

Similarity. In the N-terminal section; belongs to the glucose-6-phosphate dehydrogenase family. In the C-terminal section; belongs to the glucosamine/galactosamine-6-phosphate isomerase family. 6-phosphogluconolactonase subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
O95479-1	1	yes
O95479-2	2

RefSeq proteins (2): NP_001269516, NP_004276* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001282	G6P_DH	Family
IPR005900	6-phosphogluconolactonase_DevB	Domain
IPR006148	Glc/Gal-6P_isomerase	Domain
IPR019796	G6P_DH_AS	Active_site
IPR022674	G6P_DH_NAD-bd	Domain
IPR022675	G6P_DH_C	Domain
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily
IPR037171	NagB/RpiA_transferase-like	Homologous_superfamily

Pfam: PF00479, PF01182, PF02781

Catalyzed reactions (Rhea), 11 shown:

• 6-phospho-D-glucono-1,5-lactone + H2O = 6-phospho-D-gluconate + H(+) (RHEA:12556)
• D-glucose + NAD(+) = D-glucono-1,5-lactone + NADH + H(+) (RHEA:14293)
• D-glucose + NADP(+) = D-glucono-1,5-lactone + NADPH + H(+) (RHEA:14405)
• D-glucose 6-phosphate + NADP(+) = 6-phospho-D-glucono-1,5-lactone + NADPH + H(+) (RHEA:15841)
• D-glucose 6-phosphate + NAD(+) = 6-phospho-D-glucono-1,5-lactone + NADH + H(+) (RHEA:38215)
• 2-deoxy-D-glucose 6-phosphate + NAD(+) = 2-deoxy-6-phospho-D-glucono-1,5-lactone + NADH + H(+) (RHEA:62064)
• 2-deoxy-D-glucose 6-phosphate + NADP(+) = 2-deoxy-6-phospho-D-glucono-1,5-lactone + NADPH + H(+) (RHEA:62068)
• D-galactose 6-phosphate + NADP(+) = 6-phospho-D-galactono-1,5-lactone + NADPH + H(+) (RHEA:62072)
• D-galactose 6-phosphate + NAD(+) = 6-phospho-D-galactono-1,5-lactone + NADH + H(+) (RHEA:62076)
• D-glucose 6-sulfate + NADP(+) = 6-sulfo-D-glucono-1,5-lactone + NADPH + H(+) (RHEA:62080)
• D-glucosamine 6-phosphate + NADP(+) = 2-amino-2-deoxy-6-phospho-D-glucono-1,5-lactone + NADPH + 2 H(+) (RHEA:62088)

UniProt features (85 total): strand 23, helix 22, binding site 11, sequence variant 10, turn 6, glycosylation site 3, region of interest 3, modified residue 2, signal peptide 1, chain 1, splice variant 1, sequence conflict 1, active site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8EM2	ELECTRON MICROSCOPY	3.02

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95479-F1	90.89	0.75

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 267 (proton acceptor)

Ligand- & substrate-binding residues (11): 204–208; 243; 262; 360; 365; 370; 617; 32–39; 149; 174; 174

Post-translational modifications (2): 20, 208

Glycosylation sites (3): 157, 282, 683

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 283 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, GOBP_NADPPLUS_METABOLIC_PROCESS, GOBP_GLUCOCORTICOID_METABOLIC_PROCESS, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_KETONE_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_GLUCOSE_6_PHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_LIPID_METABOLIC_PROCESS, UEDA_PERIFERAL_CLOCK, MODULE_379

GO Biological Process (8): glucose metabolic process (GO:0006006), pentose-phosphate shunt, oxidative branch (GO:0009051), response to nutrient levels (GO:0031667), response to alcohol (GO:0097305), regulation of cortisol biosynthetic process (GO:2000064), carbohydrate metabolic process (GO:0005975), pentose-phosphate shunt (GO:0006098), NADP+ metabolic process (GO:0006739)

GO Molecular Function (11): glucose-6-phosphate dehydrogenase activity (GO:0004345), 6-phosphogluconolactonase activity (GO:0017057), carbohydrate binding (GO:0030246), glucose 1-dehydrogenase (NAD+) activity (GO:0047934), glucose 1-dehydrogenase (NADP+) activity (GO:0047935), NADP binding (GO:0050661), catalytic activity (GO:0003824), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on CH-OH group of donors (GO:0016614), hydrolase activity (GO:0016787), glucose 1-dehydrogenase [NAD(P)+] activity (GO:0047936)

GO Cellular Component (3): endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), sarcoplasmic reticulum (GO:0016529)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
NADPH regeneration	2
oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor	2
glucose 1-dehydrogenase [NAD(P)+] activity	2
catalytic activity	2
endoplasmic reticulum	2
hexose metabolic process	1
glucose-6-phosphate dehydrogenase activity	1
phosphogluconate dehydrogenase (decarboxylating) activity	1
pentose-phosphate shunt	1
6-phosphogluconolactonase activity	1
carbohydrate derivative metabolic process	1
response to stimulus	1
response to oxygen-containing compound	1
regulation of ketone biosynthetic process	1
regulation of glucocorticoid biosynthetic process	1
cortisol biosynthetic process	1
regulation of alcohol biosynthetic process	1
primary metabolic process	1
pentose-phosphate shunt, oxidative branch	1
pentose-phosphate shunt, non-oxidative branch	1
glucose 6-phosphate metabolic process	1
purine nucleotide metabolic process	1
nicotinamide nucleotide metabolic process	1
carboxylic ester hydrolase activity	1
binding	1
adenyl nucleotide binding	1
molecular_function	1
oxidoreductase activity	1
glucose dehydrogenase activity	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1
sarcoplasm	1

Protein interactions and networks

STRING

5403 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
H6PD	PGD	P52209	956
H6PD	GPI	P06744	955
H6PD	HSD11B1	P28845	916
H6PD	GSR	P00390	912
H6PD	TP53	P04637	878
H6PD	HSD11B2	P80365	878
H6PD	TKT	P29401	847
H6PD	TKTL1	P51854	846
H6PD	GCK	P35557	845
H6PD	TKTL2	Q9H0I9	844
H6PD	GNPDA1	P46926	840
H6PD	LDHA	P00338	829
H6PD	HSPB1	P04792	819
H6PD	TALDO1	P37837	811
H6PD	GAPDH	P00354	806

IntAct

32 interactions, top by confidence:

A	B	Type	Score
FBXO6	MAN2B1	psi-mi:“MI:0914”(association)	0.640
ANTXR1	POTEF	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
ANTXR1	WFS1	psi-mi:“MI:0914”(association)	0.530
CRP	QSOX1	psi-mi:“MI:0914”(association)	0.530
TAZ	MANBA	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
PDGFRA	GXYLT2	psi-mi:“MI:0914”(association)	0.350
CCL3	KRBA1	psi-mi:“MI:0914”(association)	0.350
SCGB2A2	RTL8C	psi-mi:“MI:0914”(association)	0.350
ST6GALNAC6	A2ML1	psi-mi:“MI:0914”(association)	0.350
PTDSS1	IGLL5	psi-mi:“MI:0914”(association)	0.350
CCL3L1	QSOX1	psi-mi:“MI:0914”(association)	0.350
TAFAZZIN	MANBA	psi-mi:“MI:0914”(association)	0.350
C1QTNF7	AGRN	psi-mi:“MI:0914”(association)	0.350
HSPA5	CRLF1	psi-mi:“MI:0914”(association)	0.350
DNAJB9	POTEF	psi-mi:“MI:0914”(association)	0.350
SARAF	A2ML1	psi-mi:“MI:0914”(association)	0.350
PRG2	QSOX1	psi-mi:“MI:0914”(association)	0.350
SDF2L1	MANBA	psi-mi:“MI:0914”(association)	0.350
GGH	MANBA	psi-mi:“MI:0914”(association)	0.350
SKP1	RNASET2	psi-mi:“MI:0914”(association)	0.350
PTGDS	H6PD	psi-mi:“MI:0914”(association)	0.350
CSH1	H6PD	psi-mi:“MI:0914”(association)	0.350
FBXO6	TMEM131L	psi-mi:“MI:0914”(association)	0.350

BioGRID (38): H6PD (Affinity Capture-MS), H6PD (Affinity Capture-MS), H6PD (Affinity Capture-MS), H6PD (Affinity Capture-MS), H6PD (Affinity Capture-MS), H6PD (Affinity Capture-MS), H6PD (Affinity Capture-RNA), H6PD (Affinity Capture-RNA), H6PD (Affinity Capture-MS), H6PD (Affinity Capture-MS), H6PD (Affinity Capture-MS), H6PD (Affinity Capture-MS), H6PD (Affinity Capture-MS), H6PD (Affinity Capture-MS), H6PD (Affinity Capture-MS)

ESM2 similar proteins: A0JMP0, A4IG42, A5PJN5, A6QLU7, A6QQ07, F1N2K1, O00462, O18835, O43280, O77695, O95479, O97524, P08236, P10253, P12265, P19813, P70699, P82450, Q3U4H6, Q4FAT7, Q4FZV0, Q5E985, Q5FVF9, Q5R5N6, Q5R7A9, Q5R8R3, Q5RFU0, Q5XHI4, Q641Z7, Q6P6V7, Q6P7A9, Q6QR59, Q6RHW4, Q76HN1, Q865R1, Q8BFW6, Q8BNE1, Q8BP56, Q8C0L6, Q8CFX1

Diamond homologs: A0A1E5S1A9, A0QP90, O00091, O14137, O24357, O51581, O54537, O55044, O59812, O68282, O83491, O84188, O95479, P05370, P0A585, P0A587, P0AC53, P0AC54, P11410, P11411, P11412, P11413, P12646, P15588, P21907, P29686, P37830, P37986, P41571, P41764, P44311, P48826, P48828, P48848, P48992, P54547, P54996, P57405, P73411, P77809

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 38 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
ERAD pathway	6	32.0×	4e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

327 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	1
Uncertain significance	180
Likely benign	77
Benign	40

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
16130	NM_004285.4(H6PD):c.1860_1861insACAGGTGGTTGACCTGTGGCCGGGTCTGA (p.Glu621delinsThrGlyGlyTer)	Pathogenic
3020543	NM_004285.4(H6PD):c.652C>T (p.Arg218Ter)	Pathogenic
31584	NM_004285.4(H6PD):c.960G>A (p.Val320=)	Pathogenic
31585	NM_004285.4(H6PD):c.1076G>A (p.Gly359Asp)	Pathogenic
31586	NM_004285.4(H6PD):c.948C>G (p.Tyr316Ter)	Pathogenic
31587	NM_004285.4(H6PD):c.325del (p.Arg109fs)	Pathogenic
4849419	NM_004285.4(H6PD):c.1113_1116del (p.Leu372fs)	Likely pathogenic

SpliceAI

1528 predictions. Top by Δscore:

Variant	Effect	Δscore
1:9235063:GGAA:G	donor_gain	1.0000
1:9235064:GAAG:G	donor_gain	1.0000
1:9235067:G:GG	donor_gain	1.0000
1:9245558:GCAG:G	donor_gain	1.0000
1:9245559:CAGGT:C	donor_loss	1.0000
1:9245561:GGTGA:G	donor_loss	1.0000
1:9245562:G:GA	donor_loss	1.0000
1:9247081:AAG:A	donor_loss	1.0000
1:9247083:GG:G	donor_loss	1.0000
1:9247084:GTGT:G	donor_gain	1.0000
1:9247085:T:G	donor_loss	1.0000
1:9234962:G:GT	donor_gain	0.9900
1:9235064:G:T	donor_gain	0.9900
1:9235064:GAA:G	donor_gain	0.9900
1:9244918:A:AG	acceptor_gain	0.9900
1:9244919:C:G	acceptor_gain	0.9900
1:9244920:CCCA:C	acceptor_loss	0.9900
1:9244921:CCAG:C	acceptor_loss	0.9900
1:9244922:CAGG:C	acceptor_loss	0.9900
1:9244923:A:AG	acceptor_gain	0.9900
1:9244923:AG:A	acceptor_gain	0.9900
1:9244923:AGG:A	acceptor_loss	0.9900
1:9244924:G:A	acceptor_loss	0.9900
1:9244924:G:GA	acceptor_gain	0.9900
1:9244924:GG:G	acceptor_gain	0.9900
1:9244924:GGC:G	acceptor_gain	0.9900
1:9246756:A:AG	acceptor_gain	0.9900
1:9246961:GACA:G	acceptor_loss	0.9900
1:9246962:ACAG:A	acceptor_loss	0.9900
1:9246964:A:AG	acceptor_gain	0.9900

AlphaMissense

5171 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:9264681:A:C	S730R	0.996
1:9264683:C:A	S730R	0.996
1:9264683:C:G	S730R	0.996
1:9264342:T:A	W617R	0.994
1:9264342:T:C	W617R	0.994
1:9263538:T:A	W349R	0.990
1:9263538:T:C	W349R	0.990
1:9264837:T:A	W782R	0.990
1:9264837:T:C	W782R	0.990
1:9264724:T:A	V744D	0.985
1:9263540:G:C	W349C	0.984
1:9263540:G:T	W349C	0.984
1:9264193:T:C	L567P	0.984
1:9264216:G:C	A575P	0.984
1:9264352:A:T	D620V	0.984
1:9264217:C:A	A575D	0.982
1:9264273:A:C	S594R	0.982
1:9264275:C:A	S594R	0.982
1:9264275:C:G	S594R	0.982
1:9264324:T:A	W611R	0.982
1:9264324:T:C	W611R	0.982
1:9264360:T:C	C623R	0.982
1:9264709:C:A	A739D	0.982
1:9264344:G:C	W617C	0.981
1:9264344:G:T	W617C	0.981
1:9264600:T:C	F703L	0.981
1:9264602:C:A	F703L	0.981
1:9264602:C:G	F703L	0.981
1:9247045:G:C	R236P	0.980
1:9264253:T:C	L587P	0.980

dbSNP variants (sampled 300 via entrez): RS1000105469 (1:9235866 C>T), RS1000122859 (1:9242887 G>A,C), RS1000142417 (1:9251728 G>A), RS1000178816 (1:9251360 A>C,G), RS1000219785 (1:9242763 C>G), RS1000220470 (1:9267635 A>C), RS1000450814 (1:9237313 A>G), RS1000477485 (1:9261943 C>G,T), RS1000504482 (1:9261509 C>T), RS1000536299 (1:9247887 A>G), RS1000562520 (1:9235545 A>G), RS1000696355 (1:9262072 C>T), RS1000910286 (1:9242690 C>T), RS1000970252 (1:9251752 C>G), RS1001021724 (1:9265028 T>C)

Disease associations

OMIM: gene MIM:138090 | disease phenotypes: MIM:604931

GenCC curated gene-disease

Disease	Classification	Inheritance
cortisone reductase deficiency 1	Strong	Autosomal recessive
cortisone reductase deficiency	Supportive	Autosomal dominant

Mondo (3): cortisone reductase deficiency 1 (MONDO:0011503), neuromuscular disease (MONDO:0019056), cortisone reductase deficiency (MONDO:0000193)

Orphanet (2): Hyperandrogenism due to cortisone reductase deficiency (Orphanet:168588), Neuromuscular disease (Orphanet:68381)

HPO phenotypes

21 total (21 of 21 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000789	Infertility
HP:0000822	Hypertension
HP:0000826	Precocious puberty
HP:0000858	Irregular menstruation
HP:0000876	Oligomenorrhea
HP:0001007	Hirsutism
HP:0001061	Acne
HP:0001513	Obesity
HP:0001596	Alopecia
HP:0002900	Hypokalemia
HP:0003351	Decreased circulating renin concentration
HP:0003581	Adult onset
HP:0003596	Middle age onset
HP:0003621	Juvenile onset
HP:0008258	Congenital adrenal hyperplasia
HP:0012412	Premature adrenarche
HP:0025436	Elevated serum 11-deoxycortisol
HP:0025710	Late young adult onset
HP:0030348	Increased circulating androgen concentration
HP:0031186	Abnormal circulating deoxycorticosterone level

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001956_11	Height	3.000000e-10
GCST002647_4	Height	9.000000e-13
GCST006585_1885	Blood protein levels	9.000000e-96
GCST008162_40	Hip circumference	4.000000e-06
GCST008839_508	Height	6.000000e-08
GCST012227_1121	Hip circumference adjusted for BMI	1.000000e-09
GCST012227_1122	Hip circumference adjusted for BMI	2.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D009468	Neuromuscular Diseases	C10.668
C536447	Cortisone reductase deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

56 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, decreases methylation, increases expression	4
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
Acetaminophen	decreases expression	2
Arsenic	affects expression, increases methylation, affects cotreatment, decreases expression, increases abundance	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Silicon Dioxide	decreases expression	2
Valproic Acid	affects expression, decreases expression, increases methylation	2
Aflatoxin B1	decreases expression, increases methylation	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
dicrotophos	increases expression	1
beta-lapachone	decreases expression	1
arsenite	increases expression	1
butyraldehyde	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
benzo(e)pyrene	increases methylation	1
4-hydroxy-2-nonenal	decreases activity	1
2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline	decreases expression	1
pentanal	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
perfluorooctane sulfonic acid	increases expression	1
methylarsine oxide	increases expression	1
abrine	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	increases expression	1
(+)-JQ1 compound	increases expression	1
Bortezomib	decreases expression	1
Temozolomide	decreases expression	1
Arsenic Trioxide	decreases expression	1

Clinical trials (associated diseases)

198 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00331656	PHASE4	UNKNOWN	Comparative Study of Non-Invasive Mask Ventilation vs Cuirass Ventilation in Patients With Acute Respiratory Failure.
NCT00994552	PHASE4	UNKNOWN	Comparison of Pressure Support and Pressure Control Ventilation in Chronic Respiratory Failure
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00942227	PHASE3	COMPLETED	The Value of Traction in Treatment of Lumbar Radiculopathy
NCT00979108	PHASE3	COMPLETED	The Value of Traction in the Treatment of Cervical Radiculopathy
NCT01826487	PHASE3	COMPLETED	Phase 3 Study of Ataluren in Participants With Nonsense Mutation Duchenne Muscular Dystrophy (nmDMD)
NCT02090959	PHASE3	TERMINATED	An Extension Study of Ataluren (PTC124) in Participants With Nonsense Mutation Dystrophinopathy
NCT02436096	PHASE3	COMPLETED	A Study to Evaluate eFFIcacy and Safety of Sublingual TNX-102 SL Tablet Taken at Bedtime in Patients With fibRoMyalgia
NCT02829814	PHASE3	TERMINATED	Repeat of: A Study to Evaluate Efficacy and Safety of Sublingual TNX-102 SL Tablet Taken at Bedtime in Patients With Fibromyalgia
NCT03179631	PHASE3	COMPLETED	Long-Term Outcomes of Ataluren in Duchenne Muscular Dystrophy
NCT05126758	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Deramiocel (CAP-1002) in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT05156320	PHASE3	COMPLETED	Efficacy and Safety of Apitegromab in Patients With Later-Onset Spinal Muscular Atrophy Treated With Nusinersen or Risdiplam
NCT05337553	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Efficacy and Safety of Taldefgrobep Alfa in Participants With Spinal Muscular Atrophy
NCT05626855	PHASE3	ACTIVE_NOT_RECRUITING	Long-Term Safety & Efficacy of Apitegromab in Patients With SMA Who Completed Previous Trials of Apitegromab
NCT06672237	PHASE3	RECRUITING	A Phase 3 Study of NTLA-2001 in ATTRv-PN
NCT01074359	PHASE2	TERMINATED	Safety and Efficacy Study of A0001 in Patients With the A3243G Mitochondrial DNA Point Mutation
NCT01371149	PHASE2	COMPLETED	Patient -Ventilator Interaction in Chronic Respiratory Failure
NCT02022072	PHASE2	TERMINATED	Evaluation of Vital Capacity
NCT03127514	PHASE2	COMPLETED	AMX0035 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT03406780	PHASE2	COMPLETED	A Study of CAP-1002 in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT03921528	PHASE2	COMPLETED	An Active Treatment Study of SRK-015 in Patients With Type 2 or Type 3 Spinal Muscular Atrophy
NCT05479981	PHASE2	COMPLETED	Extension of AOC 1001-CS1 (MARINA) Study in Adult Myotonic Dystrophy Type 1 (DM1) Patients
NCT06339580	PHASE2	RECRUITING	Assessment of Volume-targeted Ventilation in Patients With Neuromuscular Disease
NCT07071935	PHASE2	NOT_YET_RECRUITING	A Clinical Trial of Early Ventilation in Amyotrophic Lateral Sclerosis (EVENT ALS)
NCT07287189	PHASE2	RECRUITING	Phase 2 Study of SAT-3247 in Pediatric Ambulatory Patients
NCT00252252	PHASE1	COMPLETED	AutoVPAP Versus VPAP; Assessment of Sleep and Ventilation
NCT01560741	PHASE1	UNKNOWN	Telemedicine and Ventilator Titration in Chronic Respiratory Patients Initiating Non-invasive Ventilation
NCT01621984	PHASE1	COMPLETED	Therapeutic Riding and Neuromuscular Disease
NCT01758510	PHASE1	COMPLETED	Safety Study of HLA-haplo Matched Allogenic Bone Marrow Derived Stem Cell Treatment in Amyotrophic Lateral Sclerosis
NCT03440034	PHASE1	COMPLETED	Study of Pioglitazone in Sporadic Inclusion Body Myositis
NCT05730842	PHASE1	COMPLETED	Absorption, Metabolism, Excretion and Absolute Bioavailability of EDG-5506 in Healthy Volunteers
NCT03272802	PHASE2/PHASE3	UNKNOWN	Treatment Effect of Edaravone in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00860951	PHASE1/PHASE2	COMPLETED	P300 Brain Computer Interface Keyboard to Operate Assistive Technology
NCT02362425	PHASE1/PHASE2	COMPLETED	Antioxidant Therapy in RYR1-Related Congenital Myopathy
NCT00001201	Not specified	COMPLETED	Evaluation of Neuromuscular Disease
NCT00002044	Not specified	COMPLETED	A Pilot Study To Evaluate the Effect of Retrovir (Zidovudine: AZT) in the Treatment of Human Immunodeficiency Virus (HIV) Associated Dementia and Neuromuscular Diseases
NCT00004553	Not specified	COMPLETED	Electromyography to Diagnose Neuromuscular Disorders
NCT00015470	Not specified	COMPLETED	Diagnostic Evaluation of Patients With Neuromuscular Disease
NCT00017745	Not specified	COMPLETED	Phenotype/Genotype Correlations in Neuromuscular Disorders
NCT00695591	Not specified	COMPLETED	Home Sleep Testing in Neuromuscular Disease Patients