HAO2

Summary

HAO2 (hydroxyacid oxidase 2, HGNC:4810) is a protein-coding gene on chromosome 1p12, encoding 2-Hydroxyacid oxidase 2 (Q9NYQ3). Oxidase that catalyzes the oxidation of medium and long chain hydroxyacids such as 2-hydroxyhexadecanoate and 2-hydroxyoctanoate, to the corresponding 2-oxoacids.

This gene is one of three related genes that have 2-hydroxyacid oxidase activity. The encoded protein localizes to the peroxisome has the highest activity toward the substrate 2-hydroxypalmitate. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 51179 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 60 total
• GTEx eGene: eQTL in 13 tissues, sQTL in 1 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.33 (unconstrained)
• MANE Select transcript: NM_016527
• Interaction hub: 1,764 STRING partners (top 10% of genes corpus-wide)
• Notable: 60 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4810
Approved symbol	HAO2
Name	hydroxyacid oxidase 2
Location	1p12
Locus type	gene with protein product
Status	Approved
Aliases	HAOX2, GIG16
Ensembl gene	ENSG00000116882
Ensembl biotype	protein_coding
OMIM	605176
Entrez	51179

Gene structure

Transcript identifiers

Ensembl transcripts: 54 — 45 protein_coding, 8 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000325945

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 1, TSL 3: 1

ENST00000325945, ENST00000361035, ENST00000457318, ENST00000482991, ENST00000622548, ENST00000864531, ENST00000864532, ENST00000864533, ENST00000864534, ENST00000864535, ENST00000864536, ENST00000864537, ENST00000864538, ENST00000864539, ENST00000864540, ENST00000864541, ENST00000864542, ENST00000864543, ENST00000864544, ENST00000864545, ENST00000864546, ENST00000864547, ENST00000864548, ENST00000864549, ENST00000864550, ENST00000864551, ENST00000864552, ENST00000864553, ENST00000864554, ENST00000864555, ENST00000864556, ENST00000864557, ENST00000864558, ENST00000864559, ENST00000864560, ENST00000864561, ENST00000979307, ENST00000979308, ENST00000979310, ENST00000979311, ENST00000979316, ENST00000979317, ENST00001092846, ENST00001092847, ENST00001118773, ENST00001118774, ENST00001118775, ENST00001118776, ENST00001118777, ENST00001118778, ENST00001118779, ENST00001118780, ENST00001118781, ENST00001145700

RefSeq mRNA: 3 — MANE Select: NM_016527 NM_001005783, NM_001377472, NM_016527

CCDS: CCDS76196, CCDS901

Canonical transcript exons

ENST00000325945 — 8 exons

Exon	Start	End
ENSE00000785225	119382915	119383066
ENSE00000785226	119384776	119385053
ENSE00000785228	119392110	119392268
ENSE00000785229	119392618	119392687
ENSE00000800638	119386622	119386831
ENSE00001814760	119368785	119368902
ENSE00001839391	119393785	119394130
ENSE00003513214	119381078	119381216

Expression profiles

Bgee: expression breadth ubiquitous, 132 present calls, max score 98.37.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1438 / max 48.4179, expressed in 11 samples.

Highest expression (Bgee): lobe of liver, liver, kidney epithelium, nephron tubule, adult mammalian kidney.

Genetic regulation across tissues (GTEx eQTL / sQTL)

HAO2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 13 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

14 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Nerve Tibial	eqtl	1.3e-12	-0.47	1:119177063:T:C
Adrenal Gland	eqtl	4.6e-10	-0.43	1:119380908:A:C
Thyroid	eqtl	2.4e-08	+0.48	1:119156143:C:T
Adipose Subcutaneous	eqtl	1.7e-07	-0.32	1:119130721:G:A
Liver	sqtl	8.5e-06	+0.62	1:119370421:T:C
Breast Mammary Tissue	eqtl	2.5e-05	-0.32	1:119130721:G:A
Artery Tibial	eqtl	6.5e-05	-0.29	1:119138966:C:T
Skin Not Sun Exposed Suprapubic	eqtl	3.7e-03	-0.32	1:119656586:T:C
Artery Coronary	eqtl	1.1e-02	-0.45	1:119219552:G:A
Minor Salivary Gland	eqtl	1.7e-02	-0.54	1:119066292:T:C
Testis	eqtl	3.0e-02	-0.34	1:119233151:G:A
Skin Sun Exposed Lower leg	eqtl	3.2e-02	+0.55	1:118727436:G:A
Adipose Visceral Omentum	eqtl	4.7e-02	+0.46	1:120270073:T:C
Whole Blood	eqtl	5.0e-02	-0.17	1:119261927:G:A

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
4917	0.0828	7
4916	0.0584	8
201635	0.0025	2

Top tissues by expression

showing 100 of 263 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	98.37	gold quality
liver	UBERON:0002107	95.68	gold quality
kidney epithelium	UBERON:0004819	94.72	gold quality
nephron tubule	UBERON:0001231	94.69	gold quality
adult mammalian kidney	UBERON:0000082	93.55	gold quality
adult organism	UBERON:0007023	93.55	gold quality
renal glomerulus	UBERON:0000074	93.40	gold quality
metanephric glomerulus	UBERON:0004736	92.92	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.55	gold quality
kidney	UBERON:0002113	90.15	gold quality
renal medulla	UBERON:0000362	87.06	gold quality
cortex of kidney	UBERON:0001225	84.64	gold quality
metanephros	UBERON:0000081	79.73	gold quality
upper leg skin	UBERON:0004262	73.80	gold quality
upper arm skin	UBERON:0004263	70.05	gold quality
mammalian vulva	UBERON:0000997	69.53	gold quality
ileal mucosa	UBERON:0000331	69.26	silver quality
thymus	UBERON:0002370	69.11	silver quality
cerebellar vermis	UBERON:0004720	68.00	gold quality
metanephros cortex	UBERON:0010533	67.19	gold quality
olfactory bulb	UBERON:0002264	66.68	gold quality
type B pancreatic cell	CL:0000169	66.48	gold quality
nipple	UBERON:0002030	65.71	gold quality
right adrenal gland cortex	UBERON:0035827	65.19	gold quality
deltoid	UBERON:0001476	63.66	silver quality
diaphragm	UBERON:0001103	63.44	gold quality
male germ cell	CL:0000015	63.42	gold quality
right adrenal gland	UBERON:0001233	63.27	gold quality
left adrenal gland	UBERON:0001234	63.03	gold quality
pancreatic ductal cell	CL:0002079	62.89	silver quality
sperm	CL:0000019	62.83	gold quality
adrenal cortex	UBERON:0001235	62.20	gold quality
left adrenal gland cortex	UBERON:0035825	61.72	gold quality
adrenal gland	UBERON:0002369	60.72	gold quality
nasal cavity epithelium	UBERON:0005384	60.70	gold quality
saphenous vein	UBERON:0007318	59.71	gold quality
pharyngeal mucosa	UBERON:0000355	59.13	gold quality
inferior vagus X ganglion	UBERON:0005363	59.13	gold quality
dorsal plus ventral thalamus	UBERON:0001897	59.06	gold quality
pericardium	UBERON:0002407	58.90	gold quality
skin of abdomen	UBERON:0001416	58.88	gold quality
ventral tegmental area	UBERON:0002691	58.72	gold quality
decidua	UBERON:0002450	58.49	gold quality
subthalamic nucleus	UBERON:0001906	58.44	gold quality
dorsal root ganglion	UBERON:0000044	58.42	gold quality
trigeminal ganglion	UBERON:0001675	58.38	gold quality
superior vestibular nucleus	UBERON:0007227	58.38	gold quality
superior surface of tongue	UBERON:0007371	58.36	gold quality
body of tongue	UBERON:0011876	58.35	gold quality
pons	UBERON:0000988	58.33	gold quality
pylorus	UBERON:0001166	58.33	gold quality
substantia nigra pars reticulata	UBERON:0001966	58.19	gold quality
substantia nigra pars compacta	UBERON:0001965	58.17	gold quality
lateral nuclear group of thalamus	UBERON:0002736	58.11	gold quality
cardia of stomach	UBERON:0001162	58.10	gold quality
tongue	UBERON:0001723	57.98	gold quality
lateral globus pallidus	UBERON:0002476	57.97	gold quality
trachea	UBERON:0003126	57.53	gold quality
medulla oblongata	UBERON:0001896	57.20	gold quality
myocardium	UBERON:0002349	57.20	gold quality
vena cava	UBERON:0004087	56.96	gold quality
gluteal muscle	UBERON:0002000	56.63	gold quality
triceps brachii	UBERON:0001509	56.48	gold quality
zone of skin	UBERON:0000014	56.46	gold quality
globus pallidus	UBERON:0001875	56.22	gold quality
quadriceps femoris	UBERON:0001377	55.68	gold quality
medial globus pallidus	UBERON:0002477	55.42	gold quality
hair follicle	UBERON:0002073	55.37	gold quality
biceps brachii	UBERON:0001507	55.22	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	55.07	gold quality
oocyte	CL:0000023	54.89	gold quality
trabecular bone tissue	UBERON:0002483	54.66	gold quality
epithelial cell of pancreas	CL:0000083	54.21	gold quality
mucosa of sigmoid colon	UBERON:0004993	53.73	gold quality
mammary duct	UBERON:0001765	53.46	gold quality
epithelium of mammary gland	UBERON:0003244	53.35	gold quality
vastus lateralis	UBERON:0001379	53.21	gold quality
buccal mucosa cell	CL:0002336	53.11	gold quality
lymph node	UBERON:0000029	52.85	gold quality
synovial joint	UBERON:0002217	52.30	gold quality
skin of leg	UBERON:0001511	52.10	gold quality
heart right ventricle	UBERON:0002080	51.80	gold quality
penis	UBERON:0000989	51.74	gold quality
layer of synovial tissue	UBERON:0007616	51.67	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	51.48	silver quality
oral cavity	UBERON:0000167	50.57	gold quality
cervix epithelium	UBERON:0004801	49.87	gold quality
nasal cavity mucosa	UBERON:0001826	49.77	gold quality
colonic mucosa	UBERON:0000317	49.60	gold quality
orbitofrontal cortex	UBERON:0004167	49.54	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	49.51	gold quality
oviduct epithelium	UBERON:0004804	49.41	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
duodenum	UBERON:0002114	49.29	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
parotid gland	UBERON:0001831	48.97	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-10	yes	32.77
E-ANND-3	yes	4.53

HPA expression

RNA tissue specificity: Group enriched

55 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Liver	tissue	397.7
Kidney	tissue	283.1
Thymus	tissue	21.7
Amygdala	tissue	10.2
Corpus callosum	tissue	10.0
Basal ganglia	tissue	9.8
Cerebral cortex	tissue	9.6
Insular cortex	tissue	9.6
Retrosplenial and cingulate cortex	tissue	9.3
Putamen	tissue	9.2
Olfactory bulb	tissue	9.2
Retrosplenial cortex	tissue	9.2
Cerebellum	tissue	9.1
Spinal cord	tissue	9.0
Ventral forebrain	tissue	9.0
Hippocampal formation	tissue	8.7
Entorhinal cortex	tissue	8.7
Temporal cortex	tissue	8.6
Prefrontal cortex	tissue	8.5
Motor cortex	tissue	8.0
Occipital cortex	tissue	7.9
Periaqueductal gray	tissue	7.8
Septum	tissue	7.8
Midbrain	tissue	7.2
Somatosensory cortex	tissue	7.2
Medulla oblongata	tissue	7.0
Hypothalamus	tissue	7.0
Substantia nigra	tissue	6.8
Thalamus	tissue	6.2
Pons	tissue	5.9
Superior colliculi	tissue	5.9
Postcentral gyrus	tissue	3.0
Locus coeruleus	tissue	1.6
Breast	tissue	0.6
Hippocampus	tissue	0.5
Adrenal gland	tissue	0.5
Nucleus accumbens	tissue	0.4
Spleen	tissue	0.4
Skin 1	tissue	0.3
Lymph node	tissue	0.3
Placenta	tissue	0.3
Colon	tissue	0.2
Tonsil	tissue	0.2
Testis	tissue	0.1
Stomach 1	tissue	0.1
Heart muscle	tissue	0.1
Rectum	tissue	0.1
Urinary bladder	tissue	0.1
Pancreas	tissue	0.1
Epididymis	tissue	0.1
Choroid plexus	tissue	0.1
Small intestine	tissue	0.1
Duodenum	tissue	0.1
Prostate	tissue	0.1
Appendix	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 184; highest nTPM — White matter (10.0), Ventral spinal cord (9.0), Dorsal spinal cord (8.7), Subiculum (8.5), Ventral hippocampus (8.1).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting HAO2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

24 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-377-3P	99.37	70.18	1905
HSA-MIR-6737-3P	98.95	68.56	1577
HSA-MIR-7157-3P	98.95	68.70	1582
HSA-MIR-5008-3P	98.73	67.50	1433
HSA-MIR-5572	98.55	65.84	970
HSA-MIR-1233-5P	98.19	66.71	1201
HSA-MIR-6778-5P	98.19	66.59	1239
HSA-MIR-615-5P	98.10	63.76	591
HSA-MIR-6847-5P	97.93	66.74	1808
HSA-MIR-450A-2-3P	97.91	67.56	1459
HSA-MIR-4257	97.86	68.05	1190
HSA-MIR-299-3P	97.73	66.67	773
HSA-MIR-4253	97.48	65.11	692
HSA-MIR-6862-5P	97.48	64.84	713
HSA-MIR-6515-5P	97.08	65.48	1219
HSA-MIR-4654	95.86	65.72	751
HSA-MIR-4769-5P	95.37	66.09	570
HSA-MIR-4442	92.35	67.08	98

Functional genomics

gnomAD constraint: pLI 2.42e-10, LOEUF 1.33, missense Z -0.36 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000325945 — one region, missense o/e 1.11.

Literature-anchored findings (GeneRIF, showing 4)

• Dysregulation of HAO2 is a very early event in the development of hepatocellular carcinoma (HCC). (PMID:26658681)
• Overexpression of HAO2 by plasmid promoted lipid catabolic process, eliminated lipid accumulation, inhibited KRAS expression, controlled the proliferation, migration, and invasion activity of clear cell renal cell carcinoma (ccRCC) tumor cells (PMID:31127626)
• miR-1293 Suppresses Tumor Malignancy by Targeting Hydrocyanic Oxidase 2: Therapeutic Potential of a miR-1293/Hydrocyanic Oxidase 2 Axis in Renal Cell Carcinoma. (PMID:31971830)
• Hydroxyacid Oxidase 2 (HAO2) Inhibits the Tumorigenicity of Hepatocellular Carcinoma and Is Negatively Regulated by miR-615-5p. (PMID:35528616)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hao2	ENSDARG00000027992
mus_musculus	Hao2	ENSMUSG00000027870
rattus_norvegicus	Hao2	ENSRNOG00000019470
drosophila_melanogaster	Hao	FBGN0061356
caenorhabditis_elegans		WBGENE00018286

Paralogs (2): HAO1 (ENSG00000101323), CARNS1 (ENSG00000172508)

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Oryza sativa Indica Group	B8AKX6	100.0%	Diamond
Oryza sativa Japonica Group	Q10CE4	100.0%	Diamond
Fusarium oxysporum f. sp. lycopersici 4287	A0A0D2YG00	97.2%	Diamond
Fusarium verticillioides 7600	W7NCP1	97.2%	Diamond
Arabidopsis thaliana	Q9LRR9	95.1%	Diamond
Fusarium fujikuroi IMI 58289	S0DRI9	93.9%	Diamond
Zea mays	A0A3L6E0R4	93.2%	Diamond
Borreliella bavariensis PBi	Q660I6	90.1%	Diamond
Spinacia oleracea	P05414	89.2%	Diamond
Bos taurus	Q3ZBW2	82.4%	Diamond
Hansenula anomala	P09437	60.0%	Diamond
Talaromyces stipitatus ATCC 10500	B8MKR3	58.5%	Diamond
Saccharomyces cerevisiae S288C	P00175	56.0%	Diamond
Dictyostelium discoideum	Q54E41	53.7%	Diamond
Lactobacillus jensenii	A0A5N1I561	52.4%	Diamond
Lentilactobacillus hilgardii DSM 20176 = ATCC 8290	C0XIJ3	52.4%	Diamond
Nostoc sp. PCC 7120 = FACHB-418	Q8Z0C8	52.1%	Diamond
Chlamydomonas reinhardtii	F8WQN2	52.0%	Diamond
Aerococcus viridans ATCC 11563 = CCUG 4311	Q44467	51.5%	Diamond
Streptococcus iniae	O33655	51.1%	Diamond
Lacticaseibacillus rhamnosus LMS2-1	C2K1F0	48.7%	Diamond
Penicillium citrinum	P0DUR7	46.7%	Diamond
Schizosaccharomyces pombe 972h-	Q9HDX2	46.7%	Diamond
Amycolatopsis orientalis	O52792	45.4%	Diamond
Roseobacter sp. GAI101	B7RR92	45.0%	Diamond
Alicycliphilus denitrificans K601	F4G5A4	45.0%	Diamond
Coccidioides immitis RS	J3KAR9	44.1%	Diamond
Rhodotorula graminis	P32953	42.4%	Diamond
Lysinibacillus sphaericus C3-41	B1HZY7	42.0%	Diamond
Mycolicibacterium smegmatis	P21795	40.1%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
WARS2-AS1	ncRNA	101929147
LINC01780	ncRNA	105378934
HSD3B2	protein-coding	3284
HAO2-IT1	ncRNA	100874270
WARS2	protein-coding	10352

Protein

Protein identifiers

2-Hydroxyacid oxidase 2 — Q9NYQ3 (reviewed: Q9NYQ3)

Alternative names: (S)-2-hydroxy-acid oxidase, peroxisomal, Cell growth-inhibiting gene 16 protein, Long chain alpha-hydroxy acid oxidase, Long-chain L-2-hydroxy acid oxidase

All UniProt accessions (2): Q9NYQ3, Q5QP02

UniProt curated annotations — full annotation on UniProt →

Function. Oxidase that catalyzes the oxidation of medium and long chain hydroxyacids such as 2-hydroxyhexadecanoate and 2-hydroxyoctanoate, to the corresponding 2-oxoacids. Its role in the oxidation of 2-hydroxy fatty acids may contribute to the general pathway of fatty acid alpha-oxidation. Active in vitro with the artificial electron acceptor 2,6-dichlorophenolindophenol (DCIP), but O2 is believed to be the physiological electron acceptor, leading to the production of H2O2. Is not active on glycolate, glyoxylate, L-lactate and 2-hydroxybutanoate.

Subunit / interactions. Homotetramer.

Subcellular location. Peroxisome.

Tissue specificity. Expressed in the liver and kidney.

Pathway. Lipid metabolism; fatty acid metabolism.

Similarity. Belongs to the FMN-dependent alpha-hydroxy acid dehydrogenase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NYQ3-1	1	yes
Q9NYQ3-2	2

RefSeq proteins (3): NP_001005783, NP_001364401, NP_057611* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000262	FMN-dep_DH	Domain
IPR008259	FMN_hydac_DH_AS	Active_site
IPR012133	Alpha-hydoxy_acid_DH_FMN	Family
IPR013785	Aldolase_TIM	Homologous_superfamily
IPR037396	FMN_HAD	Domain

Pfam: PF01070

Enzyme classification (BRENDA)

• EC 1.1.3.15 — (S)-2-hydroxy-acid oxidase (BRENDA: 44 organisms, 164 substrates, 154 inhibitors, 169 Km, 41 kcat entries)

Substrate kinetics (BRENDA)

52 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GLYCOLATE	0.0056–2.1	24
(S)-LACTATE	0.0052–103	15
L-LACTATE	0.34–16.5	14
L-2-HYDROXYISOCAPROATE	0.3–2.5	11
O2	0.022–0.64	10
DL-2-HYDROXYBUTYRATE	0.6–14	8
GLYOXYLATE	1.41–6.51	7
L-MANDELATE	0.16–20	7
DL-2-HYDROXYCAPROATE	0.15–3.2	4
DL-2-HYDROXYVALERATE	0.25–13	4
GLYCERATE	2.76–7.14	4
L-LEUCINE	5.3–15	4
DL-3-CHLOROLACTATE	0.7–28	3
DL-2-HYDROXY-4-METHYLTHIOBUTANOIC ACID	0.7–1.1	2
DL-2-HYDROXYISOVALERATE	0.6–8	2

Catalyzed reactions (Rhea)

• a (2S)-2-hydroxycarboxylate + O2 = a 2-oxocarboxylate + H2O2 (RHEA:16789)
• 2-hydroxyoctanoate + O2 = 2-oxooctanoate + H2O2 (RHEA:67940)
• 2-hydroxyhexadecanoate + O2 = 2-oxohexadecanoate + H2O2 (RHEA:67944)

UniProt features (20 total): binding site 10, sequence variant 2, sequence conflict 2, chain 1, domain 1, modified residue 1, splice variant 1, short sequence motif 1, active site 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NYQ3-F1	92.99	0.88

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Oxidoreductases, Metabolic proteins, Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; vesicles

Antibody reliability (HPA): IF approved

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)

Position	Role
246	proton acceptor

Ligand- & substrate-binding residues (10)

Position	Role
222	FMN
249	a 2-oxocarboxylate
277–281	FMN
300–301	FMN
77–79	FMN
106	FMN
128	FMN
130	a 2-oxocarboxylate
156	FMN
165	a 2-oxocarboxylate

Post-translational modifications (1)

Type	Positions
Phosphothreonine	178

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 6; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

6 pathways:

ID	Pathway	Evidence
R-HSA-390918	Peroxisomal lipid metabolism	curated
R-HSA-8978868	Fatty acid metabolism	—
R-HSA-1430728	Metabolism	—
R-HSA-556833	Metabolism of lipids	—
R-HSA-9033241	Peroxisomal protein import	electronic
R-HSA-9609507	Protein localization	—

MSigDB gene sets: 91 (showing top): GOBP_LIPID_MODIFICATION, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, BLALOCK_ALZHEIMERS_DISEASE_UP, TGTGTGA_MIR377, ICHIBA_GRAFT_VERSUS_HOST_DISEASE_35D_DN, CAIRO_HEPATOBLASTOMA_DN, GOBP_LIPID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, chr1p12, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_CH_OH_GROUP_OF_DONORS, GOBP_LIPID_OXIDATION, TGGAAA_NFAT_Q4_01, GOCC_MICROBODY, GOCC_MICROBODY_LUMEN, GOBP_FATTY_ACID_METABOLIC_PROCESS

GO Biological Process (3): fatty acid oxidation (GO:0019395), lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631)

GO Molecular Function (6): (S)-2-hydroxy-acid oxidase activity (GO:0003973), FMN binding (GO:0010181), protein binding (GO:0005515), glutamate synthase activity (GO:0015930), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on the CH-NH2 group of donors (GO:0016638)

GO Cellular Component (3): peroxisomal matrix (GO:0005782), cytosol (GO:0005829), peroxisome (GO:0005777)

Reactome top-level categories

4 top-level categories:

Category	Pathways
Fatty acid metabolism	1
Protein localization	1
Metabolism	1
Metabolism of lipids	1

GO top-level categories

17 GO namespaces:

Category	Terms
fatty acid metabolic process	1
lipid oxidation	1
primary metabolic process	1
lipid metabolic process	1
monocarboxylic acid metabolic process	1
oxidoreductase activity, acting on the CH-OH group of donors, oxygen as acceptor	1
ribonucleotide binding	1
anion binding	1
binding	1
oxidoreductase activity, acting on the CH-NH2 group of donors	1
catalytic activity	1
oxidoreductase activity	1
peroxisome	1
microbody lumen	1
cytoplasm	1
cellular anatomical structure	1
microbody	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 3 of 13 annotations. The rest are phylogenetic / computational / electronic (IEA).

3 experimentally-supported GO terms:

GO term	NS	Evidence
fatty acid oxidation	BP	direct assay
peroxisomal matrix	CC	direct assay
(S)-2-hydroxy-acid oxidase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,764 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HAO2	ACO1	P21399	690
HAO2	IREB2	P48200	681
HAO2	AGXT	P21549	486
HAO2	PECR	Q9BY49	459
HAO2	PIPOX	Q9P0Z9	448
HAO2	ACSL6	Q9UKU0	427
HAO2	HAAO	P46952	387
HAO2	ACAA1	P09110	382
HAO2	FAR1	Q8WVX9	373
HAO2	NUDT12	Q9BQG2	370
HAO2	AADAT	Q8N5Z0	370
HAO2	DHRS7	Q9Y394	369
HAO2	GRHPR	Q9UBQ7	367
HAO2	CRAT	P43155	367
HAO2	PCK1	P35558	365

IntAct

Human interaction partners of HAO2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

3 partners by confidence:

Partner	Interaction type	MIscore	Records
SEC14L4	physical association	0.560	3
EIF4G3	association	0.530	2
TRIM7	physical association	0.400	1

BioGRID (56 interactions; top human partners by supporting records): ASPSCR1 (Affinity Capture-MS; 2 records), BCOR (Affinity Capture-MS; 2 records), CTAGE5 (Affinity Capture-MS; 2 records), CYHR1 (Affinity Capture-MS; 2 records), EIF4G3 (Affinity Capture-MS; 2 records), GSE1 (Affinity Capture-MS; 2 records), HSPA8 (Affinity Capture-MS; 2 records), MIA3 (Affinity Capture-MS; 2 records), PM20D2 (Affinity Capture-MS; 2 records), PPFIBP1 (Affinity Capture-MS; 2 records), PPM1A (Affinity Capture-MS; 2 records), RBPMS (Affinity Capture-MS; 2 records), RBPMS2 (Affinity Capture-MS; 2 records), SF1 (Affinity Capture-MS; 2 records), SMG6 (Affinity Capture-MS; 2 records)

Disease & clinical

Genetic variants

Variant evidence for HAO2: 60 ClinVar records (0 pathogenic / likely pathogenic); 8 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	51
Likely benign	6
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 23 predictions of 840):

Position(s)	Effect	Δscore	Sites
1:119385332	donor_gain	1.0000
1:119392219	donor_gain	1.0000
1:119382981	donor_gain	0.9900
1:119383886	donor_gain	0.9900
1:119384774–119384775	acceptor_loss	0.9900	6
1:119385205	donor_gain	0.9900
1:119385364	donor_gain	0.9900
1:119381216–119381218	donor_loss	0.9800	7
1:119382988	donor_gain	0.9800
1:119385054–119385055	donor_loss	0.9800	3

AlphaMissense

628 missense substitutions predicted likely pathogenic (of 2,288 scored), across 200 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D158	8	0.967	0.980
H246	8	0.958	0.973
D277	8	0.955	0.972
D229	8	0.885	0.956
D252	8	0.838	0.957
D285	8	0.790	0.897
D8	8	0.742	0.845
K222	7	0.940	0.998
W205	7	0.918	0.978
W126	7	0.898	0.992
E89	7	0.891	0.952
N38	7	0.870	0.980
S106	7	0.867	0.992
F42	7	0.866	0.932
F127	7	0.864	0.954
N245	7	0.864	0.984
W305	7	0.849	0.957
F24	7	0.840	0.963
Q128	7	0.821	0.922
G223	6	0.973	0.989

HPA cancer prognostics

RNA cancer specificity: Group enriched (Kidney Renal Clear Cell Carcinoma, Kidney Renal Papillary Cell Carcinoma, Liver Hepatocellular Carcinoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

4 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	1.43e-08
Kidney Renal Clear Cell Carcinoma (validation)	favorable	5.51e-06
Liver Hepatocellular Carcinoma (validation)	favorable	1e-05
Kidney Renal Papillary Cell Carcinoma (TCGA)	favorable	0.000175

Disease associations

OMIM: gene MIM:605176 | disease phenotypes:

GWAS associations

8 associations:

Study	Trait	p-value
GCST012020_309	Serum metabolite levels	5e-27
GCST012353_4	Serum metabolite concentrations in chronic kidney disease	4e-19
GCST012020_310	Serum metabolite levels	6e-17
GCST012353_5	Serum metabolite concentrations in chronic kidney disease	1e-14
GCST003996_8	Monobrow	4e-11
GCST008971_32	Urate levels	2e-8
GCST008972_148	Urate levels	2e-8
GCST007239_2	Ovarian cancer	8e-7

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0007906	synophrys measurement
EFO:0004531	urate measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2169732 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL2172058	IC50	950 nM

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.02	IC50	950	nM	CHEMBL2172058

PubChem BioAssay actives

1 with measured affinity, of 107 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-[3-(4-fluorophenyl)phenyl]-5-methyl-1H-pyrazole-3-carboxylic acid	702442: Inhibition of human Hao2-mediated oxidation of 2-hydroxyoctanoic acid assessed as proportionate release of H2O2	ic50	0.9500	uM

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, affects expression	4
Benzo(a)pyrene	decreases expression, increases methylation	3
Aflatoxin B1	affects expression, decreases expression, decreases methylation	3
perfluorooctane sulfonic acid	decreases expression	2
Cyclosporine	decreases expression	2
methyleugenol	decreases expression	1
sodium arsenite	decreases expression	1
perfluorooctanoic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
Acetaminophen	decreases expression	1
Arsenic	affects methylation	1
Chenodeoxycholic Acid	affects cotreatment, decreases expression	1
Deoxycholic Acid	affects cotreatment, decreases expression	1
Endosulfan	affects cotreatment, decreases expression	1
Estradiol	decreases expression	1
Glycochenodeoxycholic Acid	affects cotreatment, decreases expression	1
Glycocholic Acid	affects cotreatment, decreases expression	1
Glycodeoxycholic Acid	affects cotreatment, decreases expression	1
Methapyrilene	decreases expression	1
Nickel	decreases expression	1
Triclosan	affects cotreatment, decreases expression	1
Valproic Acid	decreases expression	1
Isotretinoin	decreases expression	1
Cadmium Chloride	decreases expression	1
Palmitic Acid	decreases expression	1
Okadaic Acid	decreases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2175908	Binding	Inhibition of human Hao2-mediated oxidation of 2-hydroxyoctanoic acid assessed as proportionate release of H2O2 at 10 uM	Discovery of pyrazole carboxylic acids as potent inhibitors of rat long chain L-2-hydroxy acid oxidase. — *Bioorg Med Chem Lett*

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for HAO2 across ~30M SureChEMBL compounds — explore on Sugi Predict.