CHM

Summary

CHM (CHM Rab escort protein, HGNC:1940) is a protein-coding gene on chromosome Xq21.2, encoding Rab proteins geranylgeranyltransferase component A 1 (P24386). Substrate-binding subunit of the Rab geranylgeranyltransferase (GGTase) complex. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes component A of the RAB geranylgeranyl transferase holoenzyme. In the dimeric holoenzyme, this subunit binds unprenylated Rab GTPases and then presents them to the catalytic Rab GGTase subunit for the geranylgeranyl transfer reaction. Rab GTPases need to be geranylgeranyled on either one or two cysteine residues in their C-terminus to localize to the correct intracellular membrane. Mutations in this gene are a cause of choroideremia; also known as tapetochoroidal dystrophy (TCD). This X-linked disease is characterized by progressive dystrophy of the choroid, retinal pigment epithelium and retina. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 1121 — RefSeq curated summary.

At a glance

• Gene–disease (curated): choroideremia (Definitive, ClinGen)
• GWAS associations: 3
• Clinical variants (ClinVar): 1,113 total — 298 pathogenic, 52 likely-pathogenic
• Phenotypes (HPO): 25
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000390

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1940
Approved symbol	CHM
Name	CHM Rab escort protein
Location	Xq21.2
Locus type	gene with protein product
Status	Approved
Aliases	REP-1
Ensembl gene	ENSG00000188419
Ensembl biotype	protein_coding
OMIM	300390
Entrez	1121

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 8 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000357749, ENST00000467744, ENST00000483950, ENST00000487515, ENST00000615443, ENST00000891167, ENST00000891168, ENST00000891169, ENST00000891170, ENST00000913025, ENST00000913026

RefSeq mRNA: 6 — MANE Select: NM_000390 NM_000390, NM_001145414, NM_001320959, NM_001362517, NM_001362518, NM_001362519

CCDS: CCDS14454, CCDS48139

Canonical transcript exons

ENST00000357749 — 15 exons

Exon	Start	End
ENSE00000673256	85958861	85958977
ENSE00000673257	85957855	85957975
ENSE00000673258	85956153	85956378
ENSE00000874388	85978767	85978891
ENSE00000874390	85911261	85911338
ENSE00000874391	85901084	85901188
ENSE00000874392	85900646	85900709
ENSE00000874393	85894188	85894284
ENSE00000874394	85878965	85879063
ENSE00000874395	85873052	85873212
ENSE00001124666	85861180	85864821
ENSE00001381699	86047484	86047558
ENSE00003466365	85963665	85964052
ENSE00003626759	86027491	86027557
ENSE00003684691	85981737	85981809

Expression profiles

Bgee: expression breadth ubiquitous, 264 present calls, max score 93.69.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.3729 / max 818.1560, expressed in 1764 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199875	21.5881	1757
199874	1.7848	878

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	93.69	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.66	gold quality
middle temporal gyrus	UBERON:0002771	93.50	gold quality
germinal epithelium of ovary	UBERON:0001304	89.90	gold quality
adrenal tissue	UBERON:0018303	89.27	gold quality
esophagus squamous epithelium	UBERON:0006920	88.49	gold quality
visceral pleura	UBERON:0002401	88.40	gold quality
islet of Langerhans	UBERON:0000006	88.10	gold quality
postcentral gyrus	UBERON:0002581	87.52	gold quality
parietal pleura	UBERON:0002400	87.48	gold quality
calcaneal tendon	UBERON:0003701	87.47	gold quality
lateral nuclear group of thalamus	UBERON:0002736	87.16	gold quality
primary visual cortex	UBERON:0002436	87.11	gold quality
parietal lobe	UBERON:0001872	86.90	gold quality
entorhinal cortex	UBERON:0002728	86.84	gold quality
superior frontal gyrus	UBERON:0002661	86.80	gold quality
tibia	UBERON:0000979	86.43	gold quality
pleura	UBERON:0000977	86.02	gold quality
pigmented layer of retina	UBERON:0001782	85.71	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	85.59	gold quality
skin of hip	UBERON:0001554	85.51	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.25	gold quality
right adrenal gland cortex	UBERON:0035827	85.24	gold quality
biceps brachii	UBERON:0001507	85.19	gold quality
pons	UBERON:0000988	85.13	gold quality
occipital lobe	UBERON:0002021	85.07	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	84.94	gold quality
nucleus accumbens	UBERON:0001882	84.53	gold quality
palpebral conjunctiva	UBERON:0001812	84.44	gold quality
prefrontal cortex	UBERON:0000451	84.41	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.17
E-MTAB-7303	no	246.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PARP1

miRNA regulators (miRDB)

116 targeting CHM, 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-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-6508-5P	99.92	70.67	2465

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• In vitro assembly and purification of the stoichiometric ternary complex of RabGGTase with REP-1 stabilized by a hydrolysis-resistant phosphoisoprenoid analog–farnesyl phosphonyl(methyl)phoshonate. (PMID:11886217)
• We report for the first time the identification of an intronic mutation remote from the exon-intron junctions that creates a strong acceptor splice site and leads to the inclusion of a cryptic exon into the CHM mRNA. (PMID:12827496)
• Frameshift mutation of REP-1 gene is associated with choroideremia (PMID:14566650)
• The C terminus of the REP-1 molecule functions as a mobile lid covering a conserved hydrophobic patch on the surface of REP-1 that in the complex coordinates the C terminus of Rab proteins. (PMID:15186776)
• Chm is essential for diploid trophoblast development and plays a role in the vascularization in placenta and yolk sac (PMID:15242790)
• DNA analysis revealed that the patient was heterozygous for a previously undescribed substitution mutation at the 3’-splice site of intron 6 of the CHM gene (850-1 G to C), confirmed by mRNA analysis with reverse transcriptase polymerase chain reaction. (PMID:15465555)
• The authors found a 402delT and a 555-556delAG mutation in the CHM gene, one of which (402delT) is a novel mutation. (PMID:15579993)
• Normal electroretinogram is preserved in patients with nonsense mutation in exon 6 of the choroideremia CHM gene. (PMID:16087855)
• The results represent in vivo evidence in humans for retinal remodeling and provide a marker for the earliest stage of this response to genetic retinal disease. (PMID:16936131)
• Deletion of the CHM gene causes severe choroideremia. Results of serial ERGs and fundus examinations documented progression first of rod and then of cone disease. (PMID:17698759)
• This is the first study reporting mutations in the CHM gene in Chinese families. Mutational analysis was performed at the DNA, mRNA and protein levels. Five truncating mutations were found, and two of these were novel. (PMID:18087237)
• Novel type of mutation did not result in a truncated or absent protein. Rather, these patients lost different parts of the REP-1 mRNA in-frame that in all the cases encode a conserved protein domain implicated in the interaction with Rab proteins. (PMID:18385043)
• Fundus autofluorescence patterin is specific to syndromic choroideremia carriers and thus will help to identify and differentiate between carriers of other X-linked recessive carrier states such as in X-linked retinitis pigmentosa. (PMID:18487380)
• When over-expressed in cells, REP wild-type and mutants are unable to form stable cytosolic complexes with endogenous unprenylated Rabs. (PMID:18532927)
• A novel (967-970+2)delAAAGGT mutation existed in the CHM gene of a Japanese family with choroideremia. (PMID:18773267)
• All 6 carriers of CHM showed a characteristic FAF pattern that can guide mutation analysis. (PMID:19376587)
• Genomic DNA from the living brother revealed a transition mutation, C to T, in exon 6 which resulted in a stop codon and was predicted to truncate the protein product. (PMID:19422966)
• report pathogenic mutations: a novel missense mutation, L550P; a truncation c.1542T>A, STOP; and two deletions (c.525_526delAG and c.1646delC) in the CHM gene and their phenotypic effect in choroideremia (PMID:19427510)
• The typical mottled irregularity in fundus autofluorescence is a valuable diagnostic criterion that facilitates specific genetic testing. (PMID:19597113)
• CHM gene molecular analysis and X-chromosome inactivation pattern determination in two families with choroideremia. (PMID:19764077)
• Intracellular vesicle transport, lysosomal acidification and rates of proteolytic degradation were studied in Choroideremia patients carrying 10 different loss-of-function REP1 mutations. (PMID:20027300)
• We identified a novel REP1 missense variant (c.1520A>G; p.H507R) associated with CHM that prevents REP1-Rab geranylgeranyl transferase interaction. (PMID:21905166)
• It is suggested that expression levels of alternative transcripts of the CHM gene could be used as a molecular marker system to identify human cancers. (PMID:21939745)
• an interaction between a transmembrane receptor and RGGTA (PMID:21990357)
• A novel mutation was detected in CHM gene in family 1. Another mutation within exon 14 of CHM was identified in family 2. The mutations caused night blindness, chorioretinal atrophy, and bareness of the sclera. (PMID:22025891)
• In Mainland Chinese families, the central visual acuity of male patients with CHM can be affected at an early age (second decade), whereas female CHM carriers may manifest signs and symptoms at a later age (>/= 45 years). (PMID:22355242)
• These findings demonstrate a novel CHM mutation that emphasizes severe posterior pole carrier phenotypes, age-related changes, and early choroideremia disease. (PMID:22965595)
• While likely an uncommon event, duplication within the CHM gene could be considered as an explanation for CHM cases in which no mutation is found by sequence analysis. (PMID:23273018)
• Data found pathogenic DNA variants in the genes RP1, USH2A, CNGB3, NMNAT1, CHM, and ABCA4, responsible for retinitis pigmentosa, Usher syndrome, achromatopsia, Leber congenital amaurosis, choroideremia, or recessive Stargardt/cone-rod dystrophy cases. (PMID:23940504)
• the clinical and molecular findings of an Italian family with a new mutation in the choroideremia (CHM) gene, are reported. (PMID:24672218)
• Sanger sequencing confirmed the mutations in CHM, including four novel (c.558_559delTT, c.964G>T, c.966delA, c.1166+2T>G) and two known (c.7031G>A and c.1584_1587delTGTT) mutations. (PMID:24913019)
• Six previously reported and five novel CHM mutations were detected in 11 Australian families clinically diagnosed with choroideremia. (PMID:25912515)
• We report a novel CHM mutation, c.1475_1476insCA, identified by whole-exome sequencing in a family with X-linked CHM initially diagnosed as retinitis pigmentosa. (PMID:26216097)
• The family segregated a REP1 mutation, suggesting choroideremia (CHM). (PMID:26720468)
• In Choroideremia(Y42X/y) fibroblasts, there was a recovery of prenylation activity following treatment with either PTC124 (42 +/- 5%) or PTC-414 (36 +/- 11%), although an increase in REP1 protein was not detected in these cells, in contrast to the zebrafish model. (PMID:27329764)
• We describe the causative mutations in a large cohort of patients who also were examined clinically and explore potential genotype-phenotype correlations. By so doing, we further aimed to make inferences regarding the importance of particular regions of the CHM gene with respect to mutagenesis and to infer the importance of particular regions of the REP1 protein essential for normal function. (PMID:27820636)
• we demonstrated that REP1 blocked the nuclear trans-localization of FOXO3 through physically interacting with FOXO3, thereby suppressing FOXO3-mediated apoptosis. Importantly, the inhibition of REP1 combined with 5-FU treatment could lead to significant retarded tumor growth in a xenograft tumor model of human cancer cells (PMID:28055019)
• Overexpression of REP1 in BEAS-2B cells enhanced cell growth and anchorage-independent colony formation with little increase in EGFR level and STAT3 activation. (PMID:28230863)
• These findings suggest that the CHM promoter region should be examined in patients with CHM who lack coding sequence mutations, and reveals, for the first time, features of the gene’s regulation (PMID:28271586)
• All coding exons and flanking intronic regions of the CHM gene revealed a novel small deletion at a splice site (c.184_189+3delTACCAGGTA) in one patient and a deletion of the entire exon 9 in the other. (PMID:28643494)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	chm	ENSDARG00000003845
mus_musculus	Chm	ENSMUSG00000025531
rattus_norvegicus	Chm	ENSRNOG00000000161
drosophila_melanogaster	Rep	FBGN0026378
caenorhabditis_elegans		WBGENE00022051

Paralogs (3): GDI2 (ENSG00000057608), CHML (ENSG00000203668), GDI1 (ENSG00000203879)

Protein

Protein identifiers

Rab proteins geranylgeranyltransferase component A 1 — P24386 (reviewed: P24386)

Alternative names: Choroideremia protein, Rab escort protein 1, TCD protein

All UniProt accessions (1): P24386

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-binding subunit of the Rab geranylgeranyltransferase (GGTase) complex. Binds unprenylated Rab proteins and presents the substrate peptide to the catalytic component B composed of RABGGTA and RABGGTB, and remains bound to it after the geranylgeranyl transfer reaction. The component A is thought to be regenerated by transferring its prenylated Rab back to the donor membrane. Besides, a pre-formed complex consisting of CHM and the Rab GGTase dimer (RGGT or component B) can bind to and prenylate Rab proteins; this alternative pathway is proposed to be the predominant pathway for Rab protein geranylgeranylation.

Subunit / interactions. Monomer. Heterotrimer composed of RABGGTA, RABGGTB and CHM; within this trimer, RABGGTA and RABGGTB form the catalytic component B, while CHM (component A) mediates Rab protein binding. Can associate with the Rab GGTase dimer (RGGT or component B) prior to Rab protein binding; the association is stabilized by geranylgeranyl pyrophosphate (GGpp). The CHM:RGGT:Rab complex is destabilized by GGpp. Interacts with RAB1A, RAB1B, RAB5A, RAB7A and RAB27A and mediates their prenylation. Interacts with the non-phosphorylated forms of RAB3A, RAB3B, RAB3C, RAB3D, RAB5B, RAB5C, RAB8A, RAB8B, RAB10, RAB12, RAB35, and RAB43.

Subcellular location. Cytoplasm. Cytosol.

Disease relevance. Choroideremia (CHM) [MIM:303100] An X-linked recessive disease characterized by a slowly progressive degeneration of the choroid, photoreceptors, and retinal pigment epithelium. Affected males develop night blindness in their teenage years followed by loss of peripheral vision and complete blindness at middle age. Carrier females are generally asymptomatic but funduscopic examination often shows patchy areas of chorioretinal atrophy. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the Rab GDI family.

Isoforms (2)

UniProt ID	Names	Canonical?
P24386-1	1	yes
P24386-2	2

RefSeq proteins (6): NP_000381, NP_001138886, NP_001307888, NP_001349446, NP_001349447, NP_001349448 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001738	Rab_escort	Family
IPR018203	GDP_dissociation_inhibitor	Family
IPR036188	FAD/NAD-bd_sf	Homologous_superfamily
IPR054420	RAE1_2_domI_C	Domain

Pfam: PF00996, PF22603

Enzyme classification (BRENDA):

• EC 2.5.1.60 — protein geranylgeranyltransferase type II (BRENDA: 9 organisms, 44 substrates, 88 inhibitors, 7 Km, 2 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
GERANYLGERANYL DIPHOSPHATE	—	2
RAB3A	—	1
YPT1P	0.0011	1
RAB PROTEIN	—	0

UniProt features (11 total): sequence variant 3, splice variant 2, mutagenesis site 2, chain 1, region of interest 1, sequence conflict 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P24386-F1	81.05	0.66

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
282	abolishes prenylation of rab1a and association with rggt.
290	impairs prenylation of rab1a and abolishes association with rggt.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6803205	TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain
R-HSA-8873719	RAB geranylgeranylation
R-HSA-8876198	RAB GEFs exchange GTP for GDP on RABs

MSigDB gene sets: 221 (showing top): GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_PROTEIN_TARGETING, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, GOMF_GTPASE_BINDING, CEBP_Q2, GOBP_PROTEIN_TARGETING_TO_MEMBRANE, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_MEMBRANE, MORF_RAB3A, MORF_BMPR2, MAF_Q6, GOBP_SENSORY_PERCEPTION, YY1_01

GO Biological Process (6): protein targeting to membrane (GO:0006612), intracellular protein transport (GO:0006886), small GTPase-mediated signal transduction (GO:0007264), visual perception (GO:0007601), vesicle-mediated transport (GO:0016192), protein geranylgeranylation (GO:0018344)

GO Molecular Function (5): Rab geranylgeranyltransferase activity (GO:0004663), GDP-dissociation inhibitor activity (GO:0005092), GTPase activator activity (GO:0005096), small GTPase binding (GO:0031267), protein binding (GO:0005515)

GO Cellular Component (4): nucleus (GO:0005634), cytosol (GO:0005829), Rab-protein geranylgeranyltransferase complex (GO:0005968), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
TP53 Regulates Transcription of Cell Death Genes	1
Post-translational protein modification	1
Rab regulation of trafficking	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
GTPase regulator activity	2
cytoplasm	2
cellular anatomical structure	2
protein targeting	1
establishment of protein localization to membrane	1
intracellular protein localization	1
protein transport	1
intracellular transport	1
intracellular signaling cassette	1
sensory perception of light stimulus	1
transport	1
cellular process	1
protein prenylation	1
protein geranylgeranyltransferase activity	1
GDP binding	1
GTPase activity	1
enzyme activator activity	1
GTPase binding	1
binding	1
intracellular membrane-bounded organelle	1
transferase complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1232 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CHM	RAB27A	P51159	852
CHM	SNCA	P37840	774
CHM	RAB1A	P11476	697
CHM	RAB3A	P20336	639
CHM	DYNLT2	Q8IZS6	618
CHM	ATP13A2	Q9NQ11	586
CHM	CEP290	O15078	580
CHM	RABGGTB	P53611	572
CHM	MAPT	P10636	570
CHM	RAB8A	P24407	559
CHM	CCP110	O43303	548
CHM	RPE65	Q16518	544
CHM	RABGGTA	Q92696	535
CHM	GLS	O94925	532
CHM	UBXN8	O00124	513

IntAct

109 interactions, top by confidence:

A	B	Type	Score
RABGGTA	CHM	psi-mi:“MI:0915”(physical association)	0.800
RAB11B	SH3BP5	psi-mi:“MI:0914”(association)	0.640
RAB31	CHM	psi-mi:“MI:0914”(association)	0.640
RAB32	CHM	psi-mi:“MI:0914”(association)	0.640
CHM	RAB5C	psi-mi:“MI:0914”(association)	0.640
RAB9A	CHM	psi-mi:“MI:2364”(proximity)	0.610
RAB9A	CHM	psi-mi:“MI:0914”(association)	0.610
RAB8A	WDR91	psi-mi:“MI:0914”(association)	0.600
RAB12	CHM	psi-mi:“MI:0914”(association)	0.530
RAB10	CHM	psi-mi:“MI:0914”(association)	0.530
RAB8B	BLTP3B	psi-mi:“MI:0914”(association)	0.530
RAB5C	GNAT3	psi-mi:“MI:0914”(association)	0.530
RAB17	GTPBP1	psi-mi:“MI:0914”(association)	0.530
RABGGTA	YKT6	psi-mi:“MI:0914”(association)	0.530
RAB11A	SH3BP5	psi-mi:“MI:0914”(association)	0.530
RAB5A	ATE1	psi-mi:“MI:0914”(association)	0.530
RAB7B	ATE1	psi-mi:“MI:0914”(association)	0.530
RAB30	UBB	psi-mi:“MI:0914”(association)	0.530
RAB3A	RAB3B	psi-mi:“MI:0914”(association)	0.530
RAB29	CHM	psi-mi:“MI:0914”(association)	0.530
CNTF	CHM	psi-mi:“MI:0914”(association)	0.530

BioGRID (104): CHM (Affinity Capture-MS), CHM (Affinity Capture-MS), CHM (Affinity Capture-MS), CHM (Affinity Capture-MS), CHM (Affinity Capture-MS), CHM (Affinity Capture-MS), CHM (Affinity Capture-MS), CHM (Co-fractionation), CHM (Co-fractionation), CHM (Affinity Capture-MS), CHM (Affinity Capture-MS), CHM (Affinity Capture-MS), CHM (Affinity Capture-MS), CHM (Affinity Capture-MS), CHM (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4IXF6, A0A1L8HU22, A0JMR6, A0JMU5, A2RSY6, A5D7S3, A5WW08, A6NNW6, A9LLI8, E9PUQ8, P0C218, P24386, P26374, P79457, Q12789, Q16760, Q1LWH4, Q2I6J1, Q2T9V5, Q3B7T1, Q3KR54, Q3U3W5, Q496Z9, Q4R6C7, Q5FWP4, Q5R5T0, Q5SUE7, Q5ZLG9, Q64398, Q6DDT5, Q6GQV7, Q6NVF4, Q6NZP1, Q6P256, Q6P2P2, Q6P5D8, Q6PJI9, Q6UXZ4, Q7Z2T5, Q7ZXF1

Diamond homologs: O93831, P24386, P26374, P37727, P50395, Q5RCE1, Q9QXG2, Q9QZD5, Q9V8W3, P32864, Q10305, Q8LLD4, Q9BKQ5

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CHM	“down-regulates activity”	RABGGTA	binding
CHM	“down-regulates activity”	RABGGTB	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 78 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
RAB geranylgeranylation	38	98.1×	3e-70
TBC/RABGAPs	14	54.2×	2e-19
RAB GEFs exchange GTP for GDP on RABs	25	46.3×	3e-34
Retrograde transport at the Trans-Golgi-Network	6	19.7×	5e-05
Translocation of SLC2A4 (GLUT4) to the plasma membrane	6	13.8×	3e-04
COPII-mediated vesicle transport	5	12.2×	2e-03
Neutrophil degranulation	13	4.5×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
Rab protein signal transduction	9	115.9×	3e-15
antigen processing and presentation	10	91.2×	2e-15
regulated exocytosis	5	57.6×	8e-07
melanosome transport	5	49.7×	2e-06
positive regulation of exocytosis	6	46.9×	1e-07
autophagosome assembly	9	26.3×	4e-09
endocytic recycling	7	24.3×	7e-07
exocytosis	11	21.7×	4e-10

Disease & clinical

Clinical variants and AI predictions

ClinVar

1113 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	298
Likely pathogenic	52
Uncertain significance	246
Likely benign	317
Benign	79

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068502	NM_000390.4(CHM):c.315-2A>C	Pathogenic
1069209	NM_000390.4(CHM):c.993del (p.Asn332fs)	Pathogenic
1069210	NM_000390.4(CHM):c.941-2A>G	Pathogenic
1069211	NM_000390.4(CHM):c.820-1G>C	Pathogenic
1070787	NM_000390.4(CHM):c.1340_1341del (p.Val447fs)	Pathogenic
1071244	NM_000390.4(CHM):c.1569del (p.Val524fs)	Pathogenic
1071374	NC_000023.10:g.(?84534427)(85302634_?)del	Pathogenic
1071375	NC_000023.10:g.(?85302488)(85302536_?)del	Pathogenic
1071376	NC_000023.10:g.(?85119635)(85119846_?)del	Pathogenic
1072041	NM_000390.4(CHM):c.1113_1114del (p.Pro372fs)	Pathogenic
1072298	NM_000390.4(CHM):c.1565C>A (p.Ser522Ter)	Pathogenic
1072365	NM_000390.4(CHM):c.984del (p.Lys328fs)	Pathogenic
1073117	NM_000390.4(CHM):c.1663A>T (p.Arg555Ter)	Pathogenic
1073118	NM_000390.4(CHM):c.1414-1G>A	Pathogenic
1073119	NM_000390.4(CHM):c.1413+1G>A	Pathogenic
1073120	NM_000390.4(CHM):c.1234G>T (p.Glu412Ter)	Pathogenic
1073121	NM_000390.4(CHM):c.817C>T (p.Gln273Ter)	Pathogenic
1073370	NM_000390.4(CHM):c.816del (p.Glu272fs)	Pathogenic
1073806	NM_000390.4(CHM):c.224G>A (p.Trp75Ter)	Pathogenic
1074957	NM_000390.4(CHM):c.1670C>A (p.Ser557Ter)	Pathogenic
1075258	NM_000390.4(CHM):c.616dup (p.Thr206fs)	Pathogenic
1075259	NM_000390.4(CHM):c.569C>G (p.Ser190Ter)	Pathogenic
1075553	NM_000390.4(CHM):c.1166+1G>C	Pathogenic
1075599	NM_000390.4(CHM):c.1532del (p.Thr511fs)	Pathogenic
1075716	NM_000390.4(CHM):c.1153C>T (p.Gln385Ter)	Pathogenic
1075987	NM_000390.4(CHM):c.1245-2A>G	Pathogenic
1076025	NM_000390.4(CHM):c.940+1G>C	Pathogenic
1076303	NM_000390.4(CHM):c.1660_1661del (p.Met554fs)	Pathogenic
1076316	NM_000390.4(CHM):c.283_284del (p.Ile95fs)	Pathogenic
11148	NM_000390.4(CHM):c.1358_1359delinsGA (p.Ser453Ter)	Pathogenic

SpliceAI

3701 predictions. Top by Δscore:

Variant	Effect	Δscore
X:85864670:T:A	donor_gain	1.0000
X:85870546:A:AC	donor_gain	1.0000
X:85870547:C:CC	donor_gain	1.0000
X:85870559:ATT:A	donor_gain	1.0000
X:85870559:ATTC:A	donor_gain	1.0000
X:85870782:A:AC	donor_gain	1.0000
X:85870783:G:C	donor_gain	1.0000
X:85873209:TTTT:T	acceptor_gain	1.0000
X:85873211:TT:T	acceptor_gain	1.0000
X:85873213:C:CC	acceptor_gain	1.0000
X:85894178:CTATG:C	donor_gain	1.0000
X:85894186:A:AC	donor_gain	1.0000
X:85894187:C:CC	donor_gain	1.0000
X:85894192:G:A	donor_gain	1.0000
X:85894224:A:C	donor_gain	1.0000
X:85911248:A:AC	donor_gain	1.0000
X:85911248:ATAT:A	donor_gain	1.0000
X:85911259:A:AC	donor_gain	1.0000
X:85911260:C:CC	donor_gain	1.0000
X:85911260:CTTT:C	donor_gain	1.0000
X:85911339:C:CC	acceptor_gain	1.0000
X:85957850:AATAC:A	donor_loss	1.0000
X:85957851:ATAC:A	donor_loss	1.0000
X:85957852:TAC:T	donor_loss	1.0000
X:85957854:C:A	donor_loss	1.0000
X:85957920:TTTTC:T	donor_gain	1.0000
X:85957921:TTTCT:T	donor_gain	1.0000
X:85958856:AGTAC:A	donor_loss	1.0000
X:85958857:GTAC:G	donor_loss	1.0000
X:85958858:TACCT:T	donor_loss	1.0000

AlphaMissense

4315 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:85911338:C:A	R389S	0.999
X:85911338:C:G	R389S	0.999
X:85956153:C:A	R389M	0.999
X:85956153:C:G	R389T	0.999
X:85981779:A:C	S49R	0.999
X:85981779:A:T	S49R	0.999
X:85981781:T:G	S49R	0.999
X:86027503:A:G	L35P	0.999
X:85911330:G:T	A392D	0.998
X:85956155:G:C	C388W	0.998
X:85956158:G:C	F387L	0.998
X:85956158:G:T	F387L	0.998
X:85956160:A:G	F387L	0.998
X:85956164:C:A	Q385H	0.998
X:85956164:C:G	Q385H	0.998
X:85956183:C:T	G379D	0.998
X:85957949:A:C	F282L	0.998
X:85957949:A:T	F282L	0.998
X:85957951:A:G	F282L	0.998
X:85958909:A:C	F257L	0.998
X:85958909:A:T	F257L	0.998
X:85958910:A:G	F257S	0.998
X:85958911:A:G	F257L	0.998
X:85958946:A:G	L245P	0.998
X:85911323:A:C	F394L	0.997
X:85911323:A:T	F394L	0.997
X:85911325:A:G	F394L	0.997
X:85911332:A:C	C391W	0.997
X:85956154:T:C	R389G	0.997
X:85956156:C:T	C388Y	0.997

dbSNP variants (sampled 300 via entrez): RS1000011919 (X:85953388 T>C), RS1000118513 (X:85971451 G>A), RS1000126518 (X:85904662 T>C), RS1000150003 (X:85893577 G>A,C), RS1000173120 (X:85945960 C>A,T), RS1000183019 (X:85940716 G>A), RS1000200498 (X:86027427 T>C), RS1000230722 (X:85925879 C>A), RS1000239691 (X:86002896 T>C), RS1000243508 (X:86025312 CTT>C), RS1000251721 (X:86010472 T>C,G), RS1000284941 (X:85914656 G>A), RS1000291651 (X:85861370 T>A,G), RS1000298036 (X:86014030 C>T), RS1000303012 (X:85922737 G>A)

Disease associations

OMIM: gene MIM:300390 | disease phenotypes: MIM:303100, MIM:268000

GenCC curated gene-disease

Disease	Classification	Inheritance
choroideremia	Definitive	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
choroideremia	Definitive	XL

Mondo (4): choroideremia (MONDO:0010557), inherited retinal dystrophy (MONDO:0019118), retinitis pigmentosa (MONDO:0019200), night blindness (MONDO:0004588)

Orphanet (3): Choroideremia (Orphanet:180), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Retinitis pigmentosa (Orphanet:791)

HPO phenotypes

25 total (26 of 25 shown, HPO-id order):

HPO	Term
HP:0000505	Visual impairment
HP:0000512	Abnormal electroretinogram
HP:0000529	Progressive visual loss
HP:0000533	Chorioretinal atrophy
HP:0000545	Myopia
HP:0000551	Color vision defect
HP:0000580	Pigmentary retinopathy
HP:0000662	Nyctalopia
HP:0001133	Constriction of peripheral visual field
HP:0001139	Chorioretinal scalloped atrophy
HP:0001417	X-linked inheritance
HP:0003621	Juvenile onset
HP:0007703	Abnormal retinal pigmentation
HP:0007737	Spicular pigmentation of the retina
HP:0007787	Posterior subcapsular cataract
HP:0007793	Granular macular appearance
HP:0007814	Retinal pigment epithelial mottling
HP:0007843	Attenuation of retinal blood vessels
HP:0007894	Fundus hypopigmentation
HP:0007994	Peripheral visual field loss
HP:0011463	Childhood onset
HP:0011506	Choroidal neovascularization
HP:0030505	Nummular pigmentation of the retina
HP:0030602	Abnormal fundus autofluorescence imaging
HP:0040049	Macular edema
HP:0000556	Retinal dystrophy

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002358_2	Pit-and-Fissure caries	1.000000e-06
GCST002361_13	Smooth-surface caries	8.000000e-07
GCST009391_825	Metabolite levels	6.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010398	sphingomyelin 24:1 measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D015794	Choroideremia	C11.270.142; C11.941.160.300; C16.320.290.142; C16.320.322.092
D009755	Night Blindness	C11.966.671
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): CHEMBL5169124 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	4
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Cadmium Chloride	increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
trichostatin A	increases expression	1
arsenite	decreases reaction, affects binding	1
sodium arsenite	increases expression	1
beta-methylcholine	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	decreases expression	1
NSC 689534	affects binding, increases expression	1
Temozolomide	increases expression	1
Vorinostat	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	decreases methylation	1
Clorgyline	increases expression	1
Coal	increases abundance, decreases expression	1
Copper	affects binding, increases expression	1
Demecolcine	increases expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5149410	Binding	Inhibition of Cyclin D1 in human HepG2 cells assessed as reduction in CDK4 expression by Western blot analysis	Seco-Lupane Triterpene Derivatives Induce Ferroptosis through GPX4/ACSL4 Axis and Target Cyclin D1 to Block the Cell Cycle. — J Med Chem

Cellosaurus cell lines

22 cell lines: 10 transformed cell line, 7 finite cell line, 5 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A1VZ	CRFi001-A	Induced pluripotent stem cell	Male
CVCL_B5S7	PUMCHi017-A	Induced pluripotent stem cell	Male
CVCL_B7E4	MUi032-A	Induced pluripotent stem cell	Male
CVCL_BW51	GM25382	Transformed cell line	Male
CVCL_BW52	GM25383	Finite cell line	Male
CVCL_BW53	GM25385	Transformed cell line	Male
CVCL_BW54	GM25386	Finite cell line	Male
CVCL_BW55	GM25392	Transformed cell line	Male
CVCL_BW56	GM25393	Finite cell line	Male
CVCL_D6ZA	GM28994	Finite cell line	Male

Clinical trials (associated diseases)

278 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
NCT03496012	PHASE3	COMPLETED	Efficacy and Safety of BIIB111 for the Treatment of Choroideremia
NCT03584165	PHASE3	ENROLLING_BY_INVITATION	Long-term Safety and Efficacy Follow-up of BIIB111 for the Treatment of Choroideremia and BIIB112 for the Treatment of X-Linked Retinitis Pigmentosa
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
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
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
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT02407678	PHASE2	COMPLETED	REP1 Gene Replacement Therapy for Choroideremia
NCT02553135	PHASE2	COMPLETED	Choroideremia Gene Therapy Clinical Trial
NCT02671539	PHASE2	COMPLETED	THOR - Tübingen Choroideremia Gene Therapy Trial
NCT03507686	PHASE2	COMPLETED	A Safety Study of Retinal Gene Therapy for Choroideremia With Administration of BIIB111
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
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
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
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