CERKL

Summary

CERKL (CERK like autophagy regulator, HGNC:21699) is a protein-coding gene on chromosome 2q31.3, encoding Ceramide kinase-like protein (Q49MI3). Has no detectable ceramide-kinase activity.

This gene was initially identified as a locus (RP26) associated with an autosomal recessive form of retinitis pigmentosa (arRP) disease. This gene encodes a protein with ceramide kinase-like domains, however, the protein does not phosphorylate ceramide and its target substrate is currently unknown. This protein may be a negative regulator of apoptosis in photoreceptor cells. Mutations in this gene cause a form of retinitis pigmentosa characterized by autosomal recessive cone and rod dystrophy (arCRD). Alternative splicing of this gene results in multiple transcript variants encoding different isoforms and non-coding transcripts.

Source: NCBI Gene 375298 — RefSeq curated summary.

At a glance

• Gene–disease (curated): CERKL-related retinopathy (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 1,064 total — 78 pathogenic, 89 likely-pathogenic
• Phenotypes (HPO): 35
• MANE Select transcript: NM_201548

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21699
Approved symbol	CERKL
Name	CERK like autophagy regulator
Location	2q31.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000188452
Ensembl biotype	protein_coding
OMIM	608381
Entrez	375298

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 7 protein_coding, 4 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay, 1 retained_intron

ENST00000339098, ENST00000374967, ENST00000374969, ENST00000374970, ENST00000409440, ENST00000410087, ENST00000421817, ENST00000452174, ENST00000460319, ENST00000466715, ENST00000476070, ENST00000479558, ENST00000494398, ENST00000497337, ENST00000684145

RefSeq mRNA: 5 — MANE Select: NM_201548 NM_001030311, NM_001030312, NM_001030313, NM_001160277, NM_201548

CCDS: CCDS33340, CCDS33341, CCDS42789, CCDS46466, CCDS54425

Canonical transcript exons

ENST00000410087 — 13 exons

Exon	Start	End
ENSE00001876577	181536672	181538244
ENSE00003469958	181548545	181548604
ENSE00003523731	181566058	181566121
ENSE00003529778	181544700	181544796
ENSE00003554942	181603837	181604079
ENSE00003556263	181547822	181547847
ENSE00003564743	181548680	181548857
ENSE00003574615	181549634	181549708
ENSE00003576101	181539092	181539264
ENSE00003634697	181573753	181573884
ENSE00003682322	181558566	181558708
ENSE00003685242	181547618	181547726
ENSE00003841919	181656769	181657105

Expression profiles

Bgee: expression breadth ubiquitous, 122 present calls, max score 84.71.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.8044 / max 148.5768, expressed in 172 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
32718	0.4093	112
32729	0.2132	61
32730	0.1150	48
32719	0.0389	14
32717	0.0219	9
32716	0.0061	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	84.71	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	83.88	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.88	gold quality
cerebellum	UBERON:0002037	79.23	gold quality
cerebellar cortex	UBERON:0002129	79.17	gold quality
cerebellar hemisphere	UBERON:0002245	78.97	gold quality
right uterine tube	UBERON:0001302	78.81	gold quality
right hemisphere of cerebellum	UBERON:0014890	78.47	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	76.69	gold quality
adult mammalian kidney	UBERON:0000082	73.84	gold quality
granulocyte	CL:0000094	71.80	gold quality
kidney	UBERON:0002113	70.69	gold quality
fallopian tube	UBERON:0003889	69.17	gold quality
ganglionic eminence	UBERON:0004023	68.77	gold quality
endometrium	UBERON:0001295	66.03	gold quality
duodenum	UBERON:0002114	65.16	gold quality
pancreas	UBERON:0001264	64.75	gold quality
metanephros cortex	UBERON:0010533	64.75	gold quality
gall bladder	UBERON:0002110	63.63	gold quality
cortex of kidney	UBERON:0001225	62.98	gold quality
leukocyte	CL:0000738	61.75	gold quality
lymph node	UBERON:0000029	61.38	gold quality
superior frontal gyrus	UBERON:0002661	61.36	gold quality
monocyte	CL:0000576	60.80	gold quality
blood	UBERON:0000178	60.19	gold quality
ventricular zone	UBERON:0003053	59.07	gold quality
Ammon’s horn	UBERON:0001954	58.19	gold quality
corpus callosum	UBERON:0002336	57.49	gold quality
primary visual cortex	UBERON:0002436	57.29	gold quality
spleen	UBERON:0002106	57.04	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.01
E-MTAB-6379	no	1070.50

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

69 targeting CERKL, 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-3924	100.00	72.09	2394
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-6848-3P	99.64	66.49	885
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-3975	99.62	65.97	697
HSA-MIR-6073	99.60	70.36	793
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-3153	99.55	67.59	2337

Literature-anchored findings (GeneRIF, showing 19)

• Novel mutation in CERKL which encompassed 13 exons is identified in retinitis pigmentosa (PMID:14681825)
• Data suggest a functional link between CERKL, a new ceramide kinase homolog, and its nucleolar localization. (PMID:15708351)
• Identification of a nuclear localization signal that might be responsible for nucleolar retention of CERKL. (PMID:16581028)
• c.238+1G>A is the second reported mutation of CERKL and is a prevalent founder mutation that underlies approximately 33% of autosomal recessive retinal degeneration cases in the Yemenite Jewish population. (PMID:18055789)
• This study presents the first genotype-phenotype correlation for persons carrying p.Arg257ter mutation and provides clues for a characteristic phenotype of these mutations among persons with autosomal recessive cases. (PMID:18515597)
• This is the third reported mutation in CERKL causing retinal degeneration but is the first report to show that a single amino acid change in CERKL, rather than a null mutation, can cause retinal disease. (PMID:18978954)
• Retinitis pigmentosa gene ceramide kinase-like (CERKL) was analyzed to determine CERKL function and contribution to pathogenesis. (PMID:19158957)
• The Pleckstrin Homology (PH) domain of CERK, which is required for Golgi complex localization, can substitute for the N-terminal region of CERKL and allow for wild-type CERKL localization, which is typified by nucleolar accumulation. (PMID:19501188)
• CERKL mutations are associated with widespread retinal degeneration with prominent maculopathy. (PMID:19578027)
• Our data indicate that compound heterozygous mutations of CERKL can cause RP. (PMID:19667359)
• An unexpected multiplicity of CERKL transcriptional start sites (four in each species) plus a high variety of alternative splicing events primarily affecting the 5’ half of the gene generate >20 fully validated mRNA isoforms in human and 23 in mouse. (PMID:21508105)
• The initial presenting features of CERKL-related retinopathy are distinct and unusual. Recognition of this initial presenting phenotype can facilitate earlier molecular diagnosis and genetic counseling. (PMID:24547929)
• CERKL interacts with TRX2 and plays a novel key role in the regulation of the TRX2 antioxidant pathway. (PMID:24735978)
• pVHL interacts with CERKL and ubiquitinates it for oxygen dependent proteasomal degradation. (PMID:26296657)
• Our report indicates that the first diagnostic test for Finnish patients with sporadic or autosomal recessive retinal dystrophy should be a targeted test for founder mutations in the CERKL. (PMID:29068140)
• CERKL is an important regulator of autophagy and it plays this role by stabilizing the deacetylase SIRT1. (PMID:30205735)
• CERKL mutation causing retinitis pigmentosa(RP) in Indian population - a genotype and phenotype correlation study. (PMID:32865075)
• Genetic and Clinical Findings in an Ethnically Diverse Cohort with Retinitis Pigmentosa Associated with Pathogenic Variants in CERKL. (PMID:33322828)
• CERKL-Associated Retinal Dystrophy: Genetics, Phenotype, and Natural History. (PMID:37331655)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	cerkl	ENSDARG00000079397
mus_musculus	Cerkl	ENSMUSG00000075256
rattus_norvegicus	Cerkl	ENSRNOG00000030212
drosophila_melanogaster	Sk1	FBGN0030300
drosophila_melanogaster	Cerk	FBGN0037315
drosophila_melanogaster	Sk2	FBGN0052484
caenorhabditis_elegans		WBGENE00007918
caenorhabditis_elegans	cerk-1	WBGENE00020398

Paralogs (4): AGK (ENSG00000006530), SPHK2 (ENSG00000063176), CERK (ENSG00000100422), SPHK1 (ENSG00000176170)

Protein

Protein identifiers

Ceramide kinase-like protein — Q49MI3 (reviewed: Q49MI3)

All UniProt accessions (3): A0A804HIX5, Q49MI3, G0XYE7

UniProt curated annotations — full annotation on UniProt →

Function. Has no detectable ceramide-kinase activity. Overexpression of CERKL protects cells from apoptosis in oxidative stress conditions.

Subcellular location. Cytoplasm. Nucleus. Nucleolus Cytoplasm. Nucleolus. Golgi apparatus. trans-Golgi network. Endoplasmic reticulum.

Tissue specificity. Isoform 1 and isoform 2 are expressed in adult retina, liver and pancreas as well as in fetal brain, lung and kidney. Isoform 3 is expressed in adult retina as well as in fetal lung and liver. Isoform 4 is expressed in adult retina, lung and kidney as well as in fetal lung and liver. Moderately expressed in retina, kidney, lung, testis, trachea, and pancreas. Weakly expressed in brain, placenta and liver.

Post-translational modifications. Phosphorylated on serine residues.

Disease relevance. Retinitis pigmentosa 26 (RP26) [MIM:608380] 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.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Isoforms (8)

UniProt ID	Names	Canonical?
Q49MI3-1	1, b	yes
Q49MI3-2	2, a
Q49MI3-3	3, d
Q49MI3-4	4, c
Q49MI3-5	5
Q49MI3-7	7, f
Q49MI3-8	8, e
Q49MI3-9	9

RefSeq proteins (5): NP_001025482, NP_001025483, NP_001025484, NP_001153749, NP_963842* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001206	Diacylglycerol_kinase_cat_dom	Domain
IPR016064	NAD/diacylglycerol_kinase_sf	Homologous_superfamily
IPR017438	ATP-NAD_kinase_N	Homologous_superfamily
IPR045363	CERK_C	Domain
IPR050187	Lipid_Phosphate_FormReg	Family
IPR057465	CERK_PH	Domain

Pfam: PF00781, PF19280, PF25382

UniProt features (22 total): splice variant 9, sequence variant 3, sequence conflict 3, mutagenesis site 2, short sequence motif 2, chain 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q49MI3-F1	79.82	0.58

Functional residue map

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

Mutagenesis-validated functional residues (2):

Position	Phenotype
104–106	only cytoplasmic.
260	loss of nuclear localization; in isoform 2.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 133 (showing top): AGGAAGC_MIR5163P, BENPORATH_ES_WITH_H3K27ME3, CAGCTG_AP4_Q5, HERNANDEZ_ABERRANT_MITOSIS_BY_DOCETACEL_4NM_UP, GOBP_SPHINGOLIPID_METABOLIC_PROCESS, GOBP_LIPID_METABOLIC_PROCESS, GOBP_LIPID_BIOSYNTHETIC_PROCESS, GOBP_SPHINGOLIPID_BIOSYNTHETIC_PROCESS, GOCC_NEURON_PROJECTION, GOBP_MEMBRANE_LIPID_METABOLIC_PROCESS, GTGACTT_MIR224, GOBP_MEMBRANE_LIPID_BIOSYNTHETIC_PROCESS, GOCC_PHOTORECEPTOR_INNER_SEGMENT, GOCC_NUCLEOLUS, GOCC_CILIUM

GO Biological Process (3): sphingolipid metabolic process (GO:0006665), sphingolipid biosynthetic process (GO:0030148), negative regulation of apoptotic process (GO:0043066)

GO Molecular Function (4): lipid kinase activity (GO:0001727), sphingolipid binding (GO:0046625), protein binding (GO:0005515), kinase activity (GO:0016301)

GO Cellular Component (11): photoreceptor outer segment (GO:0001750), photoreceptor inner segment (GO:0001917), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), cytosol (GO:0005829), membrane (GO:0016020), perinuclear region of cytoplasm (GO:0048471), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
cytoplasm	4
intracellular membrane-bounded organelle	3
nuclear lumen	2
endomembrane system	2
lipid metabolic process	1
sphingolipid metabolic process	1
lipid biosynthetic process	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
kinase activity	1
lipid binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
photoreceptor cell cilium	1
intracellular membraneless organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

928 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CERKL	EYS	Q5T1H1	857
CERKL	TULP1	O00294	831
CERKL	RDH12	Q96NR8	827
CERKL	CNGB1	Q14028	823
CERKL	PDE6A	P16499	821
CERKL	ABCA4	P78363	819
CERKL	PCARE	A6NGG8	805
CERKL	CNGA1	P29973	800
CERKL	PRCD	Q00LT1	800
CERKL	PRPF31	Q8WWY3	792
CERKL	IMPG2	Q9BZV3	787
CERKL	RPGR	Q92834	787
CERKL	PRPF3	O43395	781
CERKL	ZNF513	Q8N8E2	780
CERKL	FSCN2	O14926	779

IntAct

7 interactions, top by confidence:

A	B	Type	Score
CERKL	PPM1A	psi-mi:“MI:0915”(physical association)	0.620
CERKL	PPM1B	psi-mi:“MI:0914”(association)	0.530
M		psi-mi:“MI:0914”(association)	0.350
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
CERKL	PPM1G	psi-mi:“MI:0914”(association)	0.350

BioGRID (24): VHL (Affinity Capture-Western), CERKL (Affinity Capture-Western), CERKL (Reconstituted Complex), MICAL3 (Affinity Capture-MS), PPM1A (Affinity Capture-MS), SIRT1 (Affinity Capture-MS), PPM1B (Affinity Capture-MS), PPM1G (Affinity Capture-MS), EIF3I (Affinity Capture-MS), ERBB2IP (Affinity Capture-MS), EIF3G (Affinity Capture-MS), ANKHD1 (Affinity Capture-MS), MICAL3 (Affinity Capture-MS), EIF3B (Affinity Capture-MS), PPM1A (Affinity Capture-MS)

ESM2 similar proteins: A0JPF9, A1A5Q7, A2RT67, A2RUS2, A4D126, A5PKL6, A6NCI4, A6QPR9, D4ACE5, E9PYK3, F1ND48, Q05AA6, Q09M05, Q13474, Q15061, Q32PJ3, Q3TTL0, Q3UMR0, Q3UVV9, Q3UY96, Q498D5, Q49MI3, Q4R6Y8, Q4U2V3, Q502W6, Q5F204, Q5JPI3, Q5M8J0, Q5REW9, Q5RL51, Q5XIJ6, Q6DJG6, Q6RI63, Q7TNH6, Q7TPQ3, Q80V94, Q8BSE0, Q8CEL2, Q8IZC4, Q8N392

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1064 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	78
Likely pathogenic	89
Uncertain significance	307
Likely benign	453
Benign	34

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068116	NM_201548.5(CERKL):c.3G>A (p.Met1Ile)	Pathogenic
1068857	NM_201548.5(CERKL):c.1039_1040del (p.Asp347fs)	Pathogenic
1068911	NM_201548.5(CERKL):c.758del (p.Met253fs)	Pathogenic
1068912	NM_201548.5(CERKL):c.156_157insT (p.Glu53Ter)	Pathogenic
1069077	NM_201548.5(CERKL):c.526del (p.Gln176fs)	Pathogenic
1069409	NM_201548.5(CERKL):c.1100del (p.Leu367fs)	Pathogenic
1070010	NC_000002.11:g.(?182413252)(182438631_?)del	Pathogenic
1070968	NM_201548.5(CERKL):c.167_170del (p.Arg56fs)	Pathogenic
1072129	NM_201548.5(CERKL):c.954_961dup (p.Ser321fs)	Pathogenic
1073677	NM_201548.5(CERKL):c.506del (p.Ser168_Leu169insTer)	Pathogenic
1075776	NM_201548.5(CERKL):c.1389_1392dup (p.Thr465fs)	Pathogenic
1205787	NM_201548.5(CERKL):c.453G>A (p.Trp151Ter)	Pathogenic
1395469	NM_201548.5(CERKL):c.312del (p.Lys104fs)	Pathogenic
1402936	NM_201548.5(CERKL):c.38dup (p.Glu14fs)	Pathogenic
1414997	NM_201548.5(CERKL):c.744_745delinsAT (p.Lys249Ter)	Pathogenic
1443891	NM_201548.5(CERKL):c.677+609C>T	Pathogenic
1451702	NM_201548.5(CERKL):c.331C>T (p.Gln111Ter)	Pathogenic
1452355	NM_201548.5(CERKL):c.379A>T (p.Lys127Ter)	Pathogenic
1452597	NM_201548.5(CERKL):c.793C>T (p.Gln265Ter)	Pathogenic
1453427	NM_201548.5(CERKL):c.1392dup (p.Thr465fs)	Pathogenic
1453710	NM_201548.5(CERKL):c.9G>A (p.Trp3Ter)	Pathogenic
1457069	NM_201548.5(CERKL):c.1360_1364dup (p.Phe456fs)	Pathogenic
1457367	NM_201548.5(CERKL):c.490_493del (p.Asn164fs)	Pathogenic
1457548	NM_201548.5(CERKL):c.197_200del (p.Arg66fs)	Pathogenic
1458328	NM_201548.5(CERKL):c.833_834insCAAT (p.Leu279fs)	Pathogenic
1968537	NM_201548.5(CERKL):c.2T>A (p.Met1Lys)	Pathogenic
2016334	NM_201548.5(CERKL):c.630del (p.His211fs)	Pathogenic
2017481	NM_201548.5(CERKL):c.271G>T (p.Glu91Ter)	Pathogenic
2020568	NM_201548.5(CERKL):c.78del (p.Ala27fs)	Pathogenic
2020740	NM_201548.5(CERKL):c.209G>A (p.Trp70Ter)	Pathogenic

SpliceAI

3086 predictions. Top by Δscore:

Variant	Effect	Δscore
2:181538241:CAAT:C	acceptor_gain	1.0000
2:181538243:ATC:A	acceptor_loss	1.0000
2:181538245:C:CC	acceptor_gain	1.0000
2:181538245:CTGTA:C	acceptor_loss	1.0000
2:181539087:CTTA:C	donor_loss	1.0000
2:181539089:TACCT:T	donor_loss	1.0000
2:181539090:A:AC	donor_gain	1.0000
2:181539091:C:CA	donor_gain	1.0000
2:181539260:TTGAA:T	acceptor_gain	1.0000
2:181539261:TGAA:T	acceptor_gain	1.0000
2:181539262:GAA:G	acceptor_gain	1.0000
2:181539262:GAAC:G	acceptor_loss	1.0000
2:181539263:AAC:A	acceptor_loss	1.0000
2:181539264:AC:A	acceptor_loss	1.0000
2:181539265:C:CC	acceptor_gain	1.0000
2:181544792:TTAAT:T	acceptor_gain	1.0000
2:181544793:TAATC:T	acceptor_loss	1.0000
2:181544794:AATCT:A	acceptor_loss	1.0000
2:181544795:ATC:A	acceptor_loss	1.0000
2:181544796:TCT:T	acceptor_loss	1.0000
2:181544797:C:CC	acceptor_gain	1.0000
2:181544797:CTGA:C	acceptor_loss	1.0000
2:181544798:T:A	acceptor_loss	1.0000
2:181548601:TGCCC:T	acceptor_loss	1.0000
2:181548604:CCTAA:C	acceptor_loss	1.0000
2:181548605:C:A	acceptor_loss	1.0000
2:181548605:C:CC	acceptor_gain	1.0000
2:181548606:T:G	acceptor_loss	1.0000
2:181548675:CTT:C	donor_loss	1.0000
2:181548676:TTA:T	donor_loss	1.0000

AlphaMissense

3487 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:181544728:A:G	L472P	0.990
2:181544773:A:G	L457P	0.989
2:181547677:G:C	S429R	0.989
2:181547677:G:T	S429R	0.989
2:181547679:T:G	S429R	0.989
2:181539141:A:G	W523R	0.988
2:181539141:A:T	W523R	0.988
2:181603867:A:G	W151R	0.987
2:181603867:A:T	W151R	0.987
2:181539250:A:C	F486L	0.984
2:181539250:A:T	F486L	0.984
2:181539252:A:G	F486L	0.984
2:181656851:G:C	F52L	0.982
2:181656851:G:T	F52L	0.982
2:181656853:A:G	F52L	0.982
2:181544773:A:T	L457H	0.981
2:181603899:A:G	L140P	0.980
2:181539248:A:T	V487D	0.977
2:181548775:A:C	F352L	0.976
2:181548775:A:T	F352L	0.976
2:181548777:A:G	F352L	0.976
2:181656852:A:G	F52S	0.976
2:181547681:A:T	V428D	0.974
2:181656819:A:G	L63P	0.974
2:181656859:C:G	G50R	0.974
2:181544732:G:C	H471D	0.971
2:181544739:A:C	F468L	0.970
2:181544739:A:T	F468L	0.970
2:181544741:A:G	F468L	0.970
2:181544773:A:C	L457R	0.970

dbSNP variants (sampled 300 via entrez): RS1000025221 (2:181620139 G>A,C), RS1000040848 (2:181636919 T>C), RS1000041893 (2:181597180 A>G), RS1000066339 (2:181538952 C>CTCTT), RS1000098832 (2:181568964 C>A,T), RS1000132672 (2:181643370 G>C), RS1000137608 (2:181595400 T>C), RS1000216481 (2:181549034 T>C), RS1000227436 (2:181619233 C>T), RS1000244902 (2:181578240 G>A), RS1000273788 (2:181595655 C>A,T), RS1000283128 (2:181618806 T>C), RS1000290889 (2:181590227 T>C), RS1000325252 (2:181567854 A>G), RS1000334709 (2:181625204 C>T)

Disease associations

OMIM: gene MIM:608381 | disease phenotypes: MIM:608380, MIM:268000, MIM:120970, MIM:248200

GenCC curated gene-disease

Disease	Classification	Inheritance
retinitis pigmentosa 26	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
CERKL-related retinopathy	Definitive	AR

Mondo (9): retinitis pigmentosa 26 (MONDO:0012024), retinitis pigmentosa (MONDO:0019200), inherited retinal dystrophy (MONDO:0019118), cone-rod dystrophy (MONDO:0015993), cone dystrophy (MONDO:0000455), retinal disorder (MONDO:0005283), CERKL-related retinopathy (MONDO:0800401), isolated macular dystrophy (MONDO:0957048), Stargardt disease (MONDO:0019353)

Orphanet (6): Retinitis pigmentosa (Orphanet:791), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Cone rod dystrophy (Orphanet:1872), Progressive cone dystrophy (Orphanet:1871), OBSOLETE: Isolated macular dystrophy (Orphanet:519302), Stargardt disease (Orphanet:827)

HPO phenotypes

35 total (30 of 35 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:0001133	Constriction of peripheral visual field
HP:0007663	Reduced visual acuity
HP:0007675	Progressive night blindness
HP:0007688	Undetectable light- and dark-adapted electroretinogram
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:0011505	Cystoid macular edema

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000201_4	Response to iloperidone treatment (QT prolongation)	3.000000e-06
GCST001137_4	White blood cell count	3.000000e-23
GCST004683_1	Psychosis proneness (perceptual aberration scale and revised social anhedonia scale)	4.000000e-06
GCST009391_794	Metabolite levels	6.000000e-06
GCST90002388_305	Lymphocyte count	3.000000e-11

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0005091	monocyte count
EFO:0008337	psychosis predisposition measurement
EFO:0010395	sphingomyelin 22:0 measurement
EFO:0004587	lymphocyte count

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D000077765	Cone Dystrophy	C11.270.151; C11.768.216
D000071700	Cone-Rod Dystrophies	C11.270.152; C11.768.585.658.250; C16.320.290.152
D012164	Retinal Diseases	C11.768
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
D000080362	Stargardt Disease	C11.270.872; C11.768.585.439.339; C16.320.290.724
C564249	Retinitis Pigmentosa 26 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs993648	Toxicity	3	iloperidone	Acquired Long QT Syndrome (aLQTS)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs993648	CERKL	3	0.00	1	iloperidone

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
methylparaben	decreases expression	1
perfluorooctanoic acid	increases expression	1
tobacco tar	decreases expression, decreases reaction	1
diallyl disulfide	decreases expression, decreases reaction	1
nickel sulfate	decreases expression	1
allyl sulfide	decreases expression, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
abrine	decreases expression	1
bisphenol S	decreases methylation	1
Fulvestrant	decreases methylation	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	increases methylation	1
Dinitrochlorobenzene	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
N-Nitrosopyrrolidine	increases expression	1
Oxazolone	decreases expression	1
Smoke	increases abundance, increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Okadaic Acid	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_WN56	ESi066-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

234 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)
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
NCT01068561	PHASE1	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa