PGAM4

Summary

PGAM4 (phosphoglycerate mutase family member 4, HGNC:21731) is a protein-coding gene on chromosome Xq21.1, encoding Probable phosphoglycerate mutase 4 (Q8N0Y7). May catalyze the interconversion of 2-phosphoglycerate and 3-phosphoglycerate, a crucial step in glycolysis, by using 2,3-bisphosphoglycerate.

This intronless gene appears to have arisen from a retrotransposition event, yet it is thought to be an expressed, protein-coding gene. The encoded protein is a member of the phosphoglycerate mutase family, a set of enzymes that catalyze the transfer of a phosphate group from 3-phosphoglycerate to 2-phosphoglycerate.

Source: NCBI Gene 441531 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 3 total — 1 pathogenic
• MANE Select transcript: NM_001029891

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21731
Approved symbol	PGAM4
Name	phosphoglycerate mutase family member 4
Location	Xq21.1
Locus type	gene with protein product
Status	Approved
Aliases	dJ1000K24.1, PGAM3, PGAM-B, PGAM1
Ensembl gene	ENSG00000226784
Ensembl biotype	protein_coding
OMIM	300567
Entrez	441531

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000458128

RefSeq mRNA: 1 — MANE Select: NM_001029891 NM_001029891

CCDS: CCDS35338

Canonical transcript exons

ENST00000458128 — 1 exons

Exon	Start	End
ENSE00001803157	77967949	77969638

Expression profiles

Bgee: expression breadth broad, 65 present calls, max score 59.24.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bone marrow cell	CL:0002092	59.24	gold quality
stromal cell of endometrium	CL:0002255	57.86	gold quality
bone marrow	UBERON:0002371	56.59	silver quality
colonic epithelium	UBERON:0000397	55.21	silver quality
vermiform appendix	UBERON:0001154	50.91	gold quality
blood	UBERON:0000178	49.27	gold quality
prefrontal cortex	UBERON:0000451	46.81	gold quality
placenta	UBERON:0001987	46.18	gold quality
duodenum	UBERON:0002114	45.39	gold quality
ventricular zone	UBERON:0003053	44.77	gold quality
cortical plate	UBERON:0005343	44.42	silver quality
granulocyte	CL:0000094	44.13	silver quality
smooth muscle tissue	UBERON:0001135	43.85	gold quality
islet of Langerhans	UBERON:0000006	43.16	gold quality
skeletal muscle tissue	UBERON:0001134	42.92	gold quality
muscle tissue	UBERON:0002385	42.63	silver quality
frontal cortex	UBERON:0001870	42.62	gold quality
superior frontal gyrus	UBERON:0002661	42.31	silver quality
esophagus mucosa	UBERON:0002469	42.11	silver quality
ganglionic eminence	UBERON:0004023	41.80	gold quality
adrenal gland	UBERON:0002369	41.40	gold quality
left adrenal gland	UBERON:0001234	41.13	silver quality
uterine cervix	UBERON:0000002	41.05	silver quality
left adrenal gland cortex	UBERON:0035825	41.05	silver quality
esophagus	UBERON:0001043	40.99	silver quality
urinary bladder	UBERON:0001255	40.86	silver quality
heart left ventricle	UBERON:0002084	40.13	silver quality
heart	UBERON:0000948	39.85	silver quality
tibial artery	UBERON:0007610	39.56	silver quality
popliteal artery	UBERON:0002250	39.46	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.35

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

67 targeting PGAM4, 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-126-5P	100.00	72.71	3180
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488
HSA-MIR-548Y	99.94	71.28	3514
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-4302	99.89	67.94	1187

Literature-anchored findings (GeneRIF, showing 2)

• PGAM4, an X-linked retrogene, is a fundamental gene in human male reproduction and may escape meiotic sex chromosome inactivation. (PMID:22590500)
• PGAM4 coding region mutations were not observed and the G75C polymorphism is not associated with non-obstructive azoospermia susceptibility among the Chinese Han population. (PMID:23631659)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	pgam1a	ENSDARG00000005423
danio_rerio	pgam1b	ENSDARG00000014068
mus_musculus	Pgam1	ENSMUSG00000011752
rattus_norvegicus	Pgam1	ENSRNOG00000050585
drosophila_melanogaster	Pglym87	FBGN0011270
drosophila_melanogaster	Pglym78	FBGN0014869

Paralogs (3): PGAM2 (ENSG00000164708), PGAM1 (ENSG00000171314), BPGM (ENSG00000172331)

Protein

Protein identifiers

Probable phosphoglycerate mutase 4 — Q8N0Y7 (reviewed: Q8N0Y7)

All UniProt accessions (1): Q8N0Y7

UniProt curated annotations — full annotation on UniProt →

Function. May catalyze the interconversion of 2-phosphoglycerate and 3-phosphoglycerate, a crucial step in glycolysis, by using 2,3-bisphosphoglycerate. May also catalyze the interconversion of (2R)-2,3-bisphosphoglycerate and (2R)-3-phospho-glyceroyl phosphate.

Miscellaneous. This is the product of a processed gene created by retroposition from mRNA of an expressed gene. This gene seems to be expressed.

Similarity. Belongs to the phosphoglycerate mutase family. BPG-dependent PGAM subfamily.

RefSeq proteins (1): NP_001025062* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001345	PG/BPGM_mutase_AS	Active_site
IPR005952	Phosphogly_mut1	Family
IPR013078	His_Pase_superF_clade-1	Family
IPR029033	His_PPase_superfam	Homologous_superfamily

Pfam: PF00300

Catalyzed reactions (Rhea), 2 shown:

• (2R)-2-phosphoglycerate = (2R)-3-phosphoglycerate (RHEA:15901)
• (2R)-3-phospho-glyceroyl phosphate = (2R)-2,3-bisphosphoglycerate + H(+) (RHEA:17765)

UniProt features (24 total): modified residue 10, binding site 7, sequence variant 3, active site 2, chain 1, site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N0Y7-F1	94.21	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 (3): 11 (tele-phosphohistidine intermediate); 186 (transition state stabilizer); 89 (proton donor/acceptor)

Ligand- & substrate-binding residues (7): 10–17; 23–24; 62; 89–92; 100; 116–117; 187–188

Post-translational modifications (10): 14, 23, 26, 31, 106, 118, 251, 251, 253, 254

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 351 (showing top): SHEPARD_BMYB_MORPHOLINO_UP, GOBP_POSITIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, REACTOME_INNATE_IMMUNE_SYSTEM, SHIPP_DLBCL_VS_FOLLICULAR_LYMPHOMA_UP, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, GOCC_SECRETORY_GRANULE, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, HSIAO_HOUSEKEEPING_GENES, GOBP_MONOSACCHARIDE_CATABOLIC_PROCESS, DARWICHE_SKIN_TUMOR_PROMOTER_UP, MITSIADES_RESPONSE_TO_APLIDIN_DN, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_UP, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS

GO Biological Process (2): glycolytic process (GO:0006096), positive regulation of flagellated sperm motility (GO:1902093)

GO Molecular Function (6): bisphosphoglycerate mutase activity (GO:0004082), phosphoglycerate mutase activity (GO:0004619), hydrolase activity (GO:0016787), catalytic activity (GO:0003824), isomerase activity (GO:0016853), intramolecular phosphotransferase activity (GO:0016868)

GO Cellular Component (2): extracellular exosome (GO:0070062), sperm principal piece (GO:0097228)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intramolecular phosphotransferase activity	2
catalytic activity	2
phosphoglycerate kinase activity	1
phosphoglycerate mutase activity	1
phosphopyruvate hydratase activity	1
pyruvate kinase activity	1
pyruvate metabolic process	1
generation of precursor metabolites and energy	1
aerobic respiration	1
carbohydrate catabolic process	1
pyridine nucleotide catabolic process	1
glyceraldehyde-3-phosphate dehydrogenase [NAD(P)+] (phosphorylating) activity	1
ADP catabolic process	1
ATP metabolic process	1
nicotinamide nucleotide metabolic process	1
positive regulation of cilium movement	1
flagellated sperm motility	1
regulation of flagellated sperm motility	1
positive regulation of cilium-dependent cell motility	1
positive regulation of reproductive process	1
molecular_function	1
intramolecular transferase activity	1
extracellular vesicle	1
sperm flagellum	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1751 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PGAM4	PKM	P14618	897
PGAM4	PGK1	P00558	846
PGAM4	J3KPS3	J3KPS3	840
PGAM4	ALDOA	P04075	839
PGAM4	ENO1	P06733	836
PGAM4	TPI1	P00938	833
PGAM4	UBASH3B	Q8TF42	802
PGAM4	GAPDH	P00354	710
PGAM4	LDHA	P00338	707
PGAM4	ENO3	P13929	702
PGAM4	PGAM2	P15259	697
PGAM4	ENO2	P09104	684
PGAM4	PFKP	Q01813	680
PGAM4	PFKL	P17858	676
PGAM4	PKLR	P11973	661

IntAct

25 interactions, top by confidence:

A	B	Type	Score
SH2D4A	PPP1CB	psi-mi:“MI:0914”(association)	0.960
PGAM2	BPGM	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
TFEB	MITF	psi-mi:“MI:0914”(association)	0.560
SCRIB	CHD2	psi-mi:“MI:0914”(association)	0.350
PGAM4	TXNDC9	psi-mi:“MI:0914”(association)	0.350
DYM	GAPDHS	psi-mi:“MI:0914”(association)	0.350
RYK	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350
GRXCR1	VPS4B	psi-mi:“MI:0914”(association)	0.350
IL2RA	LTN1	psi-mi:“MI:0914”(association)	0.350
EPB41L4B	RPSA2	psi-mi:“MI:0914”(association)	0.350
CCSER1	RPSA2	psi-mi:“MI:0914”(association)	0.350
HEY2	RPSA2	psi-mi:“MI:0914”(association)	0.350
PPM1B	RPSA2	psi-mi:“MI:0914”(association)	0.350
SPAST	RPSA2	psi-mi:“MI:0914”(association)	0.350
CCNL1	RPSA2	psi-mi:“MI:0914”(association)	0.350
RPSA2		psi-mi:“MI:0914”(association)	0.350
BPGM	PGAM1	psi-mi:“MI:0914”(association)	0.350
CFAP20	RABEPK	psi-mi:“MI:0914”(association)	0.350
NS	MYO1C	psi-mi:“MI:0914”(association)	0.350

BioGRID (55): PGAM4 (Affinity Capture-MS), GPX4 (Co-fractionation), PGAM4 (Affinity Capture-MS), PGAM4 (Affinity Capture-MS), PGAM4 (Proximity Label-MS), PGAM4 (Affinity Capture-MS), PGAM4 (Affinity Capture-MS), PDCL (Affinity Capture-MS), PGAM4 (Affinity Capture-MS), PGAM4 (Affinity Capture-MS), PGAM4 (Affinity Capture-MS), CCT2 (Affinity Capture-MS), CCT7 (Affinity Capture-MS), CCT6A (Affinity Capture-MS), CCT6B (Affinity Capture-MS)

ESM2 similar proteins: A1BE55, A1K9B9, A1VKR6, A4JI45, A4SDM0, B0K4E2, B0KBW9, B1JZ61, B1VS80, B1Y3R5, B1YNA6, B2AGP7, B2JC95, B2S101, B2SX15, B2VBS6, B3EFK8, B4EA64, B4S616, B4SEI0, B9MEZ2, G4VJD5, O70250, P07738, P07952, P15327, P16290, P18669, P25113, Q0BBK5, Q2FTH0, Q2T1H5, Q2Y9Z7, Q39CN6, Q39V40, Q3AU60, Q3B5J2, Q3T014, Q476J7, Q4R6L7

Diamond homologs: A0AKV8, A1K9B9, A1KV25, A1TTW5, A1UZX9, A1VKR6, A1WBJ3, A1WWH7, A2RI67, A2S625, A3MQ23, A3N5B0, A3NR09, A4SDM0, A5VB15, A6VLV0, A9BUZ3, A9IFJ0, A9M1A2, B0KBW9, B0RQR7, B0SY17, B2AGP7, B2FHH6, B2SRM8, B2SX15, B3EN99, B3QPN8, B3QVL0, B4RZM6, B4S616, B4SEI0, B4SPL6, B6IYD3, B8DFA5, B8DLN4, B8GYN6, B9MEZ2, C0QV47, C1KXG0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	0
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
564861	GRCh37/hg19 Xq21.1(chrX:76902857-77454045)x2	Pathogenic

SpliceAI

873 predictions. Top by Δscore:

Variant	Effect	Δscore
10:97426416:G:GT	donor_gain	1.0000
10:97426437:GCGC:G	donor_gain	1.0000
10:97427252:GCA:G	donor_gain	1.0000
10:97427255:G:GG	donor_gain	1.0000
10:97430649:G:GG	donor_gain	1.0000
10:97430649:GTAAG:G	donor_loss	1.0000
10:97430651:AAG:A	donor_loss	1.0000
10:97430653:GG:G	donor_loss	1.0000
10:97430654:G:GA	donor_loss	1.0000
10:97430953:A:AG	acceptor_gain	1.0000
10:97430953:AG:A	acceptor_gain	1.0000
10:97430954:G:GC	acceptor_loss	1.0000
10:97430954:G:GG	acceptor_gain	1.0000
10:97430954:GG:G	acceptor_gain	1.0000
10:97430954:GGATC:G	acceptor_gain	1.0000
10:97431131:GGAGG:G	donor_gain	1.0000
10:97431132:GAGG:G	donor_gain	1.0000
10:97431132:GAGGG:G	donor_gain	1.0000
10:97431134:GG:G	donor_gain	1.0000
10:97431135:GG:G	donor_gain	1.0000
10:97431136:GTAT:G	donor_gain	1.0000
10:97432353:A:AG	acceptor_gain	1.0000
10:97432354:G:GG	acceptor_gain	1.0000
10:97430373:TTCCA:T	acceptor_loss	0.9900
10:97430376:CA:C	acceptor_loss	0.9900
10:97430377:A:AC	acceptor_loss	0.9900
10:97430378:GAT:G	acceptor_gain	0.9900
10:97430954:GGA:G	acceptor_gain	0.9900
10:97432346:T:TA	acceptor_gain	0.9900
10:97432350:TTCA:T	acceptor_loss	0.9900

AlphaMissense

1671 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:77969483:A:C	F52L	0.922
X:77969483:A:T	F52L	0.922
X:77969485:A:G	F52L	0.922
X:77968943:A:C	F232L	0.893
X:77968943:A:T	F232L	0.893
X:77968945:A:G	F232L	0.893
X:77969573:G:C	F22L	0.883
X:77969573:G:T	F22L	0.883
X:77969575:A:G	F22L	0.883
X:77969243:G:C	F132L	0.818
X:77969243:G:T	F132L	0.818
X:77969245:A:G	F132L	0.818
X:77969141:G:C	F166L	0.767
X:77969141:G:T	F166L	0.767
X:77969143:A:G	F166L	0.767
X:77969407:A:G	W78R	0.750
X:77969407:A:T	W78R	0.750
X:77969140:A:G	W167R	0.743
X:77969140:A:T	W167R	0.743
X:77969386:A:G	W85R	0.728
X:77969386:A:T	W85R	0.728
X:77969474:G:C	C55W	0.716
X:77969296:A:G	W115R	0.711
X:77969296:A:T	W115R	0.711
X:77969384:C:A	W85C	0.711
X:77969384:C:G	W85C	0.711
X:77969546:G:C	S31R	0.707
X:77969546:G:T	S31R	0.707
X:77969548:T:G	S31R	0.707
X:77969480:G:C	D53E	0.692

dbSNP variants (sampled 300 via entrez): RS1005227953 (X:77967940 T>C), RS1009079114 (X:77970376 A>G), RS1011025794 (X:77970825 G>A), RS1012246572 (X:77971433 G>C,T), RS1017695831 (X:77969914 A>G), RS1018165465 (X:77970436 C>T), RS1022274939 (X:77969974 T>C), RS1022325946 (X:77970473 C>A), RS1023976586 (X:77971436 A>G), RS1025505831 (X:77971511 A>T), RS1026462690 (X:77967526 T>G), RS1026555907 (X:77969713 C>G), RS1038014733 (X:77967941 T>C), RS1039272826 (X:77970791 A>G), RS1042265125 (X:77967773 C>A,T)

Disease associations

OMIM: gene MIM:300567 | disease phenotypes: MIM:309400

GenCC curated gene-disease

Mondo (1): Menkes disease (MONDO:0010651)

Orphanet (1): Menkes disease (Orphanet:565)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D007706	Menkes Kinky Hair Syndrome	C10.228.140.163.100.540; C10.597.606.360.455.687; C16.320.322.500.687; C16.320.400.525.687; C16.320.565.189.540; C16.320.565.618.590; C17.800.329.968; C18.452.132.100.540; C18.452.648.189.540; C18.452.648.618.590

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
chloropicrin	decreases expression, increases expression	2
Tunicamycin	decreases expression	2
aminomethylphosphonic acid (AMPA)	increases expression	1
bisphenol A	affects expression	1
sodium arsenite	increases expression	1
2-palmitoylglycerol	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Doxorubicin	decreases expression	1
Estradiol	affects binding, increases reaction	1
Dronabinol	decreases expression	1
Tretinoin	increases expression	1
Urethane	decreases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	decreases methylation	1
Thapsigargin	decreases expression	1
Nanotubes, Carbon	affects expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00811785	PHASE3	COMPLETED	Molecular Bases of Response to Copper Treatment in Menkes Disease, Related Phenotypes, and Unexplained Copper Deficiency
NCT00001262	PHASE1/PHASE2	COMPLETED	Copper Histidine Therapy for Menkes Diseases
NCT04977388	PHASE1/PHASE2	COMPLETED	NORTHERA (DROXIDOPA) for Dysautonomia in Adult Survivors of Menkes Disease and Occipital Horn Syndrome
NCT07398508	PHASE1/PHASE2	RECRUITING	Phase I/II Study of NORTHERA (DROXIDOPA) for Dysautonomia in Pediatric Survivors of Menkes Disease.
NCT05507996	EARLY_PHASE1	TERMINATED	Recombinant Adeno-associated Virus Administration for Patients With Menkes Syndrome
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT04074512	Not specified	APPROVED_FOR_MARKETING	Copper Histidinate Treatment for Menkes Disease
NCT04337684	Not specified	ACTIVE_NOT_RECRUITING	Long Term Follow-up on Menkes Disease Patients
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening