G6PC3

Summary

G6PC3 (glucose-6-phosphatase catalytic subunit 3, HGNC:24861) is a protein-coding gene on chromosome 17q21.31, encoding Glucose-6-phosphatase 3 (Q9BUM1). Hydrolyzes glucose-6-phosphate to glucose in the endoplasmic reticulum.

This gene encodes the catalytic subunit of glucose-6-phosphatase (G6Pase). G6Pase is located in the endoplasmic reticulum (ER) and catalyzes the hydrolysis of glucose-6-phosphate to glucose and phosphate in the last step of the gluconeogenic and glycogenolytic pathways. Mutations in this gene result in autosomal recessive severe congenital neutropenia. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 92579 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive severe congenital neutropenia due to G6PC3 deficiency (Definitive, ClinGen)
• GWAS associations: 4
• Clinical variants (ClinVar): 702 total — 40 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 53
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_138387

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24861
Approved symbol	G6PC3
Name	glucose-6-phosphatase catalytic subunit 3
Location	17q21.31
Locus type	gene with protein product
Status	Approved
Aliases	UGRP
Ensembl gene	ENSG00000141349
Ensembl biotype	protein_coding
OMIM	611045
Entrez	92579

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 12 protein_coding, 10 nonsense_mediated_decay, 2 retained_intron

ENST00000269097, ENST00000585361, ENST00000585962, ENST00000588558, ENST00000590253, ENST00000590639, ENST00000591696, ENST00000593115, ENST00000696383, ENST00000696384, ENST00000696385, ENST00000696386, ENST00000696387, ENST00000696388, ENST00000696389, ENST00000696390, ENST00000696391, ENST00000696392, ENST00000696393, ENST00000696405, ENST00000892385, ENST00000915747, ENST00000915748, ENST00000915749

RefSeq mRNA: 6 — MANE Select: NM_138387 NM_001319945, NM_001384165, NM_001384166, NM_001384167, NM_001384168, NM_138387

CCDS: CCDS11476, CCDS92335, CCDS92336

Canonical transcript exons

ENST00000269097 — 6 exons

Exon	Start	End
ENSE00002831738	44074680	44074770
ENSE00003525749	44075310	44075451
ENSE00003582796	44074969	44075087
ENSE00003967208	44070735	44071183
ENSE00003967216	44074160	44074266
ENSE00003967226	44075680	44076344

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 97.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 63.7194 / max 345.4034, expressed in 1814 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
161107	58.8216	1809
161105	2.6273	1287
161106	2.2704	1252

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adenohypophysis	UBERON:0002196	97.60	gold quality
pituitary gland	UBERON:0000007	97.04	gold quality
right adrenal gland	UBERON:0001233	97.03	gold quality
right adrenal gland cortex	UBERON:0035827	97.02	gold quality
left adrenal gland	UBERON:0001234	96.93	gold quality
left adrenal gland cortex	UBERON:0035825	96.81	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.70	gold quality
adrenal cortex	UBERON:0001235	96.43	gold quality
right lobe of thyroid gland	UBERON:0001119	96.41	gold quality
metanephros cortex	UBERON:0010533	96.38	gold quality
stromal cell of endometrium	CL:0002255	96.20	gold quality
spinal cord	UBERON:0002240	96.20	gold quality
left lobe of thyroid gland	UBERON:0001120	96.16	gold quality
apex of heart	UBERON:0002098	95.78	gold quality
hypothalamus	UBERON:0001898	95.69	gold quality
pigmented layer of retina	UBERON:0001782	95.67	gold quality
thyroid gland	UBERON:0002046	95.41	gold quality
adrenal gland	UBERON:0002369	95.28	gold quality
corpus epididymis	UBERON:0004359	95.28	gold quality
amygdala	UBERON:0001876	94.80	gold quality
tibial nerve	UBERON:0001323	94.65	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.64	gold quality
left uterine tube	UBERON:0001303	94.53	gold quality
anterior cingulate cortex	UBERON:0009835	94.44	gold quality
cingulate cortex	UBERON:0003027	94.42	gold quality
substantia nigra	UBERON:0002038	94.39	gold quality
left testis	UBERON:0004533	94.34	gold quality
mucosa of transverse colon	UBERON:0004991	94.33	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.30	gold quality
lower esophagus	UBERON:0013473	94.26	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.97

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HNF4A

miRNA regulators (miRDB)

43 targeting G6PC3, 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-9-5P	100.00	72.28	2361
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-6799-5P	99.14	65.72	2093
HSA-MIR-6506-5P	99.04	65.66	1386
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-4260	98.78	65.37	848
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-323A-5P	98.59	65.13	651
HSA-MIR-619-5P	98.57	64.97	1988
HSA-MIR-5572	98.55	65.84	970

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• ubiquitously expressed G6Pase catalytic subunit-related protein; has a similar predicted transmembrane topology and conservation of many catalytically important residues with the G6Pase catalytic subunit (UGRP) (PMID:12370122)
• Molecular cloning and characterization of G6PC3, a new glucose-6-phosphatase isoform. (PMID:12965222)
• Thirty-three French-Canadian families with non-dystrophic myotonia were identified.Thirteen mutations were identified in CLCN1 and five mutations were identified in SCN4A (PMID:18337100)
• Defective function of glucose-6-phosphatase, catalytic subunit 3, underlies a severe congenital neutropenia syndrome associated with cardiac and urogenital malformations. (PMID:19118303)
• describe congenital neutropenia patients with mutations in two candidate genes each,HAX1 and G6PC3, including 6 novel mutations (PMID:20220065)
• in nonapoptotic neutrophils, G6PC3 is essential for normal energy homeostasis. A G6PC3 deficiency prevents recycling of ER glucose to the cytoplasm, leading to neutrophil dysfunction (PMID:20498302)
• identified a family with 2 children with homozygous G6PC3 G260R mutations, a loss of enzymatic function, and typical syndrome features with the exception that their bone marrow biopsy pathology revealed abundant neutrophils consistent with myelokathexis (PMID:20616219)
• We provide an overview of the non-haematological features of the condition with a focus on the adult severe congenital neutropenia phenotype, which has not previously been described in detail caused by mutations in G6PC3. (PMID:20717171)
• Mutaations in G6PC3 cause severe congenital neutropenia type 4. (PMID:20799326)
• G6PC3 deficiency is a syndromic variant of severe congenital neutropenia associating congenital neutropenia with various developmental defects including cardiac and urogenital malformations (PMID:21206270)
• genetic association studies between G6PC3 mutations and bone marrow phenotype/pathology: findings do not support a genotype-phenotype relationship – possibility of founder mutations in patients with Caucasian and Middle Eastern ancestry (PMID:21264919)
• G6PC3 mutations are associated with a major defect of glycosylation resulting in glycogen storage disease type-1. (PMID:21385794)
• analysis of SLC45A2 and G6PC3 mutations in a single patient with oculocutaneous albinism and neutropenia [case report] (PMID:21677667)
• Sequence analyses of G6PC3 in 2 patients with Severe congenital neutropenia revealed two different homozygous mutations (PMID:21891829)
• The phenotypic and molecular spectrum in G6PC3 deficiency is wider than previously appreciated. The risk of transition to myelodysplastic syndrome or acute myeloid leukemia may be lower in G6PC3 deficiency compared with other subgroups of SCN (PMID:22050868)
• Three different homozygous G6PC3 mutations were detected in four of the 108 patients/kindreds studied. Parents of affected individuals were all heterozygous for the mutation. (PMID:22469094)
• G6PC3 deficiency may present with inflammatory bowel disease and T cell lymphopenia. The diagnosis should thus be considered in a patient with chronic congenital neutropenia and gastrointestinal symptoms. (PMID:23180359)
• G6PC3 mutations cause non-syndromic severe congenital neutropenia. (PMID:23298686)
• 4 ELANE mutations, 11 HAX1 mutations and 2 G6PC3 mutations have been identified in Iranian patients with severe congenital neutropenia. (PMID:23454784)
• review of clinical, molecular and genetic aspects of G6PC3 deficiency; loss of function in missense G6PC3 mutations likely results from decreased enzyme stability; the condition can be diagnosed by sequencing G6PC3 gene; a number of G6PC3 ounder mutations are known in various populations and possible genotype-phenotype relationship also exists (PMID:23758768)
• Biallelic G6PC3 defects should be considered in patients with autosomal recessive cyclic neutropenia, especially those with typical associated congenital defects. (PMID:24105461)
• Glucose 6 phosphatase catalytic subunit-3 deficiency due to mutation is a heterogenous disorder characterized by severe congenital neutropenia. (PMID:24322501)
• A role for G6PC3 in testicular differentiation and formation. (PMID:24796372)
• G6PC3 mutation is associated with severe congenital neutropenia. (PMID:25284454)
• G6PC3 defects should be considered in any case of congenital, unexplained neutropenia regardless of the clinical phenotype. (PMID:25391451)
• Severe congenital neutropenia with autosomal recessive G6PC3 mutations is associated with considerable clinical heterogeneity. (PMID:25491320)
• functional characterization of 16 of the 19 known missense mutations in severe congenital neutropenia syndrome caused by glucose-6-phosphatase-beta deficiency;14 missense mutations completely abolish G6Pase-beta activity while the p.S139I and p.R189Q mutations retain 49% and 45%, respectively of wild type activity (PMID:25492228)
• Multilineage involvement of immune system occurs in G6PC3 deficiency in addition to the previously described neutropenia and multiple abnormalities. (PMID:26479985)
• classic features of SCN IV found to share an identical inherited canonical splice-site mutation of the G6PC3 gene (c.218+1G>A). (PMID:27571123)
• mir-122 and its targets G6PC3, ALDOA and CS play roles in the hypoxia responses that regulate glucose and energy metabolism and can serve as hypoxia biomarkers. (PMID:27793029)
• these results indicated that coronin3 is significantly dysregulated in hepatocellular carcinoma tumor tissues, and may exert its function via regulating G6PC3 expression. (PMID:28713988)
• The neutropenia in patients with G6PC3 or G6PT mutations is a metabolite-repair deficiency. (PMID:30626647)
• Lentiviral gene therapy and vitamin B3 treatment enable granulocytic differentiation of G6PC3-deficient induced pluripotent stem cells. (PMID:32051561)
• A Novel Mutation in G6PC3 Gene Associated Non-syndromic Severe Congenital Neutropenia. (PMID:32562405)
• Deciphering Biochemical and Molecular Signatures Associated with Obesity in Context of Metabolic Health. (PMID:33669862)
• Novel G6PC3 Mutations in Patients with Congenital Neutropenia: Case Reports and Review of the Literature. (PMID:34137364)
• The Transplantation Resistance of Type II Diabetes Mellitus Adipose-Derived Stem Cells Is Due to G6PC and IGF1 Genes Related to the FoxO Signaling Pathway. (PMID:34205470)
• Altered Functions of Neutrophils in Two Chinese Patients With Severe Congenital Neutropenia Type 4 Caused by G6PC3 Mutations. (PMID:34305938)
• Severe congenital neutropenia due to G6PC3 deficiency: Case series of five patients and literature review. (PMID:34964150)
• G6PC indicated poor prognosis in cervical cancer and promoted cervical carcinogenesis in vitro and in vivo. (PMID:35277194)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	g6pc3	ENSDARG00000020371
mus_musculus	G6pc3	ENSMUSG00000034793
rattus_norvegicus	G6pc3	ENSRNOG00000020902
drosophila_melanogaster	G6P	FBGN0031463

Paralogs (2): G6PC1 (ENSG00000131482), G6PC2 (ENSG00000152254)

Protein

Protein identifiers

Glucose-6-phosphatase 3 — Q9BUM1 (reviewed: Q9BUM1)

Alternative names: Glucose-6-phosphatase beta, Ubiquitous glucose-6-phosphatase catalytic subunit-related protein

All UniProt accessions (11): A0A8Q3SIG5, A0A8Q3SIL0, A0A8Q3SIR5, A0A8Q3WL73, A0A8Q3WL84, A0A8Q3WME5, Q9BUM1, K7EJC5, K7ENK1, K7EQ13, K7ESE6

UniProt curated annotations — full annotation on UniProt →

Function. Hydrolyzes glucose-6-phosphate to glucose in the endoplasmic reticulum. May form with the glucose-6-phosphate transporter (SLC37A4/G6PT) a ubiquitously expressed complex responsible for glucose production through glycogenolysis and gluconeogenesis. Probably required for normal neutrophil function.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Ubiquitously expressed. Highly expressed in skeletal muscle, at intermediate levels in heart, brain, placenta, kidney, colon, thymus, spleen and pancreas. Also detected in testis, prostate, ovary, liver, lung, small intestine and peripheral blood lymphocytes.

Disease relevance. Neutropenia, severe congenital 4, autosomal recessive (SCN4) [MIM:612541] A disorder of hematopoiesis characterized by maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections. The disease is caused by variants affecting the gene represented in this entry. Dursun syndrome (DURSS) [MIM:612541] A disease characterized by pulmonary arterial hypertension, cardiac abnormalities including secundum-type atrial septal defect, intermittent neutropenia, lymphopenia, monocytosis and anemia. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by vanadate.

Pathway. Carbohydrate biosynthesis; gluconeogenesis.

Similarity. Belongs to the glucose-6-phosphatase family.

RefSeq proteins (6): NP_001306874, NP_001371094, NP_001371095, NP_001371096, NP_001371097, NP_612396* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000326	PAP2/HPO	Domain
IPR016275	Glucose-6-phosphatase	Family
IPR036938	PAP2/HPO_sf	Homologous_superfamily

Pfam: PF01569

Enzyme classification (BRENDA):

• EC 3.1.3.9 — glucose-6-phosphatase (BRENDA: 75 organisms, 95 substrates, 121 inhibitors, 58 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

14 substrates with measured Km, best-characterized 14. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
D-GLUCOSE 6-PHOSPHATE	0.1–5.3	30
CARBAMOYL PHOSPHATE	0.6–2.5	6
GLUCOSE 6-PHOSPHATE	0.51–2.7	6
DIPHOSPHATE	1.3–1.8	2
ADP	11.1	1
ATP	4.7	1
CDP	3.8	1
CTP	3.1	1
DCTP	2.6	1
GDP	2.7	1
GTP	3.6	1
ITP	6.1	1
PHOSPHOENOLPYRUVATE	6.9	1
PHOSPHORAMIDE	2.8	1

Catalyzed reactions (Rhea), 1 shown:

• D-glucose 6-phosphate + H2O = D-glucose + phosphate (RHEA:16689)

UniProt features (49 total): sequence variant 22, topological domain 10, transmembrane region 9, mutagenesis site 3, active site 2, binding site 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BUM1-F1	92.79	0.84

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 (2): 114 (proton donor); 167 (nucleophile)

Ligand- & substrate-binding residues (2): 79; 161

Mutagenesis-validated functional residues (3):

Position	Phenotype
79	loss of catalytic activity.
114	loss of catalytic activity.
167	loss of catalytic activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-3282872	Severe congenital neutropenia type 4 (G6PC3)
R-HSA-70263	Gluconeogenesis

MSigDB gene sets: 285 (showing top): RNGTGGGC_UNKNOWN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, USF_C, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_GLUCOSE_6_PHOSPHATE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_ESTER_TRANSPORT, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, ONKEN_UVEAL_MELANOMA_UP, MYCMAX_01, SMID_BREAST_CANCER_LUMINAL_B_UP, GOBP_MONOSACCHARIDE_BIOSYNTHETIC_PROCESS, KINSEY_TARGETS_OF_EWSR1_FLII_FUSION_DN, MODULE_301, GOBP_CARBOHYDRATE_METABOLIC_PROCESS, GOBP_ORGANIC_ANION_TRANSPORT

GO Biological Process (3): gluconeogenesis (GO:0006094), glucose-6-phosphate transport (GO:0015760), glucose 6-phosphate metabolic process (GO:0051156)

GO Molecular Function (2): glucose-6-phosphatase activity (GO:0004346), hydrolase activity (GO:0016787)

GO Cellular Component (3): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Glycogen storage diseases	1
Glucose metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
glucose metabolic process	1
hexose biosynthetic process	1
hexose phosphate transport	1
organophosphate metabolic process	1
carbohydrate derivative metabolic process	1
sugar-terminal-phosphatase activity	1
catalytic activity	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1706 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
G6PC3	SLC37A4	O43826	893
G6PC3	INS	P01308	867
G6PC3	GCK	P35557	837
G6PC3	GCG	P01275	808
G6PC3	PCK1	P35558	804
G6PC3	AGL	P35573	804
G6PC3	SLC2A2	P11168	794
G6PC3	PYGM	P11217	789
G6PC3	PYGL	P06737	789
G6PC3	PYGB	P11216	789
G6PC3	HAX1	O00165	762
G6PC3	PCK2	Q16822	758
G6PC3	PC	P11498	735
G6PC3	H6PD	O95479	728
G6PC3	G6PD	P11413	713

IntAct

15 interactions, top by confidence:

A	B	Type	Score
SLC6A8	ILVBL	psi-mi:“MI:0914”(association)	0.530
G6PC3	CCR9	psi-mi:“MI:0915”(physical association)	0.370
G6PC3	GPR37	psi-mi:“MI:0915”(physical association)	0.370
G6PC3	HTR2B	psi-mi:“MI:0915”(physical association)	0.370
G6PC3	PCNA	psi-mi:“MI:0915”(physical association)	0.370
CTBP1	TAF15	psi-mi:“MI:0914”(association)	0.350
CLEC4G	ARPC1B	psi-mi:“MI:0914”(association)	0.350
SCGB2A2	RTL8C	psi-mi:“MI:0914”(association)	0.350
KIR2DL4	GPR89A	psi-mi:“MI:0914”(association)	0.350
SLC5A6	SLC31A1	psi-mi:“MI:0914”(association)	0.350
G6PC3	TCEA1	psi-mi:“MI:0914”(association)	0.350
MFSD5	ILVBL	psi-mi:“MI:0914”(association)	0.350
SLC16A8	C15orf61	psi-mi:“MI:0914”(association)	0.350
SLC39A4	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (21): G6PC3 (Affinity Capture-MS), G6PC3 (Two-hybrid), G6PC3 (Two-hybrid), G6PC3 (Two-hybrid), SLC9A3R2 (Affinity Capture-MS), TCEA1 (Affinity Capture-MS), CAB39 (Affinity Capture-MS), G6PC3 (Affinity Capture-MS), G6PC3 (Affinity Capture-MS), G6PC3 (Affinity Capture-MS), G6PC3 (Reconstituted Complex), G6PC3 (Affinity Capture-MS), G6PC3 (Affinity Capture-MS), G6PC3 (Affinity Capture-RNA), G6PC3 (Proximity Label-MS)

ESM2 similar proteins: A0A8C2M425, A1A5Z0, A5D6W6, A7YWN2, B0BNG2, B2MVP8, D2HSA6, O19133, O42153, O42154, O75908, O77759, O88908, P35575, P35576, P43428, Q148G2, Q19KA1, Q29RU6, Q4FZU9, Q5E9R1, Q5KR61, Q5RKL5, Q5XK03, Q658P3, Q6AX73, Q6AZ83, Q6GQ62, Q6NSQ9, Q7TPN3, Q7TQM4, Q810K3, Q8BJ52, Q8CI59, Q8IWX5, Q8R1J1, Q8R2R1, Q8WTR4, Q91V79, Q99PR0

Diamond homologs: A1A5Z0, O19133, O42153, O42154, P35575, P35576, P43428, Q148G2, Q19KA1, Q29RU6, Q6AZ83, Q6NSQ9, Q9BUM1, Q9NQR9, Q9Z186

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
G6PC3	“up-regulates quantity”	α-D-glucose	“chemical modification”
G6PC3	“down-regulates quantity”	“alpha-D-glucose 6-phosphate(2-)”	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	40
Likely pathogenic	11
Uncertain significance	346
Likely benign	268
Benign	9

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1004638	NM_138387.4(G6PC3):c.758_781del (p.Arg253_Gly260del)	Pathogenic
1037	NM_138387.4(G6PC3):c.758G>A (p.Arg253His)	Pathogenic
1038	NM_138387.4(G6PC3):c.554T>C (p.Leu185Pro)	Pathogenic
1039	NM_138387.4(G6PC3):c.141C>G (p.Tyr47Ter)	Pathogenic
1040	NM_138387.4(G6PC3):c.784G>C (p.Gly262Arg)	Pathogenic
1042	NM_138387.4(G6PC3):c.346A>G (p.Met116Val)	Pathogenic
1066709	NM_138387.4(G6PC3):c.677+1G>A	Pathogenic
1342134	NM_138387.4(G6PC3):c.765_766del (p.Ala257fs)	Pathogenic
1430600	NM_138387.4(G6PC3):c.218+1G>A	Pathogenic
1451174	NM_138387.4(G6PC3):c.635del (p.Leu212fs)	Pathogenic
1705639	NM_138387.4(G6PC3):c.144C>A (p.Tyr48Ter)	Pathogenic
189781	NM_138387.4(G6PC3):c.130C>T (p.Pro44Ser)	Pathogenic
189782	NM_138387.4(G6PC3):c.210del (p.Phe71fs)	Pathogenic
189783	NM_138387.4(G6PC3):c.829C>T (p.Gln277Ter)	Pathogenic
189784	NM_138387.4(G6PC3):c.935dup (p.Asn313fs)	Pathogenic
2034287	NM_138387.4(G6PC3):c.765del (p.Ala257fs)	Pathogenic
2138049	NM_138387.4(G6PC3):c.481C>T (p.Arg161Ter)	Pathogenic
2427235	NC_000017.10:g.(?42151508)(42153411_?)del	Pathogenic
2736600	NM_138387.4(G6PC3):c.131C>T (p.Pro44Leu)	Pathogenic
2750293	NM_138387.4(G6PC3):c.63G>A (p.Trp21Ter)	Pathogenic
2760959	NM_138387.4(G6PC3):c.246G>A (p.Trp82Ter)	Pathogenic
2767618	NM_138387.4(G6PC3):c.218+2T>C	Pathogenic
2769107	NM_138387.4(G6PC3):c.376del (p.Ile125_Met126insTer)	Pathogenic
2777278	NM_138387.4(G6PC3):c.210_213del (p.Phe71fs)	Pathogenic
2832417	NM_138387.4(G6PC3):c.267C>G (p.Tyr89Ter)	Pathogenic
2837752	NM_138387.4(G6PC3):c.3G>T (p.Met1Ile)	Pathogenic
2838564	NM_138387.4(G6PC3):c.575dup (p.Met192fs)	Pathogenic
2853520	NM_138387.4(G6PC3):c.163del (p.Ile55fs)	Pathogenic
2858133	NM_138387.4(G6PC3):c.62G>A (p.Trp21Ter)	Pathogenic
30874	NM_138387.4(G6PC3):c.778G>C (p.Gly260Arg)	Pathogenic

SpliceAI

1675 predictions. Top by Δscore:

Variant	Effect	Δscore
17:44071181:GTG:G	donor_gain	1.0000
17:44075304:TCCTA:T	acceptor_loss	1.0000
17:44075305:CCTA:C	acceptor_loss	1.0000
17:44075306:CTAG:C	acceptor_loss	1.0000
17:44075307:TAGG:T	acceptor_loss	1.0000
17:44075308:A:AG	acceptor_gain	1.0000
17:44075308:AGGC:A	acceptor_gain	1.0000
17:44075309:G:GA	acceptor_gain	1.0000
17:44075309:G:GC	acceptor_loss	1.0000
17:44075309:GGC:G	acceptor_gain	1.0000
17:44075309:GGCG:G	acceptor_gain	1.0000
17:44075448:CTTGG:C	donor_loss	1.0000
17:44075449:TTG:T	donor_gain	1.0000
17:44075450:TGG:T	donor_loss	1.0000
17:44075451:GGT:G	donor_loss	1.0000
17:44075452:G:GG	donor_gain	1.0000
17:44075452:GTAAG:G	donor_loss	1.0000
17:44075453:T:A	donor_loss	1.0000
17:44078661:TTTGC:T	acceptor_gain	1.0000
17:44078662:TTGC:T	acceptor_gain	1.0000
17:44078663:TGC:T	acceptor_gain	1.0000
17:44078664:GC:G	acceptor_gain	1.0000
17:44078664:GCCT:G	acceptor_loss	1.0000
17:44078665:CC:C	acceptor_gain	1.0000
17:44078666:C:CC	acceptor_gain	1.0000
17:44078666:C:G	acceptor_loss	1.0000
17:44078668:G:C	acceptor_gain	1.0000
17:44078673:C:CT	acceptor_gain	1.0000
17:44078674:G:T	acceptor_gain	1.0000
17:44078756:C:CA	donor_gain	1.0000

AlphaMissense

2229 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:44071181:G:C	K72N	0.992
17:44071181:G:T	K72N	0.992
17:44075054:T:C	F168L	0.992
17:44075056:C:A	F168L	0.992
17:44075056:C:G	F168L	0.992
17:44074187:G:C	W82C	0.990
17:44074187:G:T	W82C	0.990
17:44074177:G:T	R79M	0.989
17:44075760:G:C	R253P	0.988
17:44075780:G:C	G260R	0.988
17:44075781:G:A	G260D	0.988
17:44074178:G:C	R79S	0.987
17:44074178:G:T	R79S	0.987
17:44074252:G:A	C104Y	0.987
17:44074682:A:C	S110R	0.987
17:44074684:C:A	S110R	0.987
17:44074684:C:G	S110R	0.987
17:44075034:G:C	R161P	0.987
17:44071140:T:A	W59R	0.986
17:44071140:T:C	W59R	0.986
17:44074177:G:C	R79T	0.986
17:44074185:T:A	W82R	0.986
17:44074185:T:C	W82R	0.986
17:44075055:T:G	F168C	0.986
17:44075768:G:T	G256W	0.986
17:44075786:G:C	G262R	0.986
17:44075787:G:A	G262D	0.986
17:44071161:T:A	W66R	0.985
17:44071161:T:C	W66R	0.985
17:44071169:C:A	N68K	0.985

dbSNP variants (sampled 300 via entrez): RS1000178793 (17:44069902 G>A), RS1000201812 (17:44070145 G>A), RS1000581162 (17:44075201 C>G,T), RS1000819752 (17:44076797 A>G), RS1001155353 (17:44069234 G>A,C), RS1001498441 (17:44071631 C>G,T), RS1001762610 (17:44071319 C>A,T), RS1001863607 (17:44071231 C>G), RS1001875067 (17:44071440 A>C), RS1002261835 (17:44076546 A>G), RS1002360547 (17:44069971 T>C), RS1002424458 (17:44070653 C>A,T), RS1003539649 (17:44072844 T>C), RS1003848861 (17:44073086 C>T), RS1004260812 (17:44072152 C>T)

Disease associations

OMIM: gene MIM:611045 | disease phenotypes: MIM:612541

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive severe congenital neutropenia due to G6PC3 deficiency	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
autosomal recessive severe congenital neutropenia due to G6PC3 deficiency	Definitive	AR

Mondo (1): autosomal recessive severe congenital neutropenia due to G6PC3 deficiency (MONDO:0012930)

Orphanet (1): Severe congenital neutropenia due to G6PC3 deficiency (Orphanet:331176)

HPO phenotypes

53 total (30 of 53 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000126	Hydronephrosis
HP:0000155	Oral ulcer
HP:0000175	Cleft palate
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000365	Hearing impairment
HP:0000388	Otitis media
HP:0000407	Sensorineural hearing impairment
HP:0000431	Wide nasal bridge
HP:0000768	Pectus carinatum
HP:0000778	Hypoplasia of the thymus
HP:0000954	Single transverse palmar crease
HP:0001015	Prominent superficial veins
HP:0001263	Global developmental delay
HP:0001433	Hepatosplenomegaly
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001642	Pulmonic stenosis
HP:0001643	Patent ductus arteriosus
HP:0001653	Mitral regurgitation
HP:0001684	Secundum atrial septal defect
HP:0001744	Splenomegaly
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count
HP:0001882	Decreased total leukocyte count
HP:0001888	Decreased total lymphocyte count

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002270_1	Glycated hemoglobin levels	1.000000e-24
GCST008103_24	Bipolar disorder	2.000000e-08
GCST90013466_18	Height	3.000000e-08
GCST90013466_57	Height	4.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004541	HbA1c measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression	2
sodium arsenite	decreases expression, increases expression	2
Cisplatin	affects cotreatment, increases expression, decreases expression	2
Cadmium Chloride	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
arsenite	affects binding, increases reaction	1
cobaltous chloride	decreases expression	1
ginsenoside Rg2	decreases expression, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
dorsomorphin	decreases expression, decreases reaction	1
jinfukang	affects cotreatment, increases expression	1
MT19c compound	decreases expression	1
Arsenic Trioxide	increases expression	1
Glyphosate	decreases expression	1
Ethanol	affects cotreatment, increases abundance, increases expression	1
Aspirin	increases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	decreases expression, increases abundance	1
Chelating Agents	affects binding, decreases expression	1
Copper	decreases expression, affects binding	1
Gasoline	affects cotreatment, increases abundance, increases expression	1
Plant Extracts	decreases expression	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, increases abundance, increases expression	1
Smoke	decreases expression	1
Dronabinol	increases expression	1
Thiram	decreases expression	1
Valproic Acid	decreases expression	1
Cyclosporine	decreases expression	1
Gold Compounds	decreases methylation, increases expression	1

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2XH	Abcam HEK293T G6PC3 KO	Transformed cell line	Female
CVCL_D8LP	Ubigene HCT 116 G6PC3 KO	Cancer cell line	Male
CVCL_E0UA	Ubigene Hep G2 G6PC3 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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