ENO4

Summary

ENO4 (enolase 4, HGNC:31670) is a protein-coding gene on chromosome 10q25.3, encoding Enolase 4 (A6NNW6). Enolase that catalyzes the conversion of 2-phosphoglycerate to phosphoenolpyruvate in glycolysis and the reverse reaction in gluconeogenesis.

Predicted to enable phosphopyruvate hydratase activity. Predicted to be involved in glycolytic process. Predicted to act upstream of or within cilium organization and flagellated sperm motility. Predicted to be located in sperm principal piece. Predicted to be part of phosphopyruvate hydratase complex.

Source: NCBI Gene 387712 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 115 total
• MANE Select transcript: NM_001242699

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:31670
Approved symbol	ENO4
Name	enolase 4
Location	10q25.3
Locus type	gene with protein product
Status	Approved
Aliases	AC023283.3
Ensembl gene	ENSG00000188316
Ensembl biotype	protein_coding
OMIM	131375
Entrez	387712

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000341276, ENST00000369207, ENST00000409522, ENST00000969696, ENST00000969697

RefSeq mRNA: 1 — MANE Select: NM_001242699 NM_001242699

CCDS: CCDS73206

Canonical transcript exons

ENST00000341276 — 14 exons

Exon	Start	End
ENSE00001364242	116874076	116874201
ENSE00001371208	116876065	116876260
ENSE00001377548	116879869	116879986
ENSE00001377791	116861059	116861190
ENSE00001381026	116871125	116871292
ENSE00001390219	116868650	116868706
ENSE00001391582	116879291	116879358
ENSE00001449129	116862799	116862852
ENSE00001504190	116858990	116859138
ENSE00001504191	116856492	116856682
ENSE00002043355	116849499	116849731
ENSE00003589787	116860794	116860963
ENSE00003637897	116855623	116855751
ENSE00003898874	116881515	116882601

Expression profiles

Bgee: expression breadth ubiquitous, 114 present calls, max score 80.33.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3059 / max 9.0857, expressed in 161 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
107249	0.3059	161

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.33	gold quality
right uterine tube	UBERON:0001302	77.38	gold quality
corpus callosum	UBERON:0002336	73.86	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	72.60	gold quality
fallopian tube	UBERON:0003889	62.69	gold quality
ventricular zone	UBERON:0003053	59.35	gold quality
prefrontal cortex	UBERON:0000451	59.12	gold quality
testis	UBERON:0000473	58.92	gold quality
calcaneal tendon	UBERON:0003701	58.89	gold quality
cortical plate	UBERON:0005343	58.86	gold quality
adenohypophysis	UBERON:0002196	58.83	gold quality
endometrium	UBERON:0001295	58.81	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	58.05	silver quality
right testis	UBERON:0004534	57.67	gold quality
left testis	UBERON:0004533	57.66	gold quality
hypothalamus	UBERON:0001898	57.13	gold quality
pituitary gland	UBERON:0000007	56.23	gold quality
frontal cortex	UBERON:0001870	56.21	gold quality
superior frontal gyrus	UBERON:0002661	56.21	gold quality
caudate nucleus	UBERON:0001873	56.08	gold quality
Ammon’s horn	UBERON:0001954	56.00	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	55.50	gold quality
primary visual cortex	UBERON:0002436	54.80	gold quality
ganglionic eminence	UBERON:0004023	54.61	gold quality
cerebral cortex	UBERON:0000956	54.52	gold quality
nucleus accumbens	UBERON:0001882	54.01	gold quality
Brodmann (1909) area 9	UBERON:0013540	53.44	gold quality
gall bladder	UBERON:0002110	53.42	gold quality
brain	UBERON:0000955	53.28	gold quality
ovary	UBERON:0000992	52.91	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-180759	yes	563.53
E-ANND-3	yes	4.36

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

73 targeting ENO4, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-374C-5P	99.80	72.06	2910

Literature-anchored findings (GeneRIF, showing 2)

• A novel association with advanced primary open-angle glaucoma (POAG) in the EN04 locus was identified putatively in persons of AD. In addition to this finding, this genome-wide association study in POAG patients of AD contributes to POAG genetics by identification of novel signals in prior loci (9p21) (PMID:30352225)
• A variant in sperm-specific glycolytic enzyme enolase 4 (ENO4) causes human male infertility. (PMID:37640479)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	eno4	ENSDARG00000070598
mus_musculus	Eno4	ENSMUSG00000048029
rattus_norvegicus	Eno4	ENSRNOG00000018310
drosophila_melanogaster	Eno	FBGN0000579
caenorhabditis_elegans		WBGENE00011884

Paralogs (3): ENO1 (ENSG00000074800), ENO3 (ENSG00000108515), ENO2 (ENSG00000111674)

Protein

Protein identifiers

Enolase 4 — A6NNW6 (reviewed: A6NNW6)

Alternative names: 2-phospho-D-glycerate hydro-lyase

All UniProt accessions (2): A0A5H1ZRQ0, A6NNW6

UniProt curated annotations — full annotation on UniProt →

Function. Enolase that catalyzes the conversion of 2-phosphoglycerate to phosphoenolpyruvate in glycolysis and the reverse reaction in gluconeogenesis. May be required for sperm motility and function.

Subunit / interactions. Interacts with ENO1 and AKAP4.

Post-translational modifications. Synthesized as an approximately 70-kDa precursor, which then undergoes proteolytic cleavage to an approximately 60-kDa enzyme; HOATZ associates directly or indirectly with ENO4 to mediate this process before its transport to mature flagella.

Pathway. Carbohydrate degradation; glycolysis; pyruvate from D-glyceraldehyde 3-phosphate: step 4/5.

Similarity. Belongs to the enolase family.

Isoforms (3)

UniProt ID	Names	Canonical?
A6NNW6-3	3	yes
A6NNW6-2	2
A6NNW6-4	4

RefSeq proteins (1): NP_001229628* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000941	Enolase	Family
IPR020810	Enolase_C	Domain
IPR020811	Enolase_N	Domain
IPR029017	Enolase-like_N	Homologous_superfamily
IPR036849	Enolase-like_C_sf	Homologous_superfamily
IPR047500	DD_ENO4	Domain

Pfam: PF00113

Catalyzed reactions (Rhea), 1 shown:

• (2R)-2-phosphoglycerate = phosphoenolpyruvate + H2O (RHEA:10164)

UniProt features (15 total): splice variant 5, region of interest 3, compositionally biased region 2, binding site 2, chain 1, sequence conflict 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A6NNW6-F1	84.70	0.66

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): 497 (proton acceptor)

Ligand- & substrate-binding residues (2): 300; 548

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-70171	Glycolysis
R-HSA-70263	Gluconeogenesis

MSigDB gene sets: 76 (showing top): GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_NUCLEOSIDE_TRIPHOSPHATE_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_METABOLIC_PROCESS, REACTOME_GLUCONEOGENESIS, GOBP_ORGANOPHOSPHATE_CATABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_CATABOLIC_PROCESS, GOMF_HYDRO_LYASE_ACTIVITY

GO Biological Process (1): glycolytic process (GO:0006096)

GO Molecular Function (3): magnesium ion binding (GO:0000287), phosphopyruvate hydratase activity (GO:0004634), lyase activity (GO:0016829)

GO Cellular Component (1): phosphopyruvate hydratase complex (GO:0000015)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Glucose metabolism	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
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
metal ion binding	1
hydro-lyase activity	1
catalytic activity	1
cytosol	1
catalytic complex	1

Protein interactions and networks

STRING

3506 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ENO4	PKLR	P11973	633
ENO4	PGK2	P07205	579
ENO4	PFKL	P17858	552
ENO4	TPI1	P00938	544
ENO4	PGAM2	P15259	544
ENO4	PNPT1	Q8TCS8	539
ENO4	GPI	P06744	535
ENO4	PFKP	Q01813	528
ENO4	PKM	P14618	506
ENO4	SPEM1	Q8N4L4	480
ENO4	PGK1	P00558	480
ENO4	PGAM1	P18669	472
ENO4	PFKM	P08237	462
ENO4	MDH2	P40926	453
ENO4	NKD2	Q969F2	436

IntAct

3 interactions, top by confidence:

A	B	Type	Score
ENO4	WDR3	psi-mi:“MI:0915”(physical association)	0.400
ENO4	CKAP4	psi-mi:“MI:0915”(physical association)	0.400

ESM2 similar proteins: A0JML8, A0JP70, A2BID5, A2CEI4, A6NNW6, A9JTS5, E7FAW3, F1QNV4, O75153, O75800, O95248, P0CI65, P56192, P97874, Q08CY4, Q0VC30, Q14689, Q17QN2, Q1LWH4, Q1LXZ7, Q29S07, Q2T9L8, Q32PH0, Q3B7U4, Q3U308, Q3UAW9, Q3UH60, Q3UY23, Q4R4F1, Q641Y9, Q68FL6, Q6DG91, Q6GPP1, Q6PJN8, Q6TEN6, Q6ZNJ1, Q6ZPE2, Q6ZQA0, Q7T006, Q8BWT5

Diamond homologs: A0PW55, A1A143, A1KHG1, A1QQ97, A1SSQ7, A4F804, A5U166, A6NNW6, A9UMP7, B0BM20, B1MKG1, B1VFL0, B2HDI5, B3DSV2, B7GTK2, B8DTI9, C1A306, C1AM14, C1AY93, P9WNL0, P9WNL1, Q086B0, Q08BC6, Q0S4I1, Q1LTN8, Q5YQ30, Q74AR6, Q7U0U6, Q8C042, Q8G5I9, Q9CD42, A0KU82, A1TZ48, A4YHC1, A7HNS8, A7ZFN1, A9KQ46, B0KSB9, B1JB38, B3PJB3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	100
Likely benign	6
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

3284 predictions. Top by Δscore:

Variant	Effect	Δscore
10:116849675:G:GT	donor_gain	1.0000
10:116849728:CCTGG:C	donor_loss	1.0000
10:116849730:TGGT:T	donor_loss	1.0000
10:116849732:G:GG	donor_gain	1.0000
10:116849732:GT:G	donor_loss	1.0000
10:116856491:GA:G	acceptor_gain	1.0000
10:116856491:GAAC:G	acceptor_gain	1.0000
10:116861115:G:GT	donor_gain	1.0000
10:116861115:G:T	donor_gain	1.0000
10:116861130:G:GT	donor_gain	1.0000
10:116861130:G:T	donor_gain	1.0000
10:116861134:C:G	donor_gain	1.0000
10:116861149:G:GT	donor_gain	1.0000
10:116861191:G:GG	donor_gain	1.0000
10:116871123:A:AG	acceptor_gain	1.0000
10:116871124:G:GG	acceptor_gain	1.0000
10:116871124:GCAGC:G	acceptor_gain	1.0000
10:116871287:GAC:G	donor_gain	1.0000
10:116871293:G:GG	donor_gain	1.0000
10:116874053:A:AG	acceptor_gain	1.0000
10:116874054:A:G	acceptor_gain	1.0000
10:116874057:T:G	acceptor_gain	1.0000
10:116874063:T:TA	acceptor_gain	1.0000
10:116874067:A:AG	acceptor_gain	1.0000
10:116874068:C:G	acceptor_gain	1.0000
10:116874070:T:G	acceptor_gain	1.0000
10:116879866:CAGGC:C	acceptor_loss	1.0000
10:116879867:A:AG	acceptor_gain	1.0000
10:116879868:G:GG	acceptor_gain	1.0000
10:116879868:G:GT	acceptor_loss	1.0000

AlphaMissense

4100 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:116874149:T:C	L430P	0.989
10:116879942:G:C	R560P	0.988
10:116876077:T:A	W452R	0.986
10:116876077:T:C	W452R	0.986
10:116849730:T:C	L55P	0.981
10:116871258:C:A	A394D	0.981
10:116871257:G:C	A394P	0.980
10:116871266:T:C	C397R	0.980
10:116874188:C:G	P443R	0.976
10:116849696:T:C	F44L	0.974
10:116849698:C:A	F44L	0.974
10:116849698:C:G	F44L	0.974
10:116849685:T:A	L40H	0.973
10:116874175:G:C	A439P	0.973
10:116874188:C:A	P443H	0.970
10:116874179:T:C	L440S	0.969
10:116879875:G:T	G538W	0.969
10:116849685:T:C	L40P	0.968
10:116871268:T:G	C397W	0.967
10:116874176:C:A	A439D	0.966
10:116849673:T:C	L36P	0.965
10:116861158:T:C	C302R	0.965
10:116874088:T:G	Y410D	0.965
10:116849661:T:A	V32D	0.964
10:116874089:A:C	Y410S	0.962
10:116849626:G:C	K20N	0.961
10:116849626:G:T	K20N	0.961
10:116855728:T:C	C91R	0.961
10:116879924:G:C	R554P	0.961
10:116849645:T:G	Y27D	0.958

dbSNP variants (sampled 300 via entrez): RS1000068967 (10:116863338 A>G), RS1000177099 (10:116880814 C>T), RS1000287185 (10:116887802 G>A,C), RS1000348917 (10:116894580 C>T), RS1000376076 (10:116900875 T>C,G), RS1000420221 (10:116863153 G>A), RS1000433517 (10:116869712 A>G), RS1000454555 (10:116900073 G>A), RS1000460656 (10:116851338 T>G), RS1000486280 (10:116894190 G>C), RS1000509976 (10:116882370 C>A), RS1000571436 (10:116882154 A>AT), RS1000592194 (10:116888784 C>T), RS1000595293 (10:116888176 T>C), RS1000608395 (10:116862386 C>A)

Disease associations

OMIM: gene MIM:131375 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST003542_200	Night sleep phenotypes	4.000000e-06
GCST004075_14	Vertical cup-disc ratio	1.000000e-06
GCST004075_15	Vertical cup-disc ratio	2.000000e-08
GCST005231_18	Major depressive disorder	6.000000e-06
GCST005951_66	Body mass index	4.000000e-08
GCST009404_13	Optic cup area	4.000000e-06
GCST009412_24	Vertical cup-disc ratio	2.000000e-07
GCST009416_7	Optic nerve head parameters (multi-trait analysis)	7.000000e-09
GCST009724_24	Vertical cup-disc ratio (multi-trait analysis)	3.000000e-13
GCST010703_309	Brain morphology (MOSTest)	2.000000e-25
GCST010988_452	Adult body size	3.000000e-11

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006939	cup-to-disc ratio measurement
EFO:0004340	body mass index
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sotorasib	affects cotreatment, increases expression	1
2-palmitoylglycerol	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
trametinib	affects cotreatment, increases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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