ALKBH6

Summary

ALKBH6 (alkB homolog 6, nucleotide demethylase, HGNC:28243) is a protein-coding gene on chromosome 19q13.12, encoding Probable RNA/DNA demethylase ALKBH6 (Q3KRA9). Probable Fe(2+)/2-oxoglutarate-dependent dioxygenase involved in oxidative demethylation of nucleic acids.

Predicted to enable dioxygenase activity and metal ion binding activity. Located in focal adhesion and nucleoplasm.

Source: NCBI Gene 84964 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 47 total — 3 pathogenic
• MANE Select transcript: NM_032878

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28243
Approved symbol	ALKBH6
Name	alkB homolog 6, nucleotide demethylase
Location	19q13.12
Locus type	gene with protein product
Status	Approved
Aliases	MGC15677
Ensembl gene	ENSG00000239382
Ensembl biotype	protein_coding
OMIM	613304
Entrez	84964

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 17 protein_coding, 9 retained_intron, 5 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000252984, ENST00000378875, ENST00000392183, ENST00000461668, ENST00000462793, ENST00000466196, ENST00000468004, ENST00000470859, ENST00000471323, ENST00000475223, ENST00000481257, ENST00000485128, ENST00000486389, ENST00000490483, ENST00000490986, ENST00000495116, ENST00000497999, ENST00000590666, ENST00000592353, ENST00000897810, ENST00000897811, ENST00000897812, ENST00000897813, ENST00000897814, ENST00000897815, ENST00000897816, ENST00000897817, ENST00000937860, ENST00000937861, ENST00000937862, ENST00000956212, ENST00000956213

RefSeq mRNA: 5 — MANE Select: NM_032878 NM_001297701, NM_001386055, NM_001386056, NM_032878, NM_198867

CCDS: CCDS74342

Canonical transcript exons

ENST00000378875 — 7 exons

Exon	Start	End
ENSE00001946374	36014175	36014213
ENSE00003462132	36011404	36011464
ENSE00003532377	36013344	36013422
ENSE00003541472	36009120	36009553
ENSE00003621392	36013021	36013089
ENSE00003642798	36010894	36011045
ENSE00003656549	36010567	36010683

Expression profiles

Bgee: expression breadth ubiquitous, 248 present calls, max score 94.15.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.6640 / max 33.1964, expressed in 1738 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
180615	5.6640	1738

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	94.15	gold quality
endothelial cell	CL:0000115	93.66	silver quality
pons	UBERON:0000988	93.29	gold quality
primary visual cortex	UBERON:0002436	92.84	gold quality
Brodmann (1909) area 23	UBERON:0013554	91.97	gold quality
substantia nigra pars compacta	UBERON:0001965	91.93	gold quality
substantia nigra pars reticulata	UBERON:0001966	91.70	gold quality
granulocyte	CL:0000094	91.67	gold quality
occipital lobe	UBERON:0002021	90.84	gold quality
prefrontal cortex	UBERON:0000451	90.30	gold quality
hypothalamus	UBERON:0001898	89.97	gold quality
Brodmann (1909) area 9	UBERON:0013540	89.89	gold quality
right frontal lobe	UBERON:0002810	89.72	gold quality
lateral globus pallidus	UBERON:0002476	89.30	gold quality
substantia nigra	UBERON:0002038	89.19	gold quality
midbrain	UBERON:0001891	89.05	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	88.95	gold quality
frontal cortex	UBERON:0001870	88.87	gold quality
nucleus accumbens	UBERON:0001882	88.80	gold quality
anterior cingulate cortex	UBERON:0009835	88.76	gold quality
neocortex	UBERON:0001950	88.55	gold quality
putamen	UBERON:0001874	88.35	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	88.33	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.23	gold quality
superior vestibular nucleus	UBERON:0007227	88.15	gold quality
right uterine tube	UBERON:0001302	88.14	gold quality
pancreatic ductal cell	CL:0002079	88.07	gold quality
ventral tegmental area	UBERON:0002691	87.85	gold quality
amygdala	UBERON:0001876	87.75	gold quality
lower esophagus muscularis layer	UBERON:0035833	87.73	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.46
E-GEOD-100618	no	59.54

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

6 targeting ALKBH6, 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-450A-1-3P	100.00	69.33	1837
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-3137	97.26	66.78	761
HSA-MIR-342-3P	96.44	67.48	1344
HSA-MIR-6890-5P	92.89	65.83	442

Literature-anchored findings (GeneRIF, showing 1)

• Structural insights into the interactions and epigenetic functions of human nucleic acid repair protein ALKBH6. (PMID:35120926)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	alkbh6	ENSDARG00000077253
mus_musculus	Alkbh6	ENSMUSG00000042831
rattus_norvegicus	Alkbh6	ENSRNOG00000025216
drosophila_melanogaster	CG6144	FBGN0032259
caenorhabditis_elegans		WBGENE00007202

Paralogs (2): ALKBH8 (ENSG00000137760), TRMT9B (ENSG00000250305)

Protein

Protein identifiers

Probable RNA/DNA demethylase ALKBH6 — Q3KRA9 (reviewed: Q3KRA9)

Alternative names: Alkylated DNA repair protein alkB homolog 6, Alpha-ketoglutarate-dependent dioxygenase alkB homolog 6, Probable nucleic acid dioxygenase ALKBH6

All UniProt accessions (8): Q3KRA9, E9PI76, H0YD66, H0YD83, H0YDL7, H0YEC4, H0YEM5, S4R3C7

UniProt curated annotations — full annotation on UniProt →

Function. Probable Fe(2+)/2-oxoglutarate-dependent dioxygenase involved in oxidative demethylation of nucleic acids. Binds nucleic acids with a preference for ssDNA or ssRNA to other types of DNAs. May play a role in nucleic acid damage repair.

Subunit / interactions. Interacts with VCPKMT.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Widely expressed, with highest expression in testis and pancreas.

Cofactor. Binds 1 Fe(2+) ion per subunit.

Similarity. Belongs to the alkB family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q3KRA9-1	1	yes
Q3KRA9-2	2
Q3KRA9-3	3

RefSeq proteins (5): NP_001284630, NP_001372984, NP_001372985, NP_116267, NP_942567 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005123	Oxoglu/Fe-dep_dioxygenase_dom	Domain
IPR027450	AlkB-like	Domain
IPR032862	ALKBH6	Family
IPR037151	AlkB-like_sf	Homologous_superfamily

Pfam: PF13532

UniProt features (38 total): strand 13, helix 7, binding site 7, mutagenesis site 5, splice variant 2, chain 1, domain 1, region of interest 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7VJV	X-RAY DIFFRACTION	1.75
7VJS	X-RAY DIFFRACTION	1.79

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q3KRA9-F1	91.21	0.78

Functional residue map

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

Ligand- & substrate-binding residues (7): 103; 105; 114; 116; 182; 218; 220

Mutagenesis-validated functional residues (5):

Position	Phenotype
68	almost completely abolished the ssdna binding activity.
74	almost completely abolished the ssdna binding activity.
103	reduces the binding of 2-oxoglutarate; when associated with a-105 and a-218.
105	reduces the binding of 2-oxoglutarate; when associated with a-103 and a-218.
218	reduces the binding of 2-oxoglutarate; when associated with a-103 and a-105.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 86 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, TGGTGCT_MIR29A_MIR29B_MIR29C, RNGTGGGC_UNKNOWN, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, NFKB_C, IRF7_01, GATA3_01, LYF1_01, RYTTCCTG_ETS2_B, IK2_01, POU3F2_02, CCCNNGGGAR_OLF1_01, TGGAAA_NFAT_Q4_01, LIU_SOX4_TARGETS_DN, RNCTGNYNRNCTGNY_UNKNOWN

GO Biological Process (0):

GO Molecular Function (5): 2-oxoglutarate-dependent dioxygenase activity (GO:0016706), metal ion binding (GO:0046872), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), dioxygenase activity (GO:0051213)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), focal adhesion (GO:0005925)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen	1
dioxygenase activity	1
cation binding	1
binding	1
catalytic activity	1
oxidoreductase activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cell-substrate junction	1

Protein interactions and networks

STRING

422 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALKBH6	ALKBH1	Q13686	953
ALKBH6	JMJD4	Q9H9V9	872
ALKBH6	ALKBH7	Q9BT30	865
ALKBH6	ALKBH4	Q9NXW9	854
ALKBH6	ALKBH2	Q6NS38	837
ALKBH6	ALKBH3	Q96Q83	669
ALKBH6	ALKBH5	Q6P6C2	644
ALKBH6	FTO	Q9C0B1	521
ALKBH6	VPS51	Q9UID3	440
ALKBH6	THAP8	Q8NA92	433
ALKBH6	RSU1	Q15404	426
ALKBH6	ALKBH8	Q96BT7	415
ALKBH6	DHX30	Q7L2E3	406
ALKBH6	E5RHQ9	E5RHQ9	399
ALKBH6	RNF121	Q9H920	393

IntAct

2 interactions, top by confidence:

A	B	Type	Score
RUNX1	ALKBH6	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (3): ALKBH6 (Affinity Capture-RNA), ALKBH6 (Two-hybrid), ALKBH6 (Affinity Capture-RNA)

ESM2 similar proteins: A4FV98, A5D7B1, A6NFX1, D3ZVU9, O00764, O08557, O35083, O43488, O46560, O73884, O94760, O95848, P82197, Q05B60, Q0II59, Q0P5C0, Q0P5M9, Q0VD18, Q14728, Q29081, Q3KN66, Q3KRA9, Q3U129, Q3UGX3, Q3ZBF0, Q4PS77, Q5I0D5, Q5SUV1, Q64380, Q67FW5, Q6GV29, Q6WZ20, Q8CIW5, Q8K2U2, Q8R2H9, Q8TCT1, Q8VCE6, Q95JH0, Q95JH2, Q96AZ1

Diamond homologs: Q3KRA9, Q5PQ59, Q6IQE9, Q8K2U2, Q9SUP1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	35
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
147631	GRCh38/hg38 19q12-13.13(chr19:29671324-37902990)x1	Pathogenic
2671623	Single allele	Pathogenic
3391938	GRCh37/hg19 19q11-13.13(chr19:28271107-38637350)x1	Pathogenic

SpliceAI

1359 predictions. Top by Δscore:

Variant	Effect	Δscore
19:36013311:T:TA	donor_gain	1.0000
19:36010562:CCCAC:C	donor_loss	0.9900
19:36010564:CA:C	donor_loss	0.9900
19:36010566:C:G	donor_loss	0.9900
19:36010586:T:TA	donor_gain	0.9900
19:36010684:C:CC	acceptor_gain	0.9900
19:36010917:A:AC	donor_gain	0.9900
19:36010918:C:CC	donor_gain	0.9900
19:36010918:CTGGT:C	donor_gain	0.9900
19:36010919:TGGTT:T	donor_gain	0.9900
19:36013327:C:CA	donor_gain	0.9900
19:36013354:CTGA:C	donor_gain	0.9900
19:36010940:G:C	donor_gain	0.9800
19:36012903:T:TA	donor_gain	0.9800
19:36012904:C:A	donor_gain	0.9800
19:36009554:C:CC	acceptor_gain	0.9700
19:36013016:GTCA:G	donor_loss	0.9700
19:36013017:TCACC:T	donor_loss	0.9700
19:36013018:CACC:C	donor_loss	0.9700
19:36013019:A:AC	donor_loss	0.9700
19:36013020:CCTG:C	donor_loss	0.9700
19:36013296:A:AC	donor_gain	0.9700
19:36013297:G:C	donor_gain	0.9700
19:36013318:C:CA	donor_gain	0.9700
19:36013326:AC:A	donor_gain	0.9700
19:36009549:CGAGG:C	acceptor_gain	0.9600
19:36009551:AGGC:A	acceptor_loss	0.9600
19:36009553:GCTGC:G	acceptor_loss	0.9600
19:36009554:C:G	acceptor_loss	0.9600
19:36009555:T:A	acceptor_loss	0.9600

AlphaMissense

1675 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:36010636:G:C	S128R	0.999
19:36010636:G:T	S128R	0.999
19:36010638:T:G	S128R	0.999
19:36010645:G:C	S125R	0.998
19:36010645:G:T	S125R	0.998
19:36010647:T:G	S125R	0.998
19:36010673:T:A	D116V	0.998
19:36010674:C:G	D116H	0.998
19:36010931:A:T	V100D	0.998
19:36011420:T:A	R56S	0.998
19:36011420:T:G	R56S	0.998
19:36011421:C:G	R56T	0.998
19:36010672:G:C	D116E	0.997
19:36010672:G:T	D116E	0.997
19:36010917:A:G	Y105H	0.997
19:36010921:G:C	N103K	0.997
19:36010921:G:T	N103K	0.997
19:36011438:C:A	W50C	0.997
19:36011438:C:G	W50C	0.997
19:36011440:A:G	W50R	0.997
19:36011440:A:T	W50R	0.997
19:36010640:A:T	I127N	0.996
19:36010673:T:C	D116G	0.996
19:36010673:T:G	D116A	0.996
19:36010680:G:C	H114D	0.996
19:36010923:T:C	N103D	0.996
19:36010928:A:T	L101H	0.996
19:36010936:G:C	N98K	0.996
19:36010936:G:T	N98K	0.996
19:36009337:G:T	R224S	0.995

dbSNP variants (sampled 300 via entrez): RS1000613564 (19:36014695 T>A), RS1000737033 (19:36014488 G>A), RS1002151520 (19:36009655 A>C,G), RS1002221880 (19:36009405 G>A), RS1002749180 (19:36011132 C>A,T), RS1004037479 (19:36009959 G>A), RS1004406082 (19:36011709 G>A,T), RS1005360949 (19:36010294 T>A,C), RS1005450239 (19:36009337 G>T), RS1006186984 (19:36015580 G>A), RS1006395186 (19:36014685 A>C), RS1006819349 (19:36016026 C>T), RS1007247847 (19:36013712 A>C), RS1008201990 (19:36012031 A>G), RS1008432360 (19:36012738 A>T)

Disease associations

OMIM: gene MIM:613304 | disease phenotypes: MIM:616680

GenCC curated gene-disease

Mondo (1): hereditary spastic paraplegia 75 (MONDO:0014729)

Orphanet (1): Autosomal recessive spastic paraplegia type 75 (Orphanet:459056)

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

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
GSK-J4	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
(+)-JQ1 compound	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Sunitinib	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Doxorubicin	decreases expression	1
Hydrogen Peroxide	increases expression	1
Methyl Methanesulfonate	increases expression	1
Smoke	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	increases expression	1
Sodium Selenite	increases expression	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E1Q9	HAP1 ALKBH6 (-) 2	Cancer cell line	Male
CVCL_E1QA	HAP1 ALKBH6 (-) 3	Cancer cell line	Male
CVCL_XL29	HAP1 ALKBH6 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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