MAK

Summary

MAK (male germ cell associated kinase, HGNC:6816) is a protein-coding gene on chromosome 6p24.2, encoding Serine/threonine-protein kinase MAK (P20794). Essential for the regulation of ciliary length and required for the long-term survival of photoreceptors.

The product of this gene is a serine/threonine protein kinase related to kinases involved in cell cycle regulation. Studies of the mouse and rat homologs have localized the kinase to the chromosomes during meiosis in spermatogenesis, specifically to the synaptonemal complex that exists while homologous chromosomes are paired. Mutations in this gene have been associated with ciliary defects resulting in retinitis pigmentosa 62. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 4117 — RefSeq curated summary.

At a glance

• Gene–disease (curated): MAK-related retinopathy (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 675 total — 67 pathogenic, 27 likely-pathogenic
• Phenotypes (HPO): 37
• Druggable target: yes — 7 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001242957

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6816
Approved symbol	MAK
Name	male germ cell associated kinase
Location	6p24.2
Locus type	gene with protein product
Status	Approved
Aliases	dJ417M14.2, RP62
Ensembl gene	ENSG00000111837
Ensembl biotype	protein_coding
OMIM	154235
Entrez	4117

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 2 nonsense_mediated_decay

ENST00000313243, ENST00000354489, ENST00000474039, ENST00000536370, ENST00000538030, ENST00000675026, ENST00000676116

RefSeq mRNA: 4 — MANE Select: NM_001242957 NM_001242385, NM_001242957, NM_001377262, NM_005906

CCDS: CCDS4516, CCDS75398, CCDS75399, CCDS93855

Canonical transcript exons

ENST00000354489 — 15 exons

Exon	Start	End
ENSE00003694962	10817850	10817971
ENSE00003695477	10803720	10803891
ENSE00003696993	10830548	10830877
ENSE00003697955	10818886	10818940
ENSE00003698201	10784424	10784572
ENSE00003699541	10808810	10808942
ENSE00003699609	10813644	10813723
ENSE00003699774	10770111	10770230
ENSE00003700335	10791675	10791847
ENSE00003700727	10775328	10775459
ENSE00003701805	10801892	10802059
ENSE00003702156	10762723	10764606
ENSE00003712208	10795998	10796309
ENSE00003735391	10773034	10773108
ENSE00003899854	10838503	10838539

Expression profiles

Bgee: expression breadth ubiquitous, 184 present calls, max score 96.55.

FANTOM5 (CAGE): breadth broad, TPM avg 1.5386 / max 116.6709, expressed in 405 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
71699	1.2311	333
71700	0.1829	67
71698	0.0832	38
71697	0.0414	17

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	96.55	gold quality
male germ cell	CL:0000015	92.51	gold quality
choroid plexus epithelium	UBERON:0003911	86.47	gold quality
bronchial epithelial cell	CL:0002328	85.06	gold quality
epithelium of bronchus	UBERON:0002031	83.95	gold quality
right uterine tube	UBERON:0001302	82.78	gold quality
bronchus	UBERON:0002185	82.42	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.04	gold quality
epithelium of nasopharynx	UBERON:0001951	76.65	gold quality
blood	UBERON:0000178	76.32	gold quality
mucosa of paranasal sinus	UBERON:0005030	74.88	gold quality
left testis	UBERON:0004533	74.72	gold quality
right testis	UBERON:0004534	74.23	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	74.19	gold quality
testis	UBERON:0000473	73.97	gold quality
caput epididymis	UBERON:0004358	73.59	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	71.73	gold quality
secondary oocyte	CL:0000655	70.68	silver quality
fallopian tube	UBERON:0003889	68.54	gold quality
oviduct epithelium	UBERON:0004804	67.67	gold quality
colonic epithelium	UBERON:0000397	66.73	silver quality
monocyte	CL:0000576	66.50	gold quality
leukocyte	CL:0000738	66.36	gold quality
mononuclear cell	CL:0000842	66.05	gold quality
nasal cavity epithelium	UBERON:0005384	64.75	silver quality
palpebral conjunctiva	UBERON:0001812	63.43	silver quality
calcaneal tendon	UBERON:0003701	63.02	gold quality
neuron projection bundle connecting eye with brain	UBERON:0004904	62.49	silver quality
buccal mucosa cell	CL:0002336	62.41	gold quality
nasal cavity mucosa	UBERON:0001826	61.90	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7316	yes	29.05
E-GEOD-137537	yes	17.80
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

62 targeting MAK, 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-4795-3P	100.00	74.62	4024
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-96-5P	99.95	72.80	2140
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4639-5P	99.81	67.37	1028
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-8084	99.73	69.57	1760

Literature-anchored findings (GeneRIF, showing 15)

• identification and transcriptional activation by androgen in prostate cancer cells (PMID:12084720)
• MAK plays a general role in androgen receptor(AR) function in prostate cancer cells and is likely to be a general coactivator of AR in prostate tissues. (PMID:16951154)
• MRK phosphorylates Scythe at T1080 in vitro as determined by site-directed mutagenesis and mass spectrometry, supporting the consensus and suggesting Scythe as a physiological substrate for MRK. (PMID:16954377)
• Exome sequencing to identify a homozygous Alu insertion in exon 9 of male germ cell-associated kinase (MAK) as the cause of disease in an isolated individual with retinitis pigmentosa. (PMID:21825139)
• Exome sequencing combined with this approach identified a homozygous nonsense mutation in male germ cell-associated kinase (MAK) in the single affected member of a consanguineous Turkish family with retinitis pigmentosa. (PMID:21835304)
• these data implicate MAK in both adrogen receptor activation and chromosomal instability, acting in both early and late prostate cancer development. (PMID:21986944)
• The patterns of disease expression in the MAK form of arRP showed some resemblance to patterns described in autosomal dominant RP, especially the form caused by RP1 mutations. (PMID:22110072)
• In glioblastoma cells with deregulated high levels of CCRK, its depletion restores cilia through ICK and an ICK-related kinase MAK, thereby inhibiting glioblastoma cell proliferation. (PMID:23743448)
• the expressions of ICK/MAK/MOK proteins in the intestinal tract can be differentially and dynamically regulated, implicating a significant functional diversity within this group of protein kinases. (PMID:24244486)
• We identified the MAK and DHDDS mutations homozygously in only 2.1% and 0.8%, respectively, of patients of mixed ethnicity, but in 25.7% and 8.6%, respectively, of cases reporting Jewish ancestry (PMID:25255364)
• Nonsense and missense mutations in MAK give rise to a non-syndromic recessive RP phenotype without apparent extra-ocular features. (PMID:25385675)
• One patient was homozygous for the insertion, one compound heterozygous with a missense change on the other allele (c. 46G>A; p.Gly16Arg), and three were heterozygous carriers. (PMID:26558903)
• We report the first case of leaking intraretinal cystoid spaces due to mutation in MAK. Mak regulates microtubule stability via phosphorylating RP1. Abnormal Mak may impact retinal photoreceptor ciliary length and subcompartmentalization. (PMID:26894652)
• The clinical data show that in general, patients with biallelic MAK mutations had a later age of onset and a milder retinal phenotype compared with patients with biallelic DHDDS mutations. (PMID:29276052)
• The natural history of this individual’s retinitis pigmentosa (RP) is consistent with previously described MAK mutations, being significantly milder than that associated with other photoreceptor ciliopathies. We suggest inclusion of MAK as part of wider genetic testing in all individuals presenting with RP. (PMID:29781741)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mak	ENSDARG00000059287
mus_musculus	Mak	ENSMUSG00000021363
rattus_norvegicus	Mak	ENSRNOG00000015101
drosophila_melanogaster	CG42366	FBGN0259712
caenorhabditis_elegans	dyf-5	WBGENE00001121

Paralogs (19): MAPK9 (ENSG00000050748), MAPK6 (ENSG00000069956), MOK (ENSG00000080823), NLK (ENSG00000087095), SRPK1 (ENSG00000096063), MAPK1 (ENSG00000100030), MAPK3 (ENSG00000102882), MAPK8 (ENSG00000107643), MAPK10 (ENSG00000109339), MAPK14 (ENSG00000112062), CILK1 (ENSG00000112144), SRPK2 (ENSG00000135250), MAPK4 (ENSG00000141639), MAPK13 (ENSG00000156711), MAPK7 (ENSG00000166484), MAPK15 (ENSG00000181085), SRPK3 (ENSG00000184343), MAPK11 (ENSG00000185386), MAPK12 (ENSG00000188130)

Protein

Protein identifiers

Serine/threonine-protein kinase MAK — P20794 (reviewed: P20794)

Alternative names: Male germ cell-associated kinase

All UniProt accessions (5): P20794, A0A140VK28, A0A6Q8PG01, A0A6Q8PH30, Q8IXN4

UniProt curated annotations — full annotation on UniProt →

Function. Essential for the regulation of ciliary length and required for the long-term survival of photoreceptors. Phosphorylates FZR1 in a cell cycle-dependent manner. Plays a role in the transcriptional coactivation of AR. Could play an important function in spermatogenesis. May play a role in chromosomal stability in prostate cancer cells.

Subunit / interactions. Interacts with RP1. Interacts with AR and CDK20. Found in a complex containing MAK, AR and NCOA3. Interacts with FZR1 (via WD repeats).

Subcellular location. Nucleus. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Spindle. Midbody. Cell projection. Cilium. Photoreceptor outer segment. Photoreceptor inner segment.

Tissue specificity. Expressed in prostate cancer cell lines at generally higher levels than in normal prostate epithelial cell lines. Isoform 1 is expressed in kidney, testis, lung, trachea, and retina. Isoform 2 is retina-specific where it is expressed in rod and cone photoreceptors.

Post-translational modifications. Autophosphorylated. Phosphorylated on serine and threonine residues.

Disease relevance. Retinitis pigmentosa 62 (RP62) [MIM:614181] A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. The disease is caused by variants affecting the gene represented in this entry.

Induction. Up-regulated by dihydrotestosterone (DHT) in androgen-sensitive LNCaP prostate cancer cells in a dose-dependent manner. Up-regulation by DHT is transient, reaching maximum levels after 24 hours and decreases slightly after 48 hours.

Similarity. Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P20794-1	1	yes
P20794-2	2
P20794-3	3

RefSeq proteins (4): NP_001229314, NP_001229886, NP_001364191, NP_005897 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR050117	MAPK	Family

Pfam: PF00069

Enzyme classification (BRENDA):

• EC 2.7.11.22 — cyclin-dependent kinase (BRENDA: 49 organisms, 441 substrates, 555 inhibitors, 8 Km, 4 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ADAQHATPPKKKRKVEDPKDF	0.046–0.521	2
ATP	0.0052–0.017	2
FIN1	0.003	1
PKTPKKAKKL	0.0029	1

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (28 total): sequence variant 12, mutagenesis site 3, modified residue 2, splice variant 2, region of interest 2, compositionally biased region 2, binding site 2, chain 1, domain 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P20794-F1	62.74	0.36

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): 125 (proton acceptor)

Ligand- & substrate-binding residues (2): 10–18; 33

Post-translational modifications (2): 159, 157

Mutagenesis-validated functional residues (3):

Position	Phenotype
33	abolishes autophosphorylation.
157	abolishes autophosphorylation and impairs kinase activity.
159	abolishes autophosphorylation and impairs kinase activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 220 (showing top): chr6p24, MODULE_64, MODULE_511, GOBP_MALE_GAMETE_GENERATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_NEGATIVE_REGULATION_OF_ORGANELLE_ASSEMBLY, ATGTTAA_MIR302C, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, GOBP_PHOTORECEPTOR_CELL_MAINTENANCE, GOBP_CILIUM_ORGANIZATION, GOCC_CENTROSOME, GOBP_ORGANELLE_ASSEMBLY, GOBP_NEGATIVE_REGULATION_OF_CELL_PROJECTION_ORGANIZATION

GO Biological Process (11): protein phosphorylation (GO:0006468), spermatogenesis (GO:0007283), cell differentiation (GO:0030154), intracellular signal transduction (GO:0035556), intraciliary transport (GO:0042073), photoreceptor cell maintenance (GO:0045494), protein autophosphorylation (GO:0046777), cilium assembly (GO:0060271), negative regulation of non-motile cilium assembly (GO:1902856), non-motile cilium assembly (GO:1905515), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (10): transcription coactivator activity (GO:0003713), protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), metal ion binding (GO:0046872), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (22): photoreceptor outer segment (GO:0001750), photoreceptor inner segment (GO:0001917), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), plasma membrane (GO:0005886), cilium (GO:0005929), axoneme (GO:0005930), midbody (GO:0030496), photoreceptor connecting cilium (GO:0032391), ciliary basal body (GO:0036064), mitotic spindle (GO:0072686), sperm principal piece (GO:0097228), sperm end piece (GO:0097229), sperm head-tail coupling apparatus (GO:0120212), spindle (GO:0005819), cytoskeleton (GO:0005856), motile cilium (GO:0031514), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	10
intracellular membraneless organelle	3
intracellular anatomical structure	2
cilium	2
cilium organization	2
protein kinase activity	2
photoreceptor cell cilium	2
nuclear lumen	2
microtubule organizing center	2
sperm flagellum	2
phosphorylation	1
protein modification process	1
developmental process involved in reproduction	1
male gamete generation	1
cellular developmental process	1
signal transduction	1
transport along microtubule	1
retina homeostasis	1
multicellular organismal process	1
protein phosphorylation	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
protein localization to cilium	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
negative regulation of cilium assembly	1
regulation of non-motile cilium assembly	1
non-motile cilium assembly	1
cilium assembly	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
adenyl ribonucleotide binding	1

Protein interactions and networks

STRING

887 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAK	EVPL	Q92817	762
MAK	RPGR	Q92834	420
MAK	RP9	Q8TA86	413
MAK	PRPH2	P23942	402
MAK	ROS1	P08922	382
MAK	DHDDS	Q86SQ9	370
MAK	CDHR1	Q96JP9	351
MAK	GCM2	O75603	349
MAK	TKFC	Q3LXA3	349
MAK	CNGA1	P29973	346
MAK	WDR19	Q8NEZ3	340
MAK	TBC1D32	Q96NH3	337
MAK	IFT88	Q13099	334
MAK	USH2A	O75445	331
MAK	PDE6A	P16499	327

IntAct

31 interactions, top by confidence:

A	B	Type	Score
KATNIP	MAK	psi-mi:“MI:0914”(association)	0.730
MAK	FZR1	psi-mi:“MI:0915”(physical association)	0.600
FZR1	MAK	psi-mi:“MI:0915”(physical association)	0.600
FZR1	MAK	psi-mi:“MI:0217”(phosphorylation reaction)	0.600
MAK	FZR1	psi-mi:“MI:0217”(phosphorylation reaction)	0.600
AR	MAK	psi-mi:“MI:0915”(physical association)	0.540
MAK	AR	psi-mi:“MI:0915”(physical association)	0.540
MAK	AR	psi-mi:“MI:0403”(colocalization)	0.540
MAK	AR	psi-mi:“MI:0914”(association)	0.540
AR	MAK	psi-mi:“MI:0914”(association)	0.540
NCOA3	AR	psi-mi:“MI:0914”(association)	0.480
CDK20	MAK	psi-mi:“MI:0915”(physical association)	0.400
CDC37	MAK	psi-mi:“MI:0915”(physical association)	0.400
NDUFB7	MAK	psi-mi:“MI:0915”(physical association)	0.370
MAK	PPP2CB	psi-mi:“MI:0915”(physical association)	0.370
SND1	MAK	psi-mi:“MI:0915”(physical association)	0.370
ANAPC11	MAK	psi-mi:“MI:0915”(physical association)	0.370
MAK	SERINC1	psi-mi:“MI:0915”(physical association)	0.370
SLAMF7	MAK	psi-mi:“MI:0915”(physical association)	0.370
NECTIN3	MAK	psi-mi:“MI:0914”(association)	0.350
KATNIP		psi-mi:“MI:0914”(association)	0.350
MAK	CNOT1	psi-mi:“MI:0914”(association)	0.350
MAK	KATNIP	psi-mi:“MI:0915”(physical association)	0.000
MAK	FLG	psi-mi:“MI:0915”(physical association)	0.000
MAK	PRDX2	psi-mi:“MI:0915”(physical association)	0.000
MAK	CILK1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (48): MAK (Affinity Capture-MS), MAK (Reconstituted Complex), MAK (Affinity Capture-MS), FLG (Affinity Capture-MS), ICK (Affinity Capture-MS), KIAA0556 (Affinity Capture-MS), PRDX2 (Affinity Capture-MS), MAK (Biochemical Activity), MAK (Affinity Capture-MS), MAK (Affinity Capture-MS), MAK (Synthetic Lethality), MAK (Affinity Capture-MS), CNOT1 (Affinity Capture-MS), EIF3F (Affinity Capture-MS), KIAA0556 (Affinity Capture-MS)

ESM2 similar proteins: A0A0K3AV08, A5ABV9, A6ZJ71, A8WJR8, A8X4H1, A8X633, G5EC32, M9PGC5, O17087, O45797, O62255, O94421, O95835, P13185, P13186, P14680, P20794, P22082, P27715, P31034, P38080, P46582, P49762, P53035, P53739, P53894, Q03306, Q09690, Q0IJ08, Q13627, Q17308, Q22703, Q2TAE3, Q5A7S7, Q5AP53, Q61214, Q63470, Q6BV06, Q6CR51, Q6FP74

Diamond homologs: A2X6X1, A2XFC8, A2XUW1, A2YCH5, A8WIP6, B0Y8W7, B3WFY8, G4N0Z0, G4NH08, G5EFV5, O04160, O23145, O42376, O42781, O80345, P16892, P18266, P20793, P20794, P21127, P23573, P24788, P27638, P38615, P39073, P43288, P43289, P43294, P46892, P47812, P49841, P51136, P51137, P51138, P51139, P54665, P54666, Q00532, Q00859, Q03957

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
MAK	“up-regulates activity”	MAK	phosphorylation
MAK	down-regulates	CDH1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	67
Likely pathogenic	27
Uncertain significance	234
Likely benign	271
Benign	14

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069936	NM_001242957.3(MAK):c.901_902del (p.Gln301fs)	Pathogenic
1070904	NM_001242957.3(MAK):c.962del (p.Pro321fs)	Pathogenic
1073188	NC_000006.11:g.(?10819119)(10819173_?)del	Pathogenic
1073189	NC_000006.11:g.(?10803953)(10819173_?)del	Pathogenic
1074357	NM_001242957.3(MAK):c.745_746dup (p.Ile250fs)	Pathogenic
1076443	NM_001242957.3(MAK):c.745_746del (p.Leu249fs)	Pathogenic
1184969	NM_001242957.3(MAK):c.475del (p.Tyr159fs)	Pathogenic
1275784	NM_001242957.3(MAK):c.639C>A (p.Cys213Ter)	Pathogenic
1379920	NM_001242957.3(MAK):c.911_914del (p.Asn304fs)	Pathogenic
1397863	NM_001242957.3(MAK):c.7dup (p.Arg3fs)	Pathogenic
1400976	NM_001242957.3(MAK):c.1433del (p.Gln478fs)	Pathogenic
1420072	NM_001242957.3(MAK):c.1360G>T (p.Glu454Ter)	Pathogenic
1422641	NM_001242957.3(MAK):c.492G>A (p.Trp164Ter)	Pathogenic
143121	NM_001242957.3(MAK):c.340dup (p.Ala114fs)	Pathogenic
1440850	NM_001242957.3(MAK):c.1084_1085del (p.Gln362fs)	Pathogenic
1457797	NM_001242957.3(MAK):c.1167del (p.His389fs)	Pathogenic
1458339	NM_001242957.3(MAK):c.560dup (p.Ser188fs)	Pathogenic
1459417	NM_001242957.3(MAK):c.321T>A (p.Tyr107Ter)	Pathogenic
1460412	NC_000006.11:g.(?10802105)(10809195_?)del	Pathogenic
1810762	NM_001242957.3(MAK):c.7_10dup (p.Tyr4fs)	Pathogenic
1948431	NM_001242957.3(MAK):c.313dup (p.Ile105fs)	Pathogenic
2025282	NM_001242957.3(MAK):c.1379_1380del (p.Ala460fs)	Pathogenic
2027144	NM_001242957.3(MAK):c.1302dup (p.Asp435fs)	Pathogenic
2179973	NM_001242957.3(MAK):c.1024C>T (p.Gln342Ter)	Pathogenic
2424009	NC_000006.11:g.(?10813857)(10813976_?)del	Pathogenic
2579195	NM_001242957.3:c.1297_1298insAlu	Pathogenic
2695675	NM_001242957.3(MAK):c.1546A>T (p.Lys516Ter)	Pathogenic
2707051	NM_001242957.3(MAK):c.1042C>T (p.Gln348Ter)	Pathogenic
2713022	NM_001242957.3(MAK):c.1136_1139dup (p.Thr381fs)	Pathogenic
2717236	NM_001242957.3(MAK):c.45dup (p.Gly16fs)	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

4265 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:10803778:C:T	G202E	1.000
6:10803779:C:A	G202W	1.000
6:10803805:A:G	L193P	1.000
6:10803823:C:T	G187E	1.000
6:10803833:A:G	W184R	1.000
6:10803833:A:T	W184R	1.000
6:10803868:A:G	L172P	1.000
6:10803886:C:G	R166P	1.000
6:10803887:G:T	R166S	1.000
6:10803890:A:G	Y165H	1.000
6:10808811:A:G	W164R	1.000
6:10808811:A:T	W164R	1.000
6:10808816:G:A	T162I	1.000
6:10808826:A:G	Y159H	1.000
6:10808857:T:A	R148S	1.000
6:10808857:T:G	R148S	1.000
6:10808864:A:G	L146P	1.000
6:10808867:C:T	G145E	1.000
6:10808868:C:G	G145R	1.000
6:10808868:C:T	G145R	1.000
6:10808872:A:C	D143E	1.000
6:10808872:A:T	D143E	1.000
6:10808873:T:A	D143V	1.000
6:10808873:T:C	D143G	1.000
6:10808873:T:G	D143A	1.000
6:10808874:C:G	D143H	1.000
6:10808876:G:T	A142D	1.000
6:10808877:C:G	A142P	1.000
6:10808881:T:A	K140N	1.000
6:10808881:T:G	K140N	1.000

dbSNP variants (sampled 300 via entrez): RS1000021216 (6:10781488 A>G), RS1000097299 (6:10819306 G>A), RS1000156754 (6:10817724 C>A,T), RS1000266361 (6:10830455 C>T), RS1000278451 (6:10764218 A>G), RS1000326877 (6:10767045 C>G,T), RS1000388034 (6:10799938 C>T), RS1000417084 (6:10779888 T>C), RS1000448565 (6:10798267 A>G), RS1000457658 (6:10799808 G>A), RS1000498996 (6:10781119 G>A), RS1000550852 (6:10800005 G>T), RS1000683433 (6:10806171 T>G), RS1000697400 (6:10835069 G>A), RS1000736989 (6:10793308 A>G)

Disease associations

OMIM: gene MIM:154235 | disease phenotypes: MIM:614181, MIM:268000

GenCC curated gene-disease

Disease	Classification	Inheritance
retinitis pigmentosa 62	Definitive	Autosomal recessive
retinitis pigmentosa	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
MAK-related retinopathy	Definitive	AR

Mondo (6): retinitis pigmentosa 62 (MONDO:0013611), retinitis pigmentosa (MONDO:0019200), inherited retinal dystrophy (MONDO:0019118), MAK-related retinopathy (MONDO:0700229), isolated macular dystrophy (MONDO:0957048), hereditary angioedema type 1 (MONDO:0015053)

Orphanet (6): Retinitis pigmentosa (Orphanet:791), OBSOLETE: Inherited retinal disorder (Orphanet:71862), OBSOLETE: Isolated macular dystrophy (Orphanet:519302), Hereditary angioedema type 1 (Orphanet:100050), Hereditary angioedema type 2 (Orphanet:100051), Hereditary angioedema (Orphanet:91378)

HPO phenotypes

37 total (30 of 37 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000501	Glaucoma
HP:0000505	Visual impairment
HP:0000510	Rod-cone dystrophy
HP:0000512	Abnormal electroretinogram
HP:0000543	Optic disc pallor
HP:0000546	Retinal degeneration
HP:0000551	Color vision defect
HP:0000563	Keratoconus
HP:0000602	Ophthalmoplegia
HP:0000613	Photophobia
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000662	Nyctalopia
HP:0000842	Hyperinsulinemia
HP:0001105	Retinal atrophy
HP:0001123	Visual field defect
HP:0003596	Middle age onset
HP:0007663	Reduced visual acuity
HP:0007675	Progressive night blindness
HP:0007703	Abnormal retinal pigmentation
HP:0007737	Spicular pigmentation of the retina
HP:0007787	Posterior subcapsular cataract
HP:0007843	Attenuation of retinal blood vessels
HP:0007994	Peripheral visual field loss
HP:0008046	Abnormal retinal vascular morphology
HP:0011462	Young adult onset

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST005230_15	Recurrent major depressive disorder	3.000000e-06
GCST005312_18	Menopause (age at onset)	2.000000e-19
GCST005312_47	Menopause (age at onset)	4.000000e-13
GCST009172_2	Response to (pegylated) interferon in HBeAg-negative hepatitis B	3.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause
EFO:0007859	response to interferon

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1163106 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

7 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 36,110 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL603469	LESTAURTINIB	3
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL384304	RG-547	2	93
CHEMBL445813	AT-7519	2	2,614
CHEMBL296468	BMS-387032	1	2,075
CHEMBL574738	AST-487	1	451

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — RCK family

ChEMBL bioactivities

13 potent at pChembl≥5 of 13 total, top 12 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.96	Kd	11	nM	RG-547
7.66	IC50	21.9	nM	STAUROSPORINE
7.64	IC50	22.7	nM	STAUROSPORINE
7.55	Kd	28	nM	ALVOCIDIB
7.54	IC50	28.7	nM	STAUROSPORINE
7.01	Kd	97	nM	AT-7519
6.05	Kd	890	nM	PHA-665752
6.00	Kd	1000	nM	AST-487
5.77	Kd	1700	nM	LESTAURTINIB
5.75	Kd	1800	nM	FORETINIB
5.64	Kd	2300	nM	BMS-387032
5.58	Kd	2600	nM	STAUROSPORINE

PubChem BioAssay actives

13 with measured affinity, of 150 total; 9 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-amino-2-[(1-methylsulfonylpiperidin-4-yl)amino]pyrimidin-5-yl]-(2,3-difluoro-6-methoxyphenyl)methanone	625025: Binding constant for MAK kinase domain	kd	0.0110	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	2198296: Inhibition of human MAK using myelin basic protein as substrate preincubated for 20 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by radiometric Hot-SpotSM Kinase assay	ic50	0.0219	uM
2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]chromen-4-one	625025: Binding constant for MAK kinase domain	kd	0.0280	uM
4-[(2,6-dichlorobenzoyl)amino]-N-piperidin-4-yl-1H-pyrazole-5-carboxamide	625025: Binding constant for MAK kinase domain	kd	0.0970	uM
(3Z)-5-[(2,6-dichlorophenyl)methylsulfonyl]-3-[[3,5-dimethyl-4-[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carbonyl]-1H-pyrrol-2-yl]methylidene]-1H-indol-2-one	625025: Binding constant for MAK kinase domain	kd	0.8900	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	625025: Binding constant for MAK kinase domain	kd	1.0000	uM
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	507595: Binding affinity to MAK	kd	1.7000	uM
1-N’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	625025: Binding constant for MAK kinase domain	kd	1.8000	uM
N-[5-[(5-tert-butyl-1,3-oxazol-2-yl)methylsulfanyl]-1,3-thiazol-2-yl]piperidine-4-carboxamide	625025: Binding constant for MAK kinase domain	kd	2.3000	uM

CTD chemical–gene interactions

38 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
trichostatin A	decreases expression, affects expression, affects cotreatment	4
Valproic Acid	affects cotreatment, decreases expression, increases expression	4
entinostat	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Dihydrotestosterone	increases expression, affects binding, increases activity, increases reaction	2
aristolochic acid I	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
(+)-JQ1 compound	increases expression	1
Arsenic Trioxide	decreases expression	1
Vorinostat	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	increases methylation	1
Cisplatin	increases expression	1
Dapsone	increases expression, decreases reaction	1
Demecolcine	increases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Lipopolysaccharides	increases expression, affects response to substance	1
Methotrexate	decreases expression	1
Methyl Methanesulfonate	increases expression	1

ChEMBL screening assays

94 unique, capped per target: 94 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1166054	Binding	Inhibition of MAK at 1 uM	Synthesis and structure-activity relationships of 1,2,3,4-tetrahydropyrido[2,3-b]pyrazines as potent and selective inhibitors of the anaplastic lymphoma kinase. — Bioorg Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SW23	HAP1 MAK (-) 1	Cancer cell line	Male
CVCL_SW24	HAP1 MAK (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa
NCT05392179	PHASE2	COMPLETED	A Study in Subjects With Retinitis Pigmentosa
NCT06627179	PHASE2	RECRUITING	Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
NCT06628947	PHASE2	RECRUITING	A Phase II Study of Intravitreal KIO-301 in Patients With Late-stage Retinitis Pigmentosa
NCT06912633	PHASE2	RECRUITING	Safety of a Single, Intravitreal Injection of 6.0M jCell (Famzeretcel) in Retinitis Pigmentosa (RP)
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT00063765	PHASE1	COMPLETED	Evaluation of Safety of Ciliary Neurotrophic Factor Implants in the Eye
NCT00065455	PHASE1	COMPLETED	Investigating the Effect of Vitamin A Supplementation on Retinitis Pigmentosa
NCT00458575	PHASE1	TERMINATED	A Study to Evaluate the Safety of CNTO 2476 in Patients With Advanced Retinitis Pigmentosa