RAB40AL

Summary

RAB40AL (RAB40A like, HGNC:25410) is a protein-coding gene on chromosome Xq22.1, encoding Ras-related protein Rab-40A-like (P0C0E4). May act as substrate-recognition component of the ECS(RAB40) E3 ubiquitin ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.

This gene encodes a member of the Rab40 subfamily of Rab small GTP-binding proteins that contains a C-terminal suppressors of cytokine signaling box. Disruptions in this gene are associated with Duchenne muscular dystrophy.

Source: NCBI Gene 282808 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked syndromic intellectual disability (Refuted, ClinGen)
• Clinical variants (ClinVar): 4 total
• MANE Select transcript: NM_001031834

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25410
Approved symbol	RAB40AL
Name	RAB40A like
Location	Xq22.1
Locus type	gene with protein product
Status	Approved
Aliases	RAR2, RLGP
Ensembl gene	ENSG00000102128
Ensembl biotype	protein_coding
OMIM	300405
Entrez	282808

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000218249

RefSeq mRNA: 1 — MANE Select: NM_001031834 NM_001031834

CCDS: CCDS35353

Canonical transcript exons

ENST00000218249 — 1 exons

Exon	Start	End
ENSE00000675363	102937272	102938300

Expression profiles

Bgee: expression breadth broad, 71 present calls, max score 64.98.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
vastus lateralis	UBERON:0001379	64.98	gold quality
stromal cell of endometrium	CL:0002255	59.56	gold quality
granulocyte	CL:0000094	51.70	gold quality
lower esophagus mucosa	UBERON:0035834	47.27	silver quality
bone marrow cell	CL:0002092	46.47	gold quality
colonic epithelium	UBERON:0000397	46.36	gold quality
sural nerve	UBERON:0015488	43.58	gold quality
apex of heart	UBERON:0002098	40.07	silver quality
duodenum	UBERON:0002114	39.02	silver quality
skeletal muscle tissue	UBERON:0001134	37.93	gold quality
body of uterus	UBERON:0009853	37.85	silver quality
ganglionic eminence	UBERON:0004023	37.65	gold quality
omental fat pad	UBERON:0010414	37.26	gold quality
muscle tissue	UBERON:0002385	37.17	silver quality
mucosa of transverse colon	UBERON:0004991	37.08	silver quality
right lobe of liver	UBERON:0001114	37.04	silver quality
myometrium	UBERON:0001296	36.85	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
left ovary	UBERON:0002119	36.43	silver quality
left lobe of thyroid gland	UBERON:0001120	36.40	silver quality
lower esophagus	UBERON:0013473	36.40	gold quality
adenohypophysis	UBERON:0002196	36.35	silver quality
lower esophagus muscularis layer	UBERON:0035833	36.32	gold quality
adipose tissue	UBERON:0001013	36.17	silver quality
prefrontal cortex	UBERON:0000451	36.06	gold quality
ovary	UBERON:0000992	35.81	silver quality
pituitary gland	UBERON:0000007	35.72	silver quality
thyroid gland	UBERON:0002046	35.69	silver quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.45

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

13 targeting RAB40AL, 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-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-4738-3P	98.98	67.98	1846

Literature-anchored findings (GeneRIF, showing 4)

• This is the first study to show that mutation of RAB40AL is associated with a human disorder. (PMID:22581972)
• We herein present an unrelated 20-year-old male with similar manifestations also with p.D59G in the RAB40AL gene, which supports the existence of this condition previously coined as Martin-Probst syndrome (PMID:24863632)
• Data question the role of RAB40AL mutation as a disease-causing change and the involvement of RAB40AL in Martin-Probst syndrome. (PMID:25044830)
• Our findings are inconsistent with a causative effect of RAB40AL p.D59G on cognitive impairment combined with severe to profound bilateral hearing loss but indicate that p.D59G is a common genetic variation. (PMID:25370018)

Cross-species orthologs

0 orthologs

Paralogs (68): RAB27B (ENSG00000041353), RAB27A (ENSG00000069974), RAB7A (ENSG00000075785), RABL2B (ENSG00000079974), RAB21 (ENSG00000080371), RAB10 (ENSG00000084733), RAB18 (ENSG00000099246), RAB36 (ENSG00000100228), IFT27 (ENSG00000100360), RAB11A (ENSG00000103769), RAB2A (ENSG00000104388), RAB3D (ENSG00000105514), RAB3A (ENSG00000105649), RAB5C (ENSG00000108774), RAB34 (ENSG00000109113), RAB5B (ENSG00000111540), RAB35 (ENSG00000111737), RAB23 (ENSG00000112210), DNAJC27 (ENSG00000115137), RAB29 (ENSG00000117280), RAB32 (ENSG00000118508), RAB14 (ENSG00000119396), RAB9B (ENSG00000123570), RAB9A (ENSG00000123595), RAB38 (ENSG00000123892), RAB22A (ENSG00000124209), RAB17 (ENSG00000124839), RAB2B (ENSG00000129472), RAB25 (ENSG00000132698), RAB33A (ENSG00000134594), RAB30 (ENSG00000137502), RAB1A (ENSG00000138069), RAB20 (ENSG00000139832), RAB15 (ENSG00000139998), RAB40B (ENSG00000141542), RAB13 (ENSG00000143545), RABL2A (ENSG00000144134), RAB5A (ENSG00000144566), RAB19 (ENSG00000146955), RAB41 (ENSG00000147127)

Protein

Protein identifiers

Ras-related protein Rab-40A-like — P0C0E4 (reviewed: P0C0E4)

Alternative names: Ras-like GTPase

All UniProt accessions (1): P0C0E4

UniProt curated annotations — full annotation on UniProt →

Function. May act as substrate-recognition component of the ECS(RAB40) E3 ubiquitin ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. The Rab40 subfamily belongs to the Rab family that are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different sets of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion.

Subcellular location. Membrane. Cytoplasm. Mitochondrion.

Tissue specificity. Expressed in brain, lung, heart, skeletal muscle, kidney and liver. Highest expression in brain. Expressed in fetal brain and kidney.

Activity regulation. Regulated by guanine nucleotide exchange factors (GEFs) which promote the exchange of bound GDP for free GTP. Regulated by GTPase activating proteins (GAPs) which increase the GTP hydrolysis activity. Inhibited by GDP dissociation inhibitors (GDIs).

Domain organisation. The SOCS box contains two defined motifs including the BC box that recruits and binds Elongin BC complex, and the Cul box which interacts with the Cullin family of proteins to form a ECS (Elongin-Cullin-SOCS-box protein) E3 ubiquitin ligase complex. Switch I, switch II and the interswitch regions are characteristic of Rab GTPases and mediate the interactions with Rab downstream effectors. The switch regions undergo conformational changes upon nucleotide binding which drive interaction with specific sets of effector proteins, with most effectors only binding to GTP-bound Rab.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the small GTPase superfamily. Rab family.

RefSeq proteins (1): NP_001027004* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001496	SOCS_box	Domain
IPR001806	Small_GTPase	Family
IPR005225	Small_GTP-bd	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036036	SOCS_box-like_dom_sf	Homologous_superfamily
IPR050305	Small_GTPase_Rab	Family

Pfam: PF00071, PF07525

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (15 total): binding site 8, lipid moiety-binding region 2, region of interest 2, chain 1, domain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P0C0E4-F1	74.68	0.39

Functional residue map

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

Ligand- & substrate-binding residues (8): 126; 127; 26; 27; 28; 28; 69; 72

Post-translational modifications (2): 270, 275

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 41 (showing top): GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_EXOCYTOSIS, GOBP_SECRETION, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOCC_EXOCYTIC_VESICLE, GOCC_SECRETORY_VESICLE, GOCC_SYNAPSE, GOCC_PRESYNAPSE, GOMF_GTPASE_ACTIVITY, GOMF_HYDROLASE_ACTIVITY_ACTING_ON_ACID_ANHYDRIDES, chrXq22, VEGF_A_UP.V1_UP, KRAS.LUNG_UP.V1_DN, KMT2D_TARGET_GENES, GSE11864_UNTREATED_VS_CSF1_IFNG_PAM3CYS_IN_MAC_DN

GO Biological Process (3): exocytosis (GO:0006887), protein ubiquitination (GO:0016567), intracellular signal transduction (GO:0035556)

GO Molecular Function (6): GTPase activity (GO:0003924), G protein activity (GO:0003925), GTP binding (GO:0005525), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), hydrolase activity (GO:0016787)

GO Cellular Component (6): cytoplasm (GO:0005737), mitochondrion (GO:0005739), endosome (GO:0005768), plasma membrane (GO:0005886), synaptic vesicle (GO:0008021), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular anatomical structure	2
cellular anatomical structure	2
vesicle-mediated transport	1
secretion by cell	1
vesicle fusion to plasma membrane	1
protein modification by small protein conjugation	1
signal transduction	1
ribonucleoside triphosphate phosphatase activity	1
GTPase activity	1
molecular function regulator activity	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
endomembrane system	1
cytoplasmic vesicle	1
membrane	1
cell periphery	1
exocytic vesicle	1
presynapse	1

Protein interactions and networks

STRING

984 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RAB40AL	FYCO1	Q9BQS8	857
RAB40AL	ULK1	O75385	702
RAB40AL	CXCR6	O00574	685
RAB40AL	RABIF	P47224	665
RAB40AL	RAB3IP	Q96QF0	664
RAB40AL	SYNGAP1	Q96PV0	655
RAB40AL	RCC1L	Q96I51	647
RAB40AL	RCC1	P18754	568
RAB40AL	RPGR	Q92834	555
RAB40AL	RPGRIP1	Q96KN7	550
RAB40AL	RAB3IL1	Q8TBN0	516
RAB40AL	NUTF2	P13662	514
RAB40AL	CDC14A	Q9UNH5	506
RAB40AL	PLP1	P04400	497
RAB40AL	RASA1	P20936	479

IntAct

11 interactions, top by confidence:

A	B	Type	Score
RAB40B	RAB40AL	psi-mi:“MI:0914”(association)	0.530
RAB40A	RAB40AL	psi-mi:“MI:0914”(association)	0.530
RAB40AL	VSIG8	psi-mi:“MI:0914”(association)	0.530
RAB40C	RAB40AL	psi-mi:“MI:0914”(association)	0.350
ELSPBP1	QSOX1	psi-mi:“MI:0914”(association)	0.350
RAB40A	ARIH2	psi-mi:“MI:0914”(association)	0.350

BioGRID (36): RAB40AL (Affinity Capture-MS), RAB40AL (Affinity Capture-MS), SPTB (Affinity Capture-MS), TCEB1 (Affinity Capture-MS), ISCA1 (Affinity Capture-MS), CUL5 (Affinity Capture-MS), PSME3 (Affinity Capture-MS), FAM192A (Affinity Capture-MS), LRRC15 (Affinity Capture-MS), VSIG8 (Affinity Capture-MS), RAB40AL (Affinity Capture-MS), RAB40AL (Affinity Capture-MS), RAB40AL (Affinity Capture-MS), SPTB (Affinity Capture-MS), LRRC15 (Affinity Capture-MS)

ESM2 similar proteins: A1DZY4, A6QP66, O35626, O35929, O88910, O88954, P0C0E4, P35295, P51157, P51158, P53667, P53668, P53669, P55040, P55041, P55043, P63032, P63033, Q06AU5, Q12829, Q13368, Q13637, Q3SWY9, Q5E9J3, Q5FVY2, Q5R541, Q5RFI2, Q6DGN0, Q6IMA3, Q6IMA7, Q6IMB1, Q6P0U3, Q6T310, Q8AVS6, Q8IYK8, Q8QFP8, Q8VEL9, Q8VHP8, Q8VHQ4, Q8WXH6

Diamond homologs: A4FV54, C4YL11, F1PTE3, O01803, O24466, O35509, P01123, P0C0E4, P0CY30, P0CY31, P10536, P11620, P16976, P17609, P20790, P20791, P22125, P22127, P22128, P22129, P24409, P28186, P28188, P31584, P33723, P34140, P35280, P35281, P35286, P35289, P36861, P40392, P41924, P46638, P51153, P55258, P59190, P61006, P61007, P61026

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	1
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

89 predictions. Top by Δscore:

Variant	Effect	Δscore
X:102938001:CTA:C	acceptor_gain	0.4700
X:102937944:TGGAC:T	donor_gain	0.4400
X:102938006:GGCC:G	donor_gain	0.4400
X:102937539:G:T	donor_gain	0.4000
X:102937972:A:AC	acceptor_gain	0.3900
X:102938052:C:G	acceptor_gain	0.3700
X:102938000:GC:G	donor_gain	0.3600
X:102938048:A:AG	acceptor_gain	0.3600
X:102937974:G:GT	donor_gain	0.3500
X:102938056:C:G	acceptor_gain	0.3500
X:102937945:GGACA:G	donor_gain	0.3400
X:102938068:A:C	acceptor_gain	0.3400
X:102937446:AC:A	donor_gain	0.3300
X:102937523:GA:G	donor_gain	0.3300
X:102937524:A:G	donor_gain	0.3300
X:102938020:GATGA:G	donor_gain	0.3300
X:102938049:C:G	acceptor_gain	0.3300
X:102938226:G:GT	donor_gain	0.3300
X:102938048:ACCAC:A	acceptor_gain	0.3200
X:102938049:CCACC:C	acceptor_gain	0.3200
X:102938154:A:AC	acceptor_gain	0.3200
X:102937424:G:GT	donor_gain	0.3100
X:102937835:A:T	donor_gain	0.3100
X:102938003:A:AC	acceptor_gain	0.3100
X:102938226:G:T	donor_gain	0.3000
X:102937522:GGA:G	donor_gain	0.2900
X:102938001:C:G	donor_gain	0.2900
X:102938054:A:AG	acceptor_gain	0.2900
X:102938055:G:GG	acceptor_gain	0.2900
X:102937539:G:GT	donor_gain	0.2800

AlphaMissense

1822 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:102937784:A:C	S156R	0.990
X:102937786:C:A	S156R	0.990
X:102937786:C:G	S156R	0.990
X:102937752:C:A	A145D	0.954
X:102937691:G:T	G125W	0.943
X:102937698:G:C	R127P	0.939
X:102937622:T:C	F102L	0.938
X:102937624:C:A	F102L	0.938
X:102937624:C:G	F102L	0.938
X:102937830:C:A	A171D	0.937
X:102937799:T:C	F161L	0.936
X:102937801:C:A	F161L	0.936
X:102937801:C:G	F161L	0.936
X:102937712:T:C	F132L	0.932
X:102937714:C:A	F132L	0.932
X:102937714:C:G	F132L	0.932
X:102937596:T:A	V93D	0.931
X:102937602:A:T	D95V	0.924
X:102937689:T:A	V124E	0.921
X:102937991:T:C	F225L	0.919
X:102937993:C:A	F225L	0.919
X:102937993:C:G	F225L	0.919
X:102937407:T:C	I30T	0.914
X:102937751:G:C	A145P	0.914
X:102937696:T:A	N126K	0.911
X:102937696:T:G	N126K	0.911
X:102937692:G:A	G125E	0.908
X:102937598:T:G	Y94D	0.907
X:102937785:G:T	S156I	0.905
X:102937803:A:T	N162I	0.903

dbSNP variants (sampled 300 via entrez): RS1001688776 (X:102936158 G>T), RS1002851918 (X:102938672 G>A), RS1002904314 (X:102938228 A>C), RS1005966159 (X:102937281 T>C,G), RS1006434356 (X:102936874 G>A), RS1007835216 (X:102938131 CAG>C), RS1009879217 (X:102935348 G>A), RS1011498309 (X:102938172 A>G), RS1014769264 (X:102936890 A>C), RS1015227530 (X:102936247 A>G), RS1016486320 (X:102938410 GA>G), RS1020244082 (X:102938198 A>C,T), RS1023931967 (X:102936104 A>G), RS1030285196 (X:102936970 T>G), RS1033303416 (X:102935300 G>A)

Disease associations

OMIM: gene MIM:300405 | disease phenotypes:

GenCC curated gene-disease

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
X-linked syndromic intellectual disability	Refuted	XL

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

4 total (human), top 4 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases methylation	1
Estradiol	affects expression	1
Valproic Acid	increases methylation	1
S-Nitrosoglutathione	increases expression	1

Clinical trials (associated diseases)

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