ALS2CL

Summary

ALS2CL (ALS2 C-terminal like, HGNC:20605) is a protein-coding gene on chromosome 3p21.31, encoding ALS2 C-terminal-like protein (Q60I27). Acts as a guanine nucleotide exchange factor (GEF) for Rab5 GTPase.

Predicted to enable guanyl-nucleotide exchange factor activity and small GTPase binding activity. Predicted to be involved in endosomal transport. Predicted to act upstream of or within protein localization. Predicted to be located in cytosol. Predicted to be active in cytoplasmic vesicle.

Source: NCBI Gene 259173 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 188 total — 2 pathogenic
• MANE Select transcript: NM_147129

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20605
Approved symbol	ALS2CL
Name	ALS2 C-terminal like
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	FLJ36525, RN49018, DKFZp686I0110
Ensembl gene	ENSG00000178038
Ensembl biotype	protein_coding
OMIM	612402
Entrez	259173

Gene structure

Transcript identifiers

Ensembl transcripts: 33 — 25 protein_coding, 4 retained_intron, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000318962, ENST00000383742, ENST00000415953, ENST00000423707, ENST00000431015, ENST00000434140, ENST00000450172, ENST00000473484, ENST00000486301, ENST00000498817, ENST00000860443, ENST00000860444, ENST00000860445, ENST00000860446, ENST00000860447, ENST00000860448, ENST00000860449, ENST00000860450, ENST00000860451, ENST00000860452, ENST00000917202, ENST00000950701, ENST00000950702, ENST00000950703, ENST00000950704, ENST00000950705, ENST00000950706, ENST00000950707, ENST00000950708, ENST00000950709, ENST00000950710, ENST00000950711, ENST00000950712

RefSeq mRNA: 2 — MANE Select: NM_147129 NM_001190707, NM_147129

CCDS: CCDS2743

Canonical transcript exons

ENST00000318962 — 26 exons

Exon	Start	End
ENSE00001343233	46668995	46671064
ENSE00001498434	46693643	46693679
ENSE00001597419	46675618	46675686
ENSE00003468968	46673339	46673381
ENSE00003488335	46680430	46680541
ENSE00003495181	46671884	46672033
ENSE00003535207	46678259	46678389
ENSE00003537030	46681500	46681598
ENSE00003543155	46676849	46677022
ENSE00003544227	46676642	46676738
ENSE00003559345	46681246	46681407
ENSE00003605872	46671488	46671584
ENSE00003611381	46674566	46674739
ENSE00003672513	46676245	46676402
ENSE00003676983	46672140	46672201
ENSE00003685804	46679210	46679287
ENSE00003711522	46685525	46685644
ENSE00003713471	46683989	46684047
ENSE00003713517	46682029	46682094
ENSE00003714574	46687619	46687684
ENSE00003718819	46686983	46687148
ENSE00003727999	46683130	46683326
ENSE00003735913	46689338	46689465
ENSE00003738286	46683782	46683848
ENSE00003742078	46688098	46688296
ENSE00003750503	46686308	46686439

Expression profiles

Bgee: expression breadth ubiquitous, 263 present calls, max score 99.02.

FANTOM5 (CAGE): breadth broad, TPM avg 1.9749 / max 187.1295, expressed in 630 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
41998	1.4945	559
41997	0.4805	215

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	99.02	gold quality
esophagus mucosa	UBERON:0002469	97.41	gold quality
metanephros cortex	UBERON:0010533	97.18	gold quality
skin of abdomen	UBERON:0001416	96.97	gold quality
right lobe of thyroid gland	UBERON:0001119	96.78	gold quality
skin of leg	UBERON:0001511	96.66	gold quality
apex of heart	UBERON:0002098	96.40	gold quality
left lobe of thyroid gland	UBERON:0001120	96.15	gold quality
thyroid gland	UBERON:0002046	94.92	gold quality
pharyngeal mucosa	UBERON:0000355	94.49	gold quality
zone of skin	UBERON:0000014	94.33	gold quality
body of tongue	UBERON:0011876	94.07	gold quality
vena cava	UBERON:0004087	93.80	silver quality
vagina	UBERON:0000996	93.78	gold quality
upper lobe of left lung	UBERON:0008952	93.45	gold quality
heart left ventricle	UBERON:0002084	93.11	gold quality
diaphragm	UBERON:0001103	93.04	silver quality
lateral nuclear group of thalamus	UBERON:0002736	93.04	silver quality
pancreatic ductal cell	CL:0002079	92.93	silver quality
cardiac ventricle	UBERON:0002082	92.90	gold quality
cervix squamous epithelium	UBERON:0006922	92.54	gold quality
minor salivary gland	UBERON:0001830	92.43	gold quality
lateral globus pallidus	UBERON:0002476	92.31	gold quality
olfactory bulb	UBERON:0002264	92.24	silver quality
mouth mucosa	UBERON:0003729	92.19	gold quality
upper lobe of lung	UBERON:0008948	92.08	gold quality
upper arm skin	UBERON:0004263	92.07	gold quality
tongue	UBERON:0001723	91.99	gold quality
right lung	UBERON:0002167	91.85	gold quality
mucosa of transverse colon	UBERON:0004991	91.80	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-119	yes	30.71
E-ANND-3	yes	4.94

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

74 targeting ALS2CL, 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-513A-5P	100.00	69.77	2465
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-4658	99.77	64.94	514
HSA-MIR-6790-5P	99.77	65.24	505
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-4470	99.66	69.35	1767
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-6727-3P	99.49	65.92	1333
HSA-MIR-940	99.37	66.14	2064

Literature-anchored findings (GeneRIF, showing 4)

• These results suggest that amyotrophic lateral sclerosis 2 C-terminal like (ALS2CL), a novel ALS2 homologue, modulates Rab5-mediated endosome dynamics in HeLa cells. (PMID:15388334)
• ALS2CL is a novel ALS2-interacting protein implicated in ALS2-mediated endosome dynamics. (PMID:17239822)
• Data provide further support that ALS2CL, EPHA3, and CMYA1 are bona-fide tumor-suppressor genes and contribute to the tumorigenesis of HNSCC. (PMID:20657180)
• This supports the notion that de novo mutations in ALS2CL are extremely rare in schizophrenia (PMID:23425335)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Als2cl	ENSMUSG00000044037
rattus_norvegicus	Als2cl	ENSRNOG00000033921
drosophila_melanogaster	CG14490	FBGN0034281

Paralogs (7): MORN1 (ENSG00000116151), MORN3 (ENSG00000139714), SETD7 (ENSG00000145391), RSPH10B (ENSG00000155026), RSPH1 (ENSG00000160188), RSPH10B2 (ENSG00000169402), MORN2 (ENSG00000188010)

Protein

Protein identifiers

ALS2 C-terminal-like protein — Q60I27 (reviewed: Q60I27)

All UniProt accessions (3): G5E9N5, H7C0M4, Q60I27

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a guanine nucleotide exchange factor (GEF) for Rab5 GTPase. Regulates the ALS2-mediated endosome dynamics.

Subunit / interactions. Homodimer. Forms a heteromeric complex with ALS2. Interacts with ALS2 and RAB5A.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed in heart and kidney.

Isoforms (6)

UniProt ID	Names	Canonical?
Q60I27-1	1	yes
Q60I27-2	2
Q60I27-3	3
Q60I27-4	4
Q60I27-5	5
Q60I27-6	6

RefSeq proteins (2): NP_001177636, NP_667340* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003123	VPS9	Domain
IPR003409	MORN	Repeat
IPR035899	DBL_dom_sf	Homologous_superfamily
IPR037191	VPS9_dom_sf	Homologous_superfamily
IPR051984	Alsin	Family
IPR057248	Alsin-like_PH	Domain

Pfam: PF02204, PF02493, PF25383

UniProt features (23 total): repeat 8, splice variant 5, sequence variant 4, sequence conflict 4, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q60I27-F1	80.50	0.21

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-8876198	RAB GEFs exchange GTP for GDP on RABs
R-HSA-199991	Membrane Trafficking
R-HSA-5653656	Vesicle-mediated transport
R-HSA-9007101	Rab regulation of trafficking

MSigDB gene sets: 141 (showing top): AP1_01, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, GOMF_GTPASE_BINDING, RICKMAN_METASTASIS_DN, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, TGANTCA_AP1_C, RYTTCCTG_ETS2_B, NFE2_01, TGGAAA_NFAT_Q4_01, GAVIN_FOXP3_TARGETS_CLUSTER_P4, GAL_LEUKEMIC_STEM_CELL_UP, GOMF_GUANYL_NUCLEOTIDE_EXCHANGE_FACTOR_ACTIVITY, ZHENG_GLIOBLASTOMA_PLASTICITY_UP, GOMF_ENZYME_ACTIVATOR_ACTIVITY

GO Biological Process (1): endosomal transport (GO:0016197)

GO Molecular Function (4): guanyl-nucleotide exchange factor activity (GO:0005085), GTPase activator activity (GO:0005096), small GTPase binding (GO:0031267), protein binding (GO:0005515)

GO Cellular Component (3): cytoplasm (GO:0005737), cytosol (GO:0005829), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Rab regulation of trafficking	1
Vesicle-mediated transport	1
Membrane Trafficking	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
GTPase regulator activity	2
cellular anatomical structure	2
cytoplasm	2
vesicle-mediated transport	1
intracellular transport	1
GTP binding	1
GDP binding	1
GTPase activity	1
enzyme activator activity	1
GTPase binding	1
binding	1
intracellular anatomical structure	1
intracellular vesicle	1

Protein interactions and networks

STRING

832 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALS2CL	RAB5A	P20339	799
ALS2CL	EEA1	Q15075	700
ALS2CL	ATXN2L	Q8WWM7	644
ALS2CL	ARHGAP17	Q68EM7	636
ALS2CL	RABIF	P47224	563
ALS2CL	ANO2	Q9NQ90	560
ALS2CL	ARHGEF19	Q8IW93	559
ALS2CL	ZMIZ2	Q8NF64	559
ALS2CL	BLTP1	Q2LD37	529
ALS2CL	LACRT	Q9GZZ8	528
ALS2CL	EXOC3L4	Q17RC7	505
ALS2CL	NAALAD2	Q9Y3Q0	483
ALS2CL	SNX16	P57768	474
ALS2CL	DERL3	Q96Q80	471
ALS2CL	MICALL2	Q8IY33	459

IntAct

23 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
RAB31	ALS2CL	psi-mi:“MI:0915”(physical association)	0.560
ALS2CL	EEF1AKMT3	psi-mi:“MI:0915”(physical association)	0.560
ALS2CL	RSPH14	psi-mi:“MI:0915”(physical association)	0.560
RAB5C	ALS2CL	psi-mi:“MI:0915”(physical association)	0.560
ALS2CL	RAB22A	psi-mi:“MI:0915”(physical association)	0.560
ALS2CL	SAXO4	psi-mi:“MI:0915”(physical association)	0.560
ALS2CL	POTEF	psi-mi:“MI:0914”(association)	0.350
RAB31	ALS2CL	psi-mi:“MI:0915”(physical association)	0.000
RAB5C	ALS2CL	psi-mi:“MI:0915”(physical association)	0.000
EEF1AKMT3	ALS2CL	psi-mi:“MI:0915”(physical association)	0.000
RSPH14	ALS2CL	psi-mi:“MI:0915”(physical association)	0.000
RAB22A	ALS2CL	psi-mi:“MI:0915”(physical association)	0.000
SAXO4	ALS2CL	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (10): RAB5A (Reconstituted Complex), ALS2CL (Two-hybrid), ALS2CL (Two-hybrid), ALS2CL (Two-hybrid), ALS2CL (Two-hybrid), ALS2CL (Two-hybrid), ALS2CL (Two-hybrid), ALS2 (Affinity Capture-MS), POTEF (Affinity Capture-MS), ALS2CL (Negative Genetic)

ESM2 similar proteins: A0JNQ6, A6NC42, A6NGQ2, A6NGR9, A6QP75, A7E3N7, A9X185, E1BDF2, E9PGG2, F6SZT2, P0C7A0, P85965, Q06VW1, Q0ZFW8, Q14DK4, Q3UK37, Q3UV16, Q3ZBN4, Q400G9, Q4VXA5, Q587J8, Q5JSQ8, Q60953, Q60I26, Q60I27, Q6NUI2, Q6ZUX3, Q810I0, Q8BH06, Q8C0R7, Q8IWB1, Q8IWY9, Q8IYX4, Q8K4C2, Q8N6L0, Q8N7F7, Q8NCV1, Q8TE82, Q91WA6, Q95JV3

Diamond homologs: A6QP75, P0C5Y8, Q5BIW4, Q60I26, Q60I27, Q920R0, Q96Q42, F1RD40, F2Z461, O75592, O95199, O95714, P18754, P23800, P25183, P52499, Q15034, Q15751, Q4U2R1, Q52KW8, Q5DX34, Q5GLZ8, Q5PQN1, Q5RCZ7, Q6NRS1, Q6NXM2, Q6PAV2, Q6ZPR6, Q7TPH6, Q80YD6, Q8BK67, Q8BTU7, Q8IVU3, Q8NDN9, Q8VE37, Q90XC2, Q96I51, Q9FJG9, Q9FN03, Q9P258

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	148
Likely benign	9
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1341974	GRCh37/hg19 3p21.31(chr3:44948482-49115809)x1	Pathogenic
144168	GRCh38/hg38 3p21.31-21.2(chr3:45879883-50749922)x4	Pathogenic

SpliceAI

5258 predictions. Top by Δscore:

Variant	Effect	Δscore
3:46671060:CAGGA:C	acceptor_gain	1.0000
3:46671065:C:CC	acceptor_gain	1.0000
3:46671482:CCTTA:C	donor_loss	1.0000
3:46671484:TTA:T	donor_loss	1.0000
3:46671485:TA:T	donor_loss	1.0000
3:46671487:C:CA	donor_loss	1.0000
3:46671604:C:CT	acceptor_gain	1.0000
3:46671605:A:T	acceptor_gain	1.0000
3:46671612:C:CT	acceptor_gain	1.0000
3:46671613:G:T	acceptor_gain	1.0000
3:46672138:A:AC	donor_gain	1.0000
3:46672139:C:CC	donor_gain	1.0000
3:46674559:GGCTT:G	donor_loss	1.0000
3:46674560:GCTTA:G	donor_loss	1.0000
3:46674561:CTTA:C	donor_loss	1.0000
3:46674562:TTA:T	donor_loss	1.0000
3:46674563:TA:T	donor_loss	1.0000
3:46674564:A:AC	donor_gain	1.0000
3:46674564:A:AT	donor_loss	1.0000
3:46674564:ACTT:A	donor_gain	1.0000
3:46674565:C:CA	donor_gain	1.0000
3:46674565:CT:C	donor_gain	1.0000
3:46674565:CTT:C	donor_gain	1.0000
3:46674565:CTTC:C	donor_gain	1.0000
3:46674566:TTCTG:T	donor_gain	1.0000
3:46674567:T:TA	donor_gain	1.0000
3:46674567:TCTGC:T	donor_gain	1.0000
3:46674575:T:TA	donor_gain	1.0000
3:46674735:GGTCC:G	acceptor_gain	1.0000
3:46674736:GTCC:G	acceptor_gain	1.0000

AlphaMissense

6186 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:46671890:C:G	R893P	0.982
3:46672152:A:G	L841P	0.980
3:46671908:A:G	L887P	0.979
3:46671506:G:C	F921L	0.978
3:46671506:G:T	F921L	0.978
3:46671508:A:G	F921L	0.978
3:46674590:A:G	L802P	0.978
3:46681535:C:A	W413C	0.978
3:46681535:C:G	W413C	0.978
3:46671920:A:G	L883P	0.977
3:46672172:G:C	F834L	0.977
3:46672172:G:T	F834L	0.977
3:46672174:A:G	F834L	0.977
3:46683198:G:C	F347L	0.977
3:46683198:G:T	F347L	0.977
3:46683200:A:G	F347L	0.977
3:46672173:A:G	F834S	0.976
3:46676343:G:C	F696L	0.976
3:46676343:G:T	F696L	0.976
3:46676345:A:G	F696L	0.976
3:46681537:A:G	W413R	0.976
3:46681537:A:T	W413R	0.976
3:46683155:A:G	W362R	0.976
3:46683155:A:T	W362R	0.976
3:46671492:A:G	L926P	0.974
3:46671888:C:G	A894P	0.973
3:46681595:G:C	F393L	0.973
3:46681595:G:T	F393L	0.973
3:46681597:A:G	F393L	0.973
3:46682086:A:G	L373P	0.973

dbSNP variants (sampled 300 via entrez): RS1000295317 (3:46695061 C>T), RS1000350399 (3:46688778 G>A), RS1000423727 (3:46689154 G>C), RS1000559691 (3:46673023 A>G), RS1000804966 (3:46672889 C>G), RS1000928780 (3:46685362 C>G,T), RS1001011639 (3:46685174 T>C), RS1001069744 (3:46678861 T>C), RS1001277757 (3:46684073 A>G), RS1001552614 (3:46668995 C>T), RS1001582067 (3:46668622 C>A,T), RS1001647294 (3:46673761 C>G,T), RS1001735289 (3:46680130 A>G), RS1001968681 (3:46674517 G>A), RS1002075295 (3:46680142 G>A)

Disease associations

OMIM: gene MIM:612402 | disease phenotypes: MIM:615760

GenCC curated gene-disease

Mondo (1): diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome (MONDO:0014335)

Orphanet (1): Diffuse cerebral and cerebellar atrophy-intractable seizures-progressive microcephaly syndrome (Orphanet:404437)

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

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	4
Zoledronic Acid	increases expression	2
Calcitriol	increases expression, affects cotreatment	2
Cisplatin	affects expression, affects cotreatment, increases expression	2
Cyclosporine	increases expression	2
chloroacetaldehyde	affects expression	1
ethyl-p-hydroxybenzoate	increases expression	1
beta-lapachone	decreases expression, increases expression	1
perfluorooctanoic acid	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
adefovir dipivoxil	increases expression	1
2-palmitoylglycerol	increases expression	1
nutlin 3	affects cotreatment, increases expression	1
bisphenol S	affects cotreatment, decreases expression	1
jinfukang	increases expression, affects cotreatment	1
Cidofovir	affects expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Camptothecin	increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Clodronic Acid	affects expression	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Ifosfamide	affects expression	1
Indomethacin	affects cotreatment, decreases expression	1
Oxygen	decreases expression	1
Selenium	increases expression	1
Testosterone	affects cotreatment, increases expression	1
Tetrachlorodibenzodioxin	increases expression	1

Clinical trials (associated diseases)

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