HIGD2A

Summary

HIGD2A (HIG1 hypoxia inducible domain family member 2A, HGNC:28311) is a protein-coding gene on chromosome 5q35.2, encoding HIG1 domain family member 2A, mitochondrial (Q9BW72). Proposed subunit of cytochrome c oxidase (COX, complex IV), which is the terminal component of the mitochondrial respiratory chain that catalyzes the reduction of oxygen to water.

The protein encoded by this gene is a subunit of the cytochrome c oxidase complex (complex IV), which is the terminal enzyme in the mitochondrial respiratory chain. The encoded protein is an inner mitochondrial membrane protein and is a functional ortholog of the yeast respiratory supercomplex factor 1 (Rcf1). In mouse, the orthologous protein enhances cell survival under conditions of hypoxia.

Source: NCBI Gene 192286 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 1 total
• MANE Select transcript: NM_138820

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28311
Approved symbol	HIGD2A
Name	HIG1 hypoxia inducible domain family member 2A
Location	5q35.2
Locus type	gene with protein product
Status	Approved
Aliases	MGC2198, RCF1B
Ensembl gene	ENSG00000146066
Ensembl biotype	protein_coding
OMIM	620788
Entrez	192286

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000274787

RefSeq mRNA: 1 — MANE Select: NM_138820 NM_138820

CCDS: CCDS4401

Canonical transcript exons

ENST00000274787 — 2 exons

Exon	Start	End
ENSE00000973688	176389331	176389761
ENSE00001314525	176388751	176388973

Expression profiles

Bgee: expression breadth ubiquitous, 135 present calls, max score 99.08.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 135.4915 / max 638.4469, expressed in 1824 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
60406	127.8473	1824
60407	7.6442	1758

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	99.08	gold quality
apex of heart	UBERON:0002098	98.95	gold quality
gastrocnemius	UBERON:0001388	98.87	gold quality
mucosa of transverse colon	UBERON:0004991	98.83	gold quality
heart left ventricle	UBERON:0002084	98.82	gold quality
granulocyte	CL:0000094	98.72	gold quality
transverse colon	UBERON:0001157	98.62	gold quality
right atrium auricular region	UBERON:0006631	98.62	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.61	gold quality
right adrenal gland	UBERON:0001233	98.55	gold quality
lower esophagus	UBERON:0013473	98.53	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.53	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.50	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.48	gold quality
right adrenal gland cortex	UBERON:0035827	98.47	gold quality
leukocyte	CL:0000738	98.44	gold quality
heart	UBERON:0000948	98.44	gold quality
monocyte	CL:0000576	98.42	gold quality
left adrenal gland cortex	UBERON:0035825	98.37	gold quality
colon	UBERON:0001155	98.34	gold quality
left adrenal gland	UBERON:0001234	98.31	gold quality
muscle of leg	UBERON:0001383	98.26	gold quality
fundus of stomach	UBERON:0001160	98.23	gold quality
putamen	UBERON:0001874	98.22	gold quality
nucleus accumbens	UBERON:0001882	98.22	gold quality
cortex of kidney	UBERON:0001225	98.21	gold quality
caudate nucleus	UBERON:0001873	98.18	gold quality
mucosa of stomach	UBERON:0001199	98.16	gold quality
body of stomach	UBERON:0001161	98.13	gold quality
adenohypophysis	UBERON:0002196	98.13	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-10042	yes	11.36
E-HCAD-13	no	3.52
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

29 targeting HIGD2A, 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-4262	100.00	73.26	3931
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-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-379-3P	99.69	69.60	1524
HSA-MIR-411-3P	99.69	69.63	1524
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-543	99.52	69.03	2595
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-3688-5P	99.12	69.67	1091
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-6749-3P	99.00	65.73	1443
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-935	98.82	69.36	1072
HSA-MIR-3922-5P	98.77	66.53	1059
HSA-MIR-891A-3P	98.05	67.99	970
HSA-MIR-7106-3P	97.33	65.33	644
HSA-MIR-6895-5P	97.05	64.96	522
HSA-MIR-1296-5P	93.94	67.71	305

Literature-anchored findings (GeneRIF, showing 3)

• Biosystem Analysis of the Hypoxia Inducible Domain Family Member 2A: Implications in Cancer Biology. (PMID:32085461)
• HIGD2A is Required for Assembly of the COX3 Module of Human Mitochondrial Complex IV. (PMID:32317297)
• Dynamic Distribution of HIG2A between the Mitochondria and the Nucleus in Response to Hypoxia and Oxidative Stress. (PMID:35008815)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	higd2a	ENSDARG00000052371
mus_musculus	Higd2a	ENSMUSG00000025868
rattus_norvegicus	AABR07035091.1	ENSRNOG00000001071
rattus_norvegicus	Higd2a	ENSRNOG00000017372

Paralogs (4): HIGD1B (ENSG00000131097), HIGD2B (ENSG00000175202), HIGD1A (ENSG00000181061), HIGD1C (ENSG00000214511)

Protein

Protein identifiers

HIG1 domain family member 2A, mitochondrial — Q9BW72 (reviewed: Q9BW72)

Alternative names: RCF1 homolog B

All UniProt accessions (1): Q9BW72

UniProt curated annotations — full annotation on UniProt →

Function. Proposed subunit of cytochrome c oxidase (COX, complex IV), which is the terminal component of the mitochondrial respiratory chain that catalyzes the reduction of oxygen to water. May be involved in cytochrome c oxidase activity. May play a role in the assembly of respiratory supercomplexes.

Subunit / interactions. Associates with cytochrome c oxidase (COX, complex IV); proposed complex component.

Subcellular location. Mitochondrion membrane. Mitochondrion inner membrane.

RefSeq proteins (1): NP_620175* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007667	Hypoxia_induced_domain	Domain
IPR050355	RCF1	Family

Pfam: PF04588

UniProt features (7 total): transmembrane region 2, initiator methionine 1, chain 1, topological domain 1, domain 1, modified residue 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9I6F	ELECTRON MICROSCOPY	2.95

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BW72-F1	62.35	0.00

Functional residue map

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

Post-translational modifications (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9864848	Complex IV assembly

MSigDB gene sets: 151 (showing top): MODULE_151, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_MITOCHONDRIAL_RESPIRATORY_CHAIN_COMPLEX_ASSEMBLY, GOCC_MITOCHONDRIAL_ENVELOPE, LIU_CMYB_TARGETS_UP, LIU_VMYB_TARGETS_UP, MODULE_114, RIZKI_TUMOR_INVASIVENESS_3D_UP, GOCC_ORGANELLE_INNER_MEMBRANE, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_12, GOCC_ORGANELLE_ENVELOPE, MARTENS_TRETINOIN_RESPONSE_DN, BOUDOUKHA_BOUND_BY_IGF2BP2, ZWANG_EGF_INTERVAL_DN, RB_P107_DN.V1_DN

GO Biological Process (2): negative regulation of apoptotic process (GO:0043066), mitochondrial respirasome assembly (GO:0097250)

GO Molecular Function (0):

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), membrane (GO:0016020), mitochondrial membrane (GO:0031966)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Respiratory electron transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
mitochondrion organization	1
mitochondrial respiratory chain complex assembly	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
cellular anatomical structure	1
mitochondrion	1
mitochondrial envelope	1
organelle membrane	1

Protein interactions and networks

STRING

1030 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HIGD2A	COX7A2L	O14548	681
HIGD2A	PIGBOS1	A0A0B4J2F0	609
HIGD2A	ARL10	Q8N8L6	544
HIGD2A	F8VZ95	F8VZ95	543
HIGD2A	COX14	Q96I36	501
HIGD2A	COX5A	P20674	472
HIGD2A	COX6A1	P12074	450
HIGD2A	COX6A2	Q02221	441
HIGD2A	ATP5MK	Q96IX5	435
HIGD2A	TMED6	Q8WW62	432
HIGD2A	ROMO1	P60602	427
HIGD2A	CBX3	Q13185	424
HIGD2A	COX5B	P10606	420
HIGD2A	NOP16	Q9Y3C1	419
HIGD2A	FAF2	Q96CS3	413

IntAct

22 interactions, top by confidence:

A	B	Type	Score
RCCD1	SPAG9	psi-mi:“MI:0914”(association)	0.640
PEX19	FAM20B	psi-mi:“MI:0914”(association)	0.530
PEX19	MYO1D	psi-mi:“MI:0914”(association)	0.530
RIPK4	VWA8	psi-mi:“MI:0914”(association)	0.350
K8.1	EXOC5	psi-mi:“MI:0914”(association)	0.350
PCDHB11	CBX4	psi-mi:“MI:0914”(association)	0.350
	TMEM223	psi-mi:“MI:0914”(association)	0.350
PCDHB11	SDCBP	psi-mi:“MI:0914”(association)	0.350
FAM8A1	SDCBP	psi-mi:“MI:0914”(association)	0.350
GRIN2A	ABCD4	psi-mi:“MI:0914”(association)	0.350
KLK1	SLC25A20	psi-mi:“MI:0914”(association)	0.350
ITGAD	HSPA5	psi-mi:“MI:0914”(association)	0.350
SAAL1	TMEM223	psi-mi:“MI:0914”(association)	0.350
SLC19A2	TMEM223	psi-mi:“MI:0914”(association)	0.350
SLC6A3	GET1	psi-mi:“MI:0914”(association)	0.350
SLC7A4	ESYT2	psi-mi:“MI:0914”(association)	0.350
AIFM1	NUDT19	psi-mi:“MI:2364”(proximity)	0.270
SFXN1	HAX1	psi-mi:“MI:2364”(proximity)	0.270
livM2	HIGD2A	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (30): HIGD2A (Affinity Capture-MS), HIGD2A (Synthetic Lethality), HIGD2A (Affinity Capture-MS), HIGD2A (Affinity Capture-MS), HIGD2A (Affinity Capture-MS), HIGD2A (Affinity Capture-MS), HIGD2A (Proximity Label-MS), HIGD2A (Proximity Label-MS), HIGD2A (Synthetic Lethality), HIGD2A (Affinity Capture-MS), HIGD2A (Affinity Capture-MS), HIGD2A (Proximity Label-MS), HIGD2A (Proximity Label-MS), HIGD2A (Proximity Label-MS), HIGD2A (Proximity Label-MS)

ESM2 similar proteins: A0A1D8PI78, A1XJK0, A1XQR6, A2RVP7, A4QNF3, O44477, O48528, P0CR88, P0CR89, P25710, P32897, P39515, P60602, P60603, P79082, P81928, P87130, P87146, Q02889, Q0WMZ5, Q12328, Q2UAP8, Q38820, Q3SZV8, Q4V7T9, Q54QM0, Q5XK94, Q6BT35, Q6BZY4, Q6CRJ6, Q6FT37, Q6INU6, Q6NYD1, Q75E80, Q7T2P6, Q8HXG6, Q8IN78, Q9BW72, Q9C1E8, Q9CQJ1

Diamond homologs: A1CHC5, A1CXG2, A2QI79, A3LVL1, A4RI25, A5DHC2, A5E2M7, A6RBB3, A6SSX6, A6ZM32, A7F679, A7TFU8, A8P006, B0D4J7, B0Y606, B2WBP3, B3LLM2, B6H465, B6K2Z6, B6QHL8, B6QHL9, B8MJJ2, B8N9M0, B9WHT6, C0NUL6, C0RYW2, C1G794, C4JHR1, C4QV79, C4Y631, C4YRP9, C5DLZ7, C5FSQ7, C5GDJ2, C5JIT3, C5MAV2, C5P447, C6H220, C7GT60, C7YJ02

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

134 predictions. Top by Δscore:

Variant	Effect	Δscore
5:176388962:T:TA	donor_gain	1.0000
5:176388963:G:GA	donor_gain	1.0000
5:176388970:ATAG:A	donor_gain	1.0000
5:176388971:TAG:T	donor_gain	1.0000
5:176388972:AGGTA:A	donor_loss	1.0000
5:176388974:G:C	donor_loss	1.0000
5:176388974:G:GG	donor_gain	1.0000
5:176388975:T:A	donor_loss	1.0000
5:176388969:CATAG:C	donor_gain	0.9900
5:176388972:AG:A	donor_gain	0.9900
5:176388973:GG:G	donor_gain	0.9900
5:176388964:G:GG	donor_gain	0.9700
5:176389326:CTCA:C	acceptor_loss	0.9700
5:176389327:TCAG:T	acceptor_loss	0.9700
5:176389328:CAG:C	acceptor_loss	0.9700
5:176389329:A:AG	acceptor_gain	0.9500
5:176389330:G:GG	acceptor_gain	0.9500
5:176389330:GGTT:G	acceptor_gain	0.9500
5:176389381:C:A	acceptor_gain	0.9500
5:176388762:CCT:C	donor_gain	0.9200
5:176388929:A:T	donor_gain	0.9200
5:176389379:ACCG:A	acceptor_gain	0.9200
5:176388928:G:GT	donor_gain	0.9100
5:176389379:ACCGG:A	acceptor_gain	0.9100
5:176389379:ACC:A	acceptor_gain	0.9000
5:176388764:TTC:T	donor_gain	0.8900
5:176388765:TC:T	donor_gain	0.8700
5:176389330:GGT:G	acceptor_gain	0.8600
5:176389382:G:A	acceptor_gain	0.8600
5:176389329:AGGTT:A	acceptor_gain	0.8400

AlphaMissense

675 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:176389430:C:A	A85D	0.995
5:176389333:T:C	C53R	0.994
5:176389412:T:C	M79T	0.990
5:176389429:G:C	A85P	0.990
5:176389435:G:C	G87R	0.988
5:176389445:T:A	V90D	0.988
5:176389436:G:A	G87D	0.986
5:176389451:C:A	A92D	0.986
5:176389352:C:A	A59D	0.983
5:176389331:G:A	G52D	0.980
5:176389410:G:A	M78I	0.980
5:176389410:G:C	M78I	0.980
5:176389410:G:T	M78I	0.980
5:176389413:G:A	M79I	0.980
5:176389413:G:C	M79I	0.980
5:176389413:G:T	M79I	0.980
5:176389450:G:C	A92P	0.977
5:176389340:C:A	A55D	0.975
5:176388971:T:A	I51K	0.974
5:176389346:C:A	A57E	0.974
5:176389375:T:C	F67L	0.974
5:176389377:C:A	F67L	0.974
5:176389377:C:G	F67L	0.974
5:176389442:C:A	T89K	0.974
5:176389364:G:A	G63D	0.973
5:176389345:G:C	A57P	0.972
5:176389434:G:C	Q86H	0.972
5:176389434:G:T	Q86H	0.972
5:176389355:T:A	L60H	0.971
5:176389462:G:C	G96R	0.970

dbSNP variants (sampled 300 via entrez): RS1000459344 (5:176389670 T>C), RS1001320589 (5:176389600 C>T), RS1001629098 (5:176387265 A>G), RS1002462273 (5:176386761 A>C), RS1003098830 (5:176387027 A>T), RS1004551807 (5:176388945 G>A,C,T), RS1005097758 (5:176390049 T>G), RS1005104678 (5:176390254 G>A), RS1005629082 (5:176389134 A>C), RS1005818842 (5:176387650 G>T), RS1005992884 (5:176387992 G>C), RS1006074640 (5:176388845 C>A,T), RS1008139861 (5:176389849 T>C,G), RS1009814635 (5:176388699 T>C), RS1009817545 (5:176389644 C>A,G,T)

Disease associations

OMIM: gene MIM:620788 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

12 total (human), top 12 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression	3
triphenyl phosphate	affects expression	1
arsenite	affects binding, increases reaction	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
chloropicrin	increases expression	1
Doxorubicin	increases expression	1
Hydralazine	affects cotreatment, increases expression	1
Smoke	decreases expression	1
Vitamin E	increases expression	1
Aflatoxin B1	increases methylation	1
Lactic Acid	affects expression	1

Clinical trials (associated diseases)

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