ALS2

Summary

ALS2 (alsin Rho guanine nucleotide exchange factor ALS2, HGNC:443) is a protein-coding gene on chromosome 2q33.1, encoding Alsin (Q96Q42). May act as a GTPase regulator.

The protein encoded by this gene contains an ATS1/RCC1-like domain, a RhoGEF domain, and a vacuolar protein sorting 9 (VPS9) domain, all of which are guanine-nucleotide exchange factors that activate members of the Ras superfamily of GTPases. The protein functions as a guanine nucleotide exchange factor for the small GTPase RAB5. The protein localizes with RAB5 on early endosomal compartments, and functions as a modulator for endosomal dynamics. Mutations in this gene result in several forms of juvenile lateral sclerosis and infantile-onset ascending spastic paralysis. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 57679 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ALS2-related motor neuron disease (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 1,216 total — 71 pathogenic, 44 likely-pathogenic (top 2% of genes corpus-wide)
• Regional missense constraint (gnomAD): 1 of 3 regions constrained (≈2% of expected missense variation)
• GTEx eGene: eQTL in 42 tissues, sQTL in 10 (q < 0.05)
• Phenotypes (HPO): 98
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.65 (unconstrained)
• MANE Select transcript: NM_020919

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:443
Approved symbol	ALS2
Name	alsin Rho guanine nucleotide exchange factor ALS2
Location	2q33.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000003393
Ensembl biotype	protein_coding
OMIM	606352
Entrez	57679

Gene structure

Transcript identifiers

Ensembl transcripts: 87 — 33 protein_coding, 23 nonsense_mediated_decay, 21 retained_intron, 10 protein_coding_CDS_not_defined

MANE Select: ENST00000264276

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 4, TSL 2: 1, TSL 3: 4, TSL 4: 3

ENST00000264276, ENST00000409632, ENST00000410052, ENST00000439495, ENST00000462747, ENST00000467448, ENST00000482789, ENST00000482891, ENST00000483703, ENST00000489440, ENST00000494017, ENST00000496244, ENST00000679409, ENST00000679416, ENST00000679427, ENST00000679435, ENST00000679503, ENST00000679516, ENST00000679549, ENST00000679550, ENST00000679618, ENST00000679630, ENST00000679635, ENST00000679686, ENST00000679701, ENST00000679728, ENST00000679916, ENST00000679939, ENST00000679949, ENST00000680000, ENST00000680135, ENST00000680149, ENST00000680163, ENST00000680174, ENST00000680188, ENST00000680236, ENST00000680287, ENST00000680404, ENST00000680441, ENST00000680497, ENST00000680508, ENST00000680569, ENST00000680630, ENST00000680634, ENST00000680644, ENST00000680722, ENST00000680723, ENST00000680726, ENST00000680737, ENST00000680759, ENST00000680814, ENST00000680819, ENST00000680828, ENST00000680861, ENST00000680927, ENST00000680939, ENST00000681144, ENST00000681152, ENST00000681250, ENST00000681256, ENST00000681279, ENST00000681303, ENST00000681307, ENST00000681312, ENST00000681378, ENST00000681461, ENST00000681495, ENST00000681558, ENST00000681619, ENST00000681663, ENST00000681692, ENST00000681716, ENST00000681758, ENST00000681768, ENST00000681808, ENST00000905985, ENST00000925368, ENST00000942930, ENST00000942931, ENST00000992883, ENST00000992884, ENST00001079440, ENST00001079442, ENST00001108045, ENST00001114688, ENST00001114689, ENST00001138643

RefSeq mRNA: 3 — MANE Select: NM_020919 NM_001135745, NM_001410975, NM_020919

CCDS: CCDS42800, CCDS46492, CCDS92925

Canonical transcript exons

ENST00000264276 — 34 exons

Exon	Start	End
ENSE00000934613	201700267	201701889
ENSE00001932788	201780877	201780933
ENSE00003469997	201723043	201723120
ENSE00003498649	201768866	201768945
ENSE00003505470	201738670	201738735
ENSE00003513641	201727212	201727278
ENSE00003525905	201715672	201715839
ENSE00003526371	201726664	201726866
ENSE00003537621	201753146	201753242
ENSE00003546342	201710991	201711108
ENSE00003553880	201705416	201705461
ENSE00003554077	201718077	201718210
ENSE00003567371	201704122	201704218
ENSE00003569651	201725356	201725454
ENSE00003595325	201724295	201724459
ENSE00003600534	201704454	201704603
ENSE00003602119	201706846	201707022
ENSE00003608497	201729052	201729183
ENSE00003615171	201757402	201757759
ENSE00003617570	201754503	201754671
ENSE00003619728	201767229	201767383
ENSE00003629440	201760881	201761818
ENSE00003631470	201746566	201746748
ENSE00003636929	201727705	201727775
ENSE00003644854	201749712	201749789
ENSE00003653809	201707869	201707991
ENSE00003656488	201723330	201723441
ENSE00003659416	201728512	201728640
ENSE00003661001	201741674	201741854
ENSE00003662379	201744258	201744429
ENSE00003667861	201709881	201710038
ENSE00003667933	201726484	201726549
ENSE00003673437	201733276	201733438
ENSE00003692637	201705139	201705200

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 96.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.3030 / max 372.8987, expressed in 1785 samples.

Highest expression (Bgee): cerebellum, cerebellar cortex, cerebellar hemisphere, hemisphere of cerebellum, cerebellar vermis.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ALS2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 42 tissues and its splicing (sQTL) in 10 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 52 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	eqtl	3.1e-49	+0.54	2:201774475:A:G
Skin Sun Exposed Lower leg	eqtl	6.8e-33	-0.46	2:201756279:T:C
Nerve Tibial	eqtl	1.8e-32	-0.42	2:201781238:C:T
Skin Not Sun Exposed Suprapubic	eqtl	6.0e-31	-0.50	2:201756279:T:C
Esophagus Mucosa	eqtl	1.4e-30	-0.55	2:201781238:C:T
Adipose Subcutaneous	eqtl	1.4e-29	-0.45	2:201781238:C:T
Cells Cultured fibroblasts	eqtl	1.5e-26	-0.41	2:201756901:AT:A
Artery Tibial	eqtl	7.3e-25	-0.40	2:201781238:C:T
Cells EBV-transformed lymphocytes	eqtl	1.6e-24	-0.70	2:201790118:A:G
Adipose Visceral Omentum	eqtl	1.8e-24	-0.45	2:201781238:C:T
Thyroid	eqtl	4.1e-23	-0.39	2:201781238:C:T
Breast Mammary Tissue	eqtl	1.3e-22	-0.42	2:201781238:C:T
Lung	eqtl	1.4e-21	-0.50	2:201781238:C:T
Artery Aorta	eqtl	1.4e-20	-0.38	2:201781238:C:T
Esophagus Gastroesophageal Junction	eqtl	2.0e-20	-0.44	2:201781238:C:T
Esophagus Muscularis	eqtl	1.4e-19	-0.44	2:201781238:C:T
Spleen	eqtl	1.0e-17	-0.57	2:201781238:C:T
Colon Transverse	eqtl	1.4e-17	+0.31	2:201783485:AT:A
Colon Sigmoid	eqtl	5.3e-16	-0.47	2:201781238:C:T
Brain Hippocampus	eqtl	1.7e-11	+0.33	2:201774475:A:G

FANTOM5 promoters

7 alternative TSS:

Promoter ID	TPM avg	Samples expressed
33262	14.5581	1784
33263	0.2087	94
33264	0.1752	63
33265	0.1660	62
33259	0.1478	34
33260	0.0264	3
33261	0.0207	7

Top tissues by expression

showing 100 of 260 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
cerebellum	UBERON:0002037	96.76	gold quality
cerebellar cortex	UBERON:0002129	96.72	gold quality
cerebellar hemisphere	UBERON:0002245	96.71	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.21	gold quality
cerebellar vermis	UBERON:0004720	95.08	gold quality
tibialis anterior	UBERON:0001385	93.64	gold quality
left ventricle myocardium	UBERON:0006566	93.12	gold quality
cardiac muscle of right atrium	UBERON:0003379	90.53	gold quality
deltoid	UBERON:0001476	90.36	gold quality
sural nerve	UBERON:0015488	90.26	gold quality
middle temporal gyrus	UBERON:0002771	89.48	gold quality
cortical plate	UBERON:0005343	89.18	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.95	gold quality
myocardium	UBERON:0002349	88.89	gold quality
calcaneal tendon	UBERON:0003701	88.51	gold quality
Brodmann (1909) area 46	UBERON:0006483	87.60	gold quality
adrenal tissue	UBERON:0018303	87.44	gold quality
oviduct epithelium	UBERON:0004804	87.37	gold quality
ileal mucosa	UBERON:0000331	86.95	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	86.56	gold quality
biceps brachii	UBERON:0001507	86.41	gold quality
secondary oocyte	CL:0000655	86.32	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.31	gold quality
islet of Langerhans	UBERON:0000006	86.20	gold quality
skeletal muscle tissue	UBERON:0001134	86.03	gold quality
ventricular zone	UBERON:0003053	85.88	gold quality
colonic epithelium	UBERON:0000397	85.78	gold quality
muscle tissue	UBERON:0002385	85.71	gold quality
postcentral gyrus	UBERON:0002581	85.71	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	85.59	gold quality
embryo	UBERON:0000922	85.42	gold quality
ganglionic eminence	UBERON:0004023	85.42	gold quality
muscle of leg	UBERON:0001383	85.41	gold quality
skeletal muscle organ	UBERON:0014892	85.38	gold quality
heart left ventricle	UBERON:0002084	85.37	gold quality
cardiac ventricle	UBERON:0002082	85.26	gold quality
superior frontal gyrus	UBERON:0002661	85.09	gold quality
gastrocnemius	UBERON:0001388	85.08	gold quality
liver	UBERON:0002107	84.83	gold quality
heart	UBERON:0000948	84.78	gold quality
frontal cortex	UBERON:0001870	84.57	gold quality
cardiac atrium	UBERON:0002081	84.55	gold quality
prefrontal cortex	UBERON:0000451	84.47	gold quality
right frontal lobe	UBERON:0002810	84.41	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	84.37	gold quality
pigmented layer of retina	UBERON:0001782	84.33	gold quality
Brodmann (1909) area 23	UBERON:0013554	84.31	gold quality
parietal lobe	UBERON:0001872	84.26	gold quality
right atrium auricular region	UBERON:0006631	84.26	gold quality
quadriceps femoris	UBERON:0001377	84.13	gold quality
right lobe of liver	UBERON:0001114	84.03	gold quality
neocortex	UBERON:0001950	83.99	gold quality
Brodmann (1909) area 9	UBERON:0013540	83.85	gold quality
bone marrow cell	CL:0002092	83.84	gold quality
heart right ventricle	UBERON:0002080	83.81	gold quality
pons	UBERON:0000988	83.68	gold quality
stromal cell of endometrium	CL:0002255	83.55	gold quality
apex of heart	UBERON:0002098	83.49	gold quality
cerebral cortex	UBERON:0000956	83.37	gold quality
corpus callosum	UBERON:0002336	83.33	gold quality
brain	UBERON:0000955	83.16	gold quality
vastus lateralis	UBERON:0001379	83.02	gold quality
pancreatic ductal cell	CL:0002079	82.83	silver quality
hindlimb stylopod muscle	UBERON:0004252	82.80	gold quality
tibial nerve	UBERON:0001323	82.50	gold quality
bronchial epithelial cell	CL:0002328	82.42	gold quality
tendon	UBERON:0000043	82.35	gold quality
primary visual cortex	UBERON:0002436	82.19	gold quality
bronchus	UBERON:0002185	81.83	gold quality
skin of hip	UBERON:0001554	81.82	gold quality
smooth muscle tissue	UBERON:0001135	81.76	gold quality
adenohypophysis	UBERON:0002196	81.61	gold quality
pituitary gland	UBERON:0000007	81.58	gold quality
anterior cingulate cortex	UBERON:0009835	81.54	gold quality
forebrain	UBERON:0001890	81.52	gold quality
occipital lobe	UBERON:0002021	81.38	gold quality
upper leg skin	UBERON:0004262	81.04	gold quality
tibia	UBERON:0000979	81.03	gold quality
epithelial cell of pancreas	CL:0000083	81.00	silver quality
fallopian tube	UBERON:0003889	80.91	gold quality
pancreas	UBERON:0001264	80.76	gold quality
Ammon’s horn	UBERON:0001954	80.67	gold quality
descending thoracic aorta	UBERON:0002345	80.49	gold quality
adult mammalian kidney	UBERON:0000082	80.43	gold quality
entorhinal cortex	UBERON:0002728	80.38	gold quality
germinal epithelium of ovary	UBERON:0001304	80.31	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	80.20	gold quality
thoracic aorta	UBERON:0001515	80.14	gold quality
ascending aorta	UBERON:0001496	80.09	gold quality
gall bladder	UBERON:0002110	80.04	gold quality
aorta	UBERON:0000947	79.89	gold quality
cortex of kidney	UBERON:0001225	79.87	gold quality
body of uterus	UBERON:0009853	79.86	gold quality
stomach	UBERON:0000945	79.85	gold quality
tibial artery	UBERON:0007610	79.78	gold quality
popliteal artery	UBERON:0002250	79.77	gold quality
mucosa of stomach	UBERON:0001199	79.69	gold quality
left coronary artery	UBERON:0001626	79.58	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	79.55	gold quality
lower esophagus muscularis layer	UBERON:0035833	79.52	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	12.88
E-MTAB-9067	yes	11.78
E-ANND-3	yes	10.65
E-MTAB-9801	yes	6.01

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Cerebellum	tissue	129.9	high
Cerebral cortex	tissue	31.8	medium
Somatosensory cortex	tissue	31.8
Occipital cortex	tissue	31.0
Hippocampal formation	tissue	28.6
Entorhinal cortex	tissue	28.6
Temporal cortex	tissue	28.4
Prefrontal cortex	tissue	28.1
Retrosplenial and cingulate cortex	tissue	27.7
Motor cortex	tissue	27.3
Insular cortex	tissue	26.0
Putamen	tissue	25.1
Retrosplenial cortex	tissue	25.0
Midbrain	tissue	23.8
Thalamus	tissue	21.9
Basal ganglia	tissue	21.8	not detected
Amygdala	tissue	21.7
Medulla oblongata	tissue	20.9
Superior colliculi	tissue	20.9
Pons	tissue	20.8
Ventral forebrain	tissue	20.8
Hypothalamus	tissue	20.4
Choroid plexus	tissue	19.5
Substantia nigra	tissue	19.1
Spinal cord	tissue	19.1
Septum	tissue	18.8
Corpus callosum	tissue	18.7
Periaqueductal gray	tissue	18.6
Postcentral gyrus	tissue	18.3
Olfactory bulb	tissue	16.7
Frontal cortex	tissue	13.3
Hippocampus	tissue	12.7	low
Locus coeruleus	tissue	12.3
Caudate putamen	tissue	12.3
Nucleus accumbens	tissue	12.1
Heart muscle	tissue	9.4	medium
Liver	tissue	8.3	medium
Epididymis	tissue	7.3	low
Tongue	tissue	5.5
Bone marrow	tissue	5.4	not detected
Retina	tissue	5.2
Kidney	tissue	4.6	high
Breast	tissue	4.5	medium
Smooth muscle	tissue	4.4	low
Adipose tissue	tissue	4.3	not detected
Skeletal muscle	tissue	4.3	low
Parathyroid gland	tissue	4.0	medium
Thyroid gland	tissue	4.0	low
Prostate	tissue	3.9	medium
Lung	tissue	3.7	medium
Pituitary gland	tissue	3.6
Skin 1	tissue	3.6	medium
Endometrium 1	tissue	3.6	medium
Testis	tissue	3.5	high
Urinary bladder	tissue	3.5	medium
Gallbladder	tissue	3.5	medium
Fallopian tube	tissue	3.5	medium
Stomach 1	tissue	3.4	medium
Placenta	tissue	3.3	low
Esophagus	tissue	3.1	low

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Vermis (64.3), Flocculonodular lobe (62.3), Cerebellar cortex (57.5), Subiculum (22.6), Ventral hippocampus (20.9).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF1, NFE2L2

miRNA regulators (miRDB)

Targeting ALS2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 98 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-323A-3P	99.79	70.30	1739

Functional genomics

gnomAD constraint: pLI 2.82e-17, LOEUF 0.649, missense Z 2.97 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000264276 splits into 3 regions with different missense tolerance; 1 is missense-constrained (≈2% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
2:201,701,854–201,757,416	1227 / 1413.5	0.87	no
2:201,757,417–201,757,513	12 / 36.6	0.33	yes (p 4.8e-05)
2:201,757,514–201,768,885	476 / 539.3	0.88	no
ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• causative genes for familial amyotrophic lateral sclerosis (PMID:12138710)
• Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene. (PMID:12145748)
• 16 patients from 11 unrelated families were studied with a phenotype of infantile ascending hereditary spastic paralysis (IAHSP); Alsin mutations were found in 4 of the 10 families, whereas haplotype analysis excluded the ALS2 locus in one family (PMID:12601111)
• Perturbation of endosomal dynamics caused by loss of ALS2 rab5GEF activity might underlie neuronal dysfunction and degeneration. (PMID:12837691)
• deletion mutations in ALS2 gene detected in ALS2 patients seem to be uncommon in Japanese AR-ALS, and that SNPs in uncoding regions might possibly be relevant to predisposition to ALS. (PMID:12866199)
• A nonsense mutation in alsin was found in infantile spastic paraplegia. Full-length alsin is probably required for the proper development and/or functioning of upper motor neurons. (PMID:12919135)
• Mutations in the ALS2 gene linked to early-onset motor neuron disease uniformly produce loss of activity through decreased protein stability of this endosomal protein. (PMID:14668431)
• Mutations of ALS2 are not a common cause of ALS. (PMID:14676054)
• Expression of alsin LF, but not alsin short form, protected motor neuronal cells from toxicity induced by mutants of the Cu/Zn-superoxide dismutase (SOD1) gene, which cause autosomal dominant ALS (PMID:14970233)
• oligomerization of the ALS2 protein is one of the fundamental features for its physiological function involving endosome dynamics in vivo (PMID:15247254)
• A peptide derived from the ALS2 protein is selectively localized to the somatodendritic compartment of motor neurons in human spinal cord. (PMID:15371724)
• 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)
• Rac1, PI3 kinase, and Akt3 have roles in an anti-apoptotic pathway triggered by ALS2 that antagonizes SOD1 mutant-induced motoneuronal cell death (PMID:15579468)
• ALS2/Alsin has a role in regulating Rac-PAK signaling and neurite outgrowth (PMID:16049005)
• colocalization of Alsin with the centrosomal markers gamma-tubulin and A kinase anchoring protein. (PMID:16085057)
• ALS2 mutations are not implicated in the pathogenesis of adult-onset primary lateral sclerosis. (PMID:17698795)
• Autosomal recessive mutations in the ALS2 gene lead to a clinical spectrum of motor dysfunction including juvenile onset amyotrophic lateral sclerosis. [REVIEW] (PMID:17955197)
• mutations in ALS2 also need to be considered in patients from northwestern Europe with early-onset spastic paralysis and amyotrophic or primary lateral sclerosis. (PMID:18523452)
• Results suggest at least four recombination events in the ALS2 gene during maternal meiosis followed by a meiosis I error and postzygotic trisomy rescue or gamete complementation, in a patient with infantile-onset ascending spastic paralysis. (PMID:18810511)
• A structural model for the N-terminal 690-residue region of alsin through comparative modelling based on regulator of chromosome condensation 1 was created. (PMID:19023603)
• This novel ALS2 splice-site mutation is causing the loss of exon 18 in the transcript which results in a frameshift after exon 17. (PMID:19122027)
• these results suggest that Als2 is a binding partner of Uxt and Als2/Uxt interaction could be important for the activation of Nf-kappaB pathway. (PMID:21907703)
• ALS2 sequencing revealed two heterozygous mutations: the missense variant c.299 G>T, leading to the replacement of a serine with an isoleucine (p.S100I), and the splicing variant c.2580-2 A>G in brothers with juvenile amyotrophic lateral sclerosis. (PMID:23282280)
• The ALS2 mutation c.2761C>T leading to infantile-onset hereditary spastic paraplegia resides in the pleckstrin domain, which is involved in the overall neuronal development or maintenance. (PMID:24315819)
• The ALS2 gene should be screened for mutations in patients who present with generalized dystonia and cerebellar signs. (PMID:24562058)
• Data indicate a splice-site mutation of the amyotrophic lateral sclerosis 2 (juvenile) protein (ALS2) in four children of a consanguineous family with infantile-onset ascending hereditary spastic paraplegia. (PMID:24704789)
• novel compound heterozygous ALS2 deletion mutations were identified in two siblings with infantile ascending hereditary spastic paraplegia. (PMID:25433428)
• We identified a novel homozygous splice-site mutation (c.3512+1G>A) in the ALS2 gene (NM_020919.3) encoding alsin that segregated with the disease in this family (PMID:25474699)
• This study identified two novel ALS2 mutations in two Pakistani families with infantile-onset ascending hereditary spastic paraplegia cosegregating with the disease. (PMID:26751646)
• We established a genetic diagnosis in six families with autosomal recessive HSP (SPG11 in three families and TFG/SPG57, SACS and ALS2 in one family each). A heterozygous mutation in a gene involved in an autosomal dominant HSP (ATL1/SPG3A) was also identified in one additional family (PMID:27601211)
• Nonsense mutation in ALS2 gene is associated with severe and progressive infantile onset of spastic paralysis. (PMID:28502191)
• These findings define a novel pathway whereby Alsin catalyzes the assembly of the Rab5 endocytic machinery on mitochondria. Defects in stress-sensing by endosomes could be crucial for mitochondrial quality control during the onset of amyotrophic lateral sclerosis. (PMID:29469808)
• This study identified a novel ALS2 pathogenic founder variant in Iran that further adds to the allelic heterogeneity of infantile-onset ascending hereditary spastic paralysis. (PMID:30128655)
• Disorganized higher structures of ALS2 variants impaired endosomal localization and the stability, leading to loss of the ALS2 function. (PMID:30224357)
• ALS2, the small GTPase Rab17-interacting protein, regulates maturation and sorting of Rab17-associated endosomes. (PMID:31959474)
• Genotype-phenotype correlation in seven motor neuron disease families with novel ALS2 mutations. (PMID:33155358)
• ALS2-related disorders in Spanish children. (PMID:33409823)
• The N-terminal intrinsically disordered region mediates intracellular localization and self-oligomerization of ALS2. (PMID:34243065)
• Tumor-derived hypoxic small extracellular vesicles promote endothelial cell migration and tube formation via ALS2/Rab5/beta-catenin signaling. (PMID:38847490)
• Conformational Dynamics and Molecular Characterization of Alsin MORN Monomer and Dimeric Assemblies. (PMID:39023312)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	als2a	ENSDARG00000075111
danio_rerio	als2b	ENSDARG00000076924
mus_musculus	Als2	ENSMUSG00000026024
rattus_norvegicus	Als2	ENSRNOG00000023280
drosophila_melanogaster	ca	FBGN0000247
drosophila_melanogaster	Rcc1	FBGN0002638
drosophila_melanogaster	CG7420	FBGN0031344
caenorhabditis_elegans		WBGENE00004304

Paralogs (9): HERC1 (ENSG00000103657), SERGEF (ENSG00000129158), RCBTB1 (ENSG00000136144), RCBTB2 (ENSG00000136161), RPGR (ENSG00000156313), RCCD1 (ENSG00000166965), RCC2 (ENSG00000179051), RCC1 (ENSG00000180198), RCC1L (ENSG00000274523)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1921268) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 29 distinct phenotype terms.

Mouse phenotype (MP)	Records
impaired coordination	3
abnormal corticospinal tract morphology	2
abnormal Purkinje cell morphology	1
decreased Purkinje cell number	1
abnormal motor neuron morphology	1
decreased motor neuron number	1
abnormal motor neuron innervation pattern	1
abnormal neuromuscular synapse morphology	1
increased body weight	1
increased anxiety-related response	1
decreased locomotor activity	1
decreased exploration in new environment	1
neurodegeneration	1
abnormal motor learning	1
abnormal neuron morphology	1
abnormal skeletal muscle fiber morphology	1
astrocytosis	1
abnormal ventral spinal root morphology	1
abnormal physical strength	1
abnormal axonal transport	1
abnormal action potential	1
abnormal axon morphology	1
axon degeneration	1
CNS inflammation	1
increased physiological sensitivity to xenobiotic	1

+4 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pongo abelii	Q5RCZ7	100.0%	Diamond
Pan troglodytes	Q5BIW4	99.8%	Diamond
Mesocricetus auratus	P23800	97.1%	Diamond
Macaca fascicularis	Q4R828	93.9%	Diamond
Bos taurus	A6QP75	86.8%	Diamond
Xenopus laevis	Q52KW8	78.2%	Diamond
Saccharomyces cerevisiae S288C	P21827	53.7%	Diamond
Candida albicans	P52499	53.7%	Diamond
Arabidopsis thaliana	Q9FJG9	36.4%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
MPP4	protein-coding	58538
CDK15	protein-coding	65061
TMEM237	protein-coding	65062
CATSPERT	protein-coding	151254
FZD7	protein-coding	8324

Protein

Protein identifiers

Alsin — Q96Q42 (reviewed: Q96Q42)

Alternative names: Amyotrophic lateral sclerosis 2 chromosomal region candidate gene 6 protein, Amyotrophic lateral sclerosis 2 protein

All UniProt accessions (32): Q96Q42, A0A0S2Z5I4, A0A0S2Z5Q7, A0A7P0T813, A0A7P0T8F3, A0A7P0T8P3, A0A7P0T8R1, A0A7P0T8T2, A0A7P0T8W6, A0A7P0T951, A0A7P0T958, A0A7P0T976, A0A7P0T980, A0A7P0T993, A0A7P0T9K3, A0A7P0T9P3, A0A7P0T9R1, A0A7P0T9U5, A0A7P0T9V4, A0A7P0TAC4, A0A7P0TAH8, A0A7P0TAM1, A0A7P0TBB0, A0A7P0TBK0, A0A7P0Z499, A0A7P0Z4F3, A0A7P0Z4I4, A0A7P0Z4J9, A0A7P0Z4M6, H0Y696, J3KQ33, J3KQ43

UniProt curated annotations — full annotation on UniProt →

Function. May act as a GTPase regulator. Controls survival and growth of spinal motoneurons.

Subunit / interactions. Forms a heteromeric complex with ALS2CL. Interacts with ALS2CL.

Disease relevance. Amyotrophic lateral sclerosis 2 (ALS2) [MIM:205100] A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. The disease is caused by variants affecting the gene represented in this entry. Juvenile primary lateral sclerosis (JPLS) [MIM:606353] A neurodegenerative disorder which is closely related to but clinically distinct from amyotrophic lateral sclerosis. It is a progressive paralytic disorder which results from dysfunction of the upper motor neurons while the lower neurons are unaffected. The disease is caused by variants affecting the gene represented in this entry. Infantile-onset ascending spastic paralysis (IAHSP) [MIM:607225] Characterized by progressive spasticity and weakness of limbs. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96Q42-1	1	yes
Q96Q42-2	2
Q96Q42-3	3

RefSeq proteins (3): NP_001129217, NP_001397904, NP_065970* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000219	DH_dom	Domain
IPR000408	Reg_chr_condens	Repeat
IPR003123	VPS9	Domain
IPR003409	MORN	Repeat
IPR009091	RCC1/BLIP-II	Homologous_superfamily
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR035899	DBL_dom_sf	Homologous_superfamily
IPR037191	VPS9_dom_sf	Homologous_superfamily
IPR051984	Alsin	Family
IPR057248	Alsin-like_PH	Domain
IPR059093	HA_Alsin	Domain

Pfam: PF00415, PF02204, PF02493, PF25383, PF25582, PF26202

UniProt features (39 total): repeat 13, modified residue 7, sequence variant 6, splice variant 4, domain 3, compositionally biased region 2, sequence conflict 2, chain 1, region of interest 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96Q42-F1	74.69	0.40

Human Protein Atlas

Protein class: Predicted intracellular proteins, Disease related genes, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; vesicles

Antibody reliability (HPA): IH enhanced · IF approved

Functional residue map

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

Post-translational modifications (7)

Type	Positions
Phosphoserine	465, 466, 483, 492, 1335
Phosphothreonine	510
N6-acetyllysine	533

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 9; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

9 pathways:

ID	Pathway	Evidence
R-HSA-8876198	RAB GEFs exchange GTP for GDP on RABs	curated
R-HSA-9013149	RAC1 GTPase cycle	curated
R-HSA-199991	Membrane Trafficking	—
R-HSA-9012999	RHO GTPase cycle	—
R-HSA-9007101	Rab regulation of trafficking	—
R-HSA-162582	Signal Transduction	—
R-HSA-194315	Signaling by Rho GTPases	—
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3	—
R-HSA-5653656	Vesicle-mediated transport	—

MSigDB gene sets: 434 (showing top): GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, GOBP_LYSOSOMAL_TRANSPORT, GOBP_BEHAVIOR, GOBP_ENDOSOME_ORGANIZATION, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_VESICLE_ORGANIZATION, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_REGULATION_OF_GTPASE_ACTIVITY, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_VACUOLAR_TRANSPORT, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOCC_RUFFLE, REACTOME_MEMBRANE_TRAFFICKING

GO Biological Process (10): endosome organization (GO:0007032), lysosomal transport (GO:0007041), endosomal transport (GO:0016197), positive regulation of Rac protein signal transduction (GO:0035022), positive regulation of GTPase activity (GO:0043547), positive regulation of protein kinase activity (GO:0045860), neuron projection morphogenesis (GO:0048812), regulation of endosome size (GO:0051036), protein homooligomerization (GO:0051260), regulation of postsynaptic membrane neurotransmitter receptor levels (GO:0099072)

GO Molecular Function (7): guanyl-nucleotide exchange factor activity (GO:0005085), GTPase activator activity (GO:0005096), small GTPase binding (GO:0031267), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein serine/threonine kinase activator activity (GO:0043539), protein binding (GO:0005515)

GO Cellular Component (14): ruffle (GO:0001726), nucleus (GO:0005634), cytoplasm (GO:0005737), early endosome (GO:0005769), centrosome (GO:0005813), cytosol (GO:0005829), postsynaptic density (GO:0014069), lamellipodium (GO:0030027), dendrite (GO:0030425), growth cone (GO:0030426), vesicle (GO:0031982), protein-containing complex (GO:0032991), dendritic spine (GO:0043197), glutamatergic synapse (GO:0098978)

Reactome top-level categories

7 top-level categories:

Category	Pathways
Rab regulation of trafficking	1
RHO GTPase cycle	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Vesicle-mediated transport	1
Membrane Trafficking	1
Signaling by Rho GTPases	1
Signal Transduction	1

GO top-level categories

52 GO namespaces:

Category	Terms
GTPase activity	2
GTPase regulator activity	2
cell leading edge	2
plasma membrane bounded cell projection	2
cellular anatomical structure	2
endomembrane system organization	1
vesicle organization	1
vacuolar transport	1
vesicle-mediated transport	1
intracellular transport	1
Rac protein signal transduction	1
regulation of Rac protein signal transduction	1
positive regulation of small GTPase mediated signal transduction	1
regulation of GTPase activity	1
positive regulation of hydrolase activity	1
positive regulation of protein phosphorylation	1
protein kinase activity	1
positive regulation of kinase activity	1
regulation of protein kinase activity	1
neuron projection development	1
plasma membrane bounded cell projection morphogenesis	1
regulation of vesicle size	1
protein complex oligomerization	1
regulation of biological quality	1
GTP binding	1
GDP binding	1
enzyme activator activity	1
GTPase binding	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
protein serine/threonine kinase activity	1
protein kinase activator activity	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
endosome	1
centriole	1
microtubule organizing center	1
cytoplasm	1
asymmetric synapse	1
postsynaptic specialization	1
neuron projection	1
dendritic tree	1
site of polarized growth	1
distal axon	1
membrane-bounded organelle	1
cellular_component	1
dendrite	1
neuron spine	1
postsynapse	1
synapse	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 19 of 31 annotations. The rest are phylogenetic / computational / electronic (IEA).

19 experimentally-supported GO terms:

GO term	NS	Evidence
lysosomal transport	BP	direct assay
neuron projection morphogenesis	BP	direct assay
positive regulation of GTPase activity	BP	direct assay
positive regulation of protein kinase activity	BP	direct assay
protein homooligomerization	BP	direct assay
regulation of endosome size	BP	expression pattern
centrosome	CC	direct assay
cytosol	CC	direct assay
dendrite	CC	direct assay
early endosome	CC	direct assay
nucleus	CC	direct assay
protein-containing complex	CC	direct assay
vesicle	CC	direct assay
GTPase activator activity	MF	direct assay
guanyl-nucleotide exchange factor activity	MF	direct assay
identical protein binding	MF	direct assay
protein homodimerization activity	MF	physical interaction
protein serine/threonine kinase activator activity	MF	direct assay
small GTPase binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,699 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALS2	SETX	Q7Z333	903
ALS2	SOD1	P00441	870
ALS2	FIG4	Q92562	865
ALS2	VAPB	O95292	863
ALS2	C9orf72	Q96LT7	829
ALS2	TARDBP	Q13148	813
ALS2	FUS	P35637	810
ALS2	DCTN1	Q14203	805
ALS2	CHMP2B	Q9UQN3	801
ALS2	RAB5A	P20339	785
ALS2	SPG11	Q96JI7	777
ALS2	OPTN	Q96CV9	771
ALS2	RABIF	P47224	728
ALS2	EEA1	Q15075	726
ALS2	NEFH	P12036	721

IntAct

Human interaction partners of ALS2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

10 partners by confidence:

Partner	Interaction type	MIscore	Records
YWHAB	physical association	0.860	2
SDF2	association	0.530	1
NEK1	physical association	0.500	1
IQSEC1	proximity	0.470	2
RAB5A	physical association	0.400	2
CDC37	physical association	0.400	1
RAC1	physical association	0.400	1
CFAP410	association	0.350	2
CHN2	association	0.350	1
EEA1	colocalization	0.270	3

BioGRID (48 interactions; top human partners by supporting records): YWHAB (Affinity Capture-MS; 4 records), DNAAF2 (Affinity Capture-MS; 3 records), NEK1 (Affinity Capture-MS; 3 records), YWHAG (Affinity Capture-MS; 3 records), YWHAH (Affinity Capture-MS; 3 records), YWHAZ (Affinity Capture-MS; 3 records), C21orf2 (Affinity Capture-MS; 2 records), SDF2 (Affinity Capture-MS; 2 records), STXBP6 (Affinity Capture-MS; 2 records), YWHAE (Affinity Capture-MS; 2 records), YWHAQ (Affinity Capture-MS; 2 records), ALS2CL (Affinity Capture-MS), ATG3 (Phenotypic Enhancement), ATG4C (Affinity Capture-MS), ATG7 (Phenotypic Enhancement)

SIGNOR signaling

3 signaling interactions:

A	Effect	B	Mechanism
ALS2	“up-regulates activity”	RAB5A	binding
RAC1	“up-regulates activity”	ALS2	binding
RAB7A	“down-regulates activity”	ALS2	binding

Disease & clinical

Genetic variants

Variant evidence for ALS2: 1,216 ClinVar records (115 pathogenic / likely pathogenic); 2 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

1,216 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	71
Likely pathogenic	44
Uncertain significance	504
Likely benign	380
Benign	93

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 115 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
4406	NM_020919.4(ALS2):c.1867_1868del (p.Leu623fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
100653	NM_020919.4(ALS2):c.2761C>T (p.Arg921Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
873268	NM_020919.4(ALS2):c.4381C>T (p.Arg1461Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
533743	NM_020919.4(ALS2):c.1233T>G (p.Tyr411Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
870950	NM_020919.4(ALS2):c.2737C>T (p.Arg913Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1679834	NM_020919.4(ALS2):c.4270C>T (p.Gln1424Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1693002	NM_020919.4(ALS2):c.2580+2T>C	Pathogenic	criteria provided, multiple submitters, no conflicts	2
3342715	NM_020919.4(ALS2):c.880_881del (p.Leu294fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
4415	NM_020919.4(ALS2):c.470G>A (p.Cys157Tyr)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	5
694319	NM_020919.4(ALS2):c.1718C>A (p.Ala573Glu)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
1339519	NM_020919.4(ALS2):c.1649C>T (p.Pro550Leu)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
2690510	NM_020919.4(ALS2):c.3047dup (p.Tyr1017fs)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
4407	NM_020919.4(ALS2):c.1427_1428del (p.Glu476fs)	Pathogenic	criteria provided, single submitter	3
4408	NM_020919.4(ALS2):c.3619del (p.Lys1206_Met1207insTer)	Pathogenic	criteria provided, single submitter	3
4411	NM_020919.4(ALS2):c.1007_1008del (p.Ile336fs)	Pathogenic	criteria provided, single submitter	3

Per-variant reference — Sugi Variant

Explore ALS2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 34 predictions of 2,928):

Position(s)	Effect	Δscore	Sites
2:201704120–201704121	donor_loss	1.0000	4
2:201705137–201705138	donor_loss	1.0000	4
2:201705201–201705202	acceptor_loss	1.0000	5
2:201706844–201706845	donor_loss	1.0000	3
2:201707023–201707024	acceptor_loss	1.0000	5
2:201707033	acceptor_gain	1.0000
2:201707904	donor_gain	1.0000
2:201707922	donor_gain	1.0000
2:201707992–201707993	acceptor_loss	1.0000	5
2:201709879–201709880	donor_loss	1.0000	5

AlphaMissense

4,134 missense substitutions predicted likely pathogenic (of 10,815 scored), across 1,000 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M1598	9	0.977	0.999
M1640	9	0.975	0.999
M903	9	0.921	0.993
M1396	9	0.904	0.985
M242	9	0.898	0.994
M1628	9	0.848	0.979
D1599	8	0.998	0.999
D247	8	0.996	0.999
D1167	8	0.994	0.998
H255	8	0.992	0.998
F931	8	0.990	1.000
F1605	8	0.988	0.998
H248	8	0.986	0.996
F948	8	0.982	1.000
F1602	8	0.981	0.998
F895	8	0.980	0.999
F939	8	0.980	0.998
D543	8	0.979	0.996
F1579	8	0.979	0.999
F1566	8	0.975	0.999

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	0.000378
Kidney Renal Papillary Cell Carcinoma (TCGA)	unfavorable	0.000406
Pancreatic Adenocarcinoma (validation)	unfavorable	0.000464

Disease associations

OMIM: gene MIM:606352 | disease phenotypes: MIM:205100, MIM:607225, MIM:606353

GenCC curated gene-disease

5 curated gene-disease records:

Disease	Classification	Inheritance	Records
ALS2-related motor neuron disease	Definitive	Autosomal recessive	2
amyotrophic lateral sclerosis type 2, juvenile	Strong	Autosomal recessive
juvenile primary lateral sclerosis	Strong	Autosomal recessive	3
infantile-onset ascending hereditary spastic paralysis	Strong	Autosomal recessive	3
juvenile amyotrophic lateral sclerosis	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
ALS2-related motor neuron disease	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (11 panels, 6 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

11 panels:

Panel	Rating
Amyotrophic lateral sclerosis/motor neuron disease	green
DDG2P	green
Hereditary spastic paraplegia	green
Hereditary spastic paraplegia, childhood onset	green
Neurodegenerative disorders, adult onset	green
Paediatric disorders	green
Adult-onset neurological disorders	amber
Hereditary spastic paraplegia, adult onset	amber
Hypotonic infant	amber
Other rare neuromuscular disorders	amber
Paediatric motor neuronopathies	amber

Mondo (6): amyotrophic lateral sclerosis type 2, juvenile (MONDO:0008780), infantile-onset ascending hereditary spastic paralysis (MONDO:0011797), amyotrophic lateral sclerosis (MONDO:0004976), juvenile amyotrophic lateral sclerosis (MONDO:0017593), juvenile primary lateral sclerosis (MONDO:0011663), ALS2-related motor neuron disease (MONDO:0100227)

Orphanet (4): Infantile-onset ascending hereditary spastic paralysis (Orphanet:293168), Juvenile amyotrophic lateral sclerosis (Orphanet:300605), Amyotrophic lateral sclerosis (Orphanet:803), Juvenile primary lateral sclerosis (Orphanet:247604)

HPO phenotypes

showing 60 of 98 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000014	Abnormality of the bladder
HP:0000020	Urinary incontinence
HP:0000183	Tongue muscle weakness
HP:0000252	Microcephaly
HP:0000271	Abnormality of the face
HP:0000478	Abnormality of the eye
HP:0000496	Abnormality of eye movement
HP:0000514	Slow saccadic eye movements
HP:0000605	Supranuclear gaze palsy
HP:0000639	Nystagmus
HP:0000708	Atypical behavior
HP:0000763	Sensory neuropathy
HP:0000980	Pallor
HP:0001152	Saccadic smooth pursuit interruptions
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001258	Spastic paraplegia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001264	Spastic diplegia
HP:0001270	Motor delay
HP:0001276	Hypertonia
HP:0001285	Spastic tetraparesis
HP:0001288	Gait disturbance
HP:0001300	Parkinsonism
HP:0001317	Abnormal cerebellum morphology
HP:0001324	Muscle weakness
HP:0001332	Dystonia
HP:0001347	Hyperreflexia
HP:0001348	Brisk reflexes
HP:0001761	Pes cavus
HP:0001771	Achilles tendon contracture
HP:0002015	Dysphagia
HP:0002061	Lower limb spasticity
HP:0002064	Spastic gait
HP:0002072	Chorea
HP:0002120	Cerebral cortical atrophy
HP:0002127	Abnormal upper motor neuron morphology
HP:0002141	Gait imbalance
HP:0002167	Abnormal speech pattern
HP:0002169	Clonus
HP:0002179	Opisthotonus
HP:0002193	Pseudobulbar affect
HP:0002307	Drooling
HP:0002366	Abnormal lower motor neuron morphology
HP:0002371	Loss of speech
HP:0002425	Anarthria
HP:0002445	Tetraplegia
HP:0002460	Distal muscle weakness
HP:0002464	Spastic dysarthria
HP:0002483	Bulbar signs
HP:0002491	Spasticity of facial muscles
HP:0002492	Abnormal corticospinal tract morphology
HP:0002501	Spasticity of pharyngeal muscles
HP:0002505	Loss of ambulation
HP:0002510	Spastic tetraplegia
HP:0002530	Axial dystonia
HP:0002540	Inability to walk
HP:0002544	Retrocollis

GWAS associations

2 associations:

Study	Trait	p-value
GCST008764_1	Perceived intensity of neohesperidin dihydrochalcone	6e-6
GCST008766_1	Perceived intensity of sweet substances	6e-6

MeSH disease descriptors

4 disease descriptors:

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
C565957	Amyotrophic Lateral Sclerosis 2, Juvenile *(supp.)*
C537217	Hereditary spastic paralysis, infantile onset ascending *(supp.)*
C536416	Primary lateral sclerosis juvenile *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	4
sodium arsenite	affects binding, affects reaction, increases reaction, increases abundance, increases expression	3
Cisplatin	affects expression, decreases expression	2
Tobacco Smoke Pollution	increases expression	2
FR900359	affects phosphorylation	1
trichostatin A	affects expression	1
cinnamaldehyde	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	increases expression	1
manganese chloride	increases abundance, increases expression	1
cupric oxide	increases 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	affects cotreatment, increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
NSC 689534	increases expression, affects binding	1
Resveratrol	affects cotreatment, increases expression	1
Decitabine	affects expression	1
Acetaldehyde	increases expression	1
Acetaminophen	increases expression	1
Arsenic	increases abundance, increases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Caffeine	affects phosphorylation	1
Calcitriol	increases expression	1
Catechin	increases expression, affects cotreatment	1
Copper	affects binding, increases expression	1
Coumestrol	decreases expression	1
Estradiol	affects expression	1
Ethyl Methanesulfonate	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C7HF	HAP1 ALS2 (-) 1	Cancer cell line	Male
CVCL_C7HG	HAP1 ALS2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 300 trials:

NCT	Phase	Status	Title
NCT00542412	Phase 4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	Phase 4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	Phase 4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	Phase 4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	Phase 4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	Phase 4	ACTIVE_NOT_RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT00021697	Phase 3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	Phase 3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	Phase 3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	Phase 3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00136110	Phase 3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	Phase 3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	Phase 3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00372879	Phase 3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
NCT00415519	Phase 3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III
NCT00424463	Phase 3	COMPLETED	Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00839033	Phase 3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00868166	Phase 3	COMPLETED	Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
NCT00965497	Phase 3	COMPLETED	Escitalopram (Lexapro) for Depression MS or ALS
NCT01016522	Phase 3	TERMINATED	Safety and Tolerability of the Ketogenic Diet in Amyotrophic Lateral Sclerosis (ALS)
NCT01160263	Phase 3	COMPLETED	Study of Dopamine and Serotonin Transporters in Patients With Amyotrophic Lateral Sclerosis and Controls
NCT01281189	Phase 3	COMPLETED	Phase 3 Study of Dexpramipexole in ALS
NCT01492686	Phase 3	COMPLETED	Phase 3 Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis
NCT01583088	Phase 3	TERMINATED	Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation
NCT01622088	Phase 3	TERMINATED	Phase 3 Extension Study of Dexpramipexole in ALS
NCT02496767	Phase 3	COMPLETED	Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
NCT02623699	Phase 3	COMPLETED	An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
NCT02936635	Phase 3	COMPLETED	A Study for Patients Who Completed VITALITY-ALS (CY 4031)
NCT03127267	Phase 3	RECRUITING	Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients
NCT03280056	Phase 3	COMPLETED	Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients
NCT03491462	Phase 3	COMPLETED	Arimoclomol in Amyotropic Lateral Sclerosis
NCT03505021	Phase 3	COMPLETED	Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
NCT03548311	Phase 3	COMPLETED	Clinical Trial of Ultra-high Dose Methylcobalamin for ALS
NCT03690791	Phase 3	UNKNOWN	Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease
NCT03800524	Phase 3	UNKNOWN	Safety and Efficacy of TUDCA as add-on Treatment in Patients Affected by ALS
NCT03836716	Phase 3	TERMINATED	Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial
NCT03948178	Phase 3	TERMINATED	Effects of Oral Levosimendan on Respiratory Function in Patients With Amyotrophic Lateral Sclerosis (ALS): Open-Label Extension
NCT04165824	Phase 3	COMPLETED	Safety Study of Oral Edaravone Administered in Subjects With ALS
NCT04248465	Phase 3	TERMINATED	An Efficacy and Safety Study of Ravulizumab in ALS Participants
NCT04569084	Phase 3	TERMINATED	Efficacy and Safety Study of Oral Edaravone Administered in Subjects With ALS
NCT04577404	Phase 3	COMPLETED	Safety Extension Study of Oral Edaravone Administered in Subjects With Amyotrophic Lateral Sclerosis (ALS)
NCT04745299	Phase 3	COMPLETED	Evaluation the Efficacy and Safety of Mutiple Lenzumestrocel (Neuronata-R® Inj.) Treatment in Patients With ALS
NCT04768972	Phase 3	ACTIVE_NOT_RECRUITING	FUSION: A Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of ION363 in Amyotrophic Lateral Sclerosis Participants With Fused in Sarcoma Mutations (FUS-ALS)
NCT04944784	Phase 3	TERMINATED	A Study to Evaluate the Efficacy and Safety of Reldesemtiv in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT05021536	Phase 3	UNKNOWN	Phase III Trial of AMX0035 for Amyotrophic Lateral Sclerosis Treatment
NCT05151471	Phase 3	TERMINATED	Efficacy and Safety Extension Study of Oral Edaravone Administered in Subjects With ALS
NCT05178810	Phase 3	COMPLETED	Study to Investigate the Efficacy and Safety of FAB122 (Daily Oral Edaravone) in Patients With Amyotrophic Lateral Sclerosis
NCT05193994	Phase 3	TERMINATED	Triumeq in Amyotrophic Lateral Sclerosis
NCT05442775	Phase 3	TERMINATED	A Phase 3, Open-Label Extension of COURAGE-ALS (CY 5031)
NCT05568615	Phase 3	COMPLETED	Extension Study Following the Studies MT-1186-A03 or A04 to Evaluate the Safety of Oral Edaravone in Subjects With ALS
NCT05619783	Phase 3	COMPLETED	Extension Study Evaluating The Safety And Tolerability of AMX0035
NCT05753852	Phase 3	UNKNOWN	Open Label Extension of TUDCA-ALS Study
NCT05866926	Phase 3	TERMINATED	Study to Investigate the Long-term Safety of FAB122 in Patients With Amyotrophic Lateral Sclerosis
NCT06008249	Phase 3	TERMINATED	Platform Trial to Assess the Efficacy of Multiple Drugs in Amyotrophic Lateral Sclerosis (ALS)
NCT06658977	Phase 3	TERMINATED	RolloverTreatment With Triumeq for People With ALS Following the Lighthouse II Trial
NCT06973629	Phase 3	NOT_YET_RECRUITING	Efficacy and Safety of MSC-NTF (NurOwn) in Participants With Early Symptomatic ALS and Moderate Disease Presentation in ALS (ENDURANCE STUDY)
NCT07174492	Phase 3	NOT_YET_RECRUITING	Efficacy and Safety of Masitinib in Combination With SoC Versus Placebo in the Treatment of ALS Patients
NCT07322003	Phase 3	RECRUITING	Pridopidine Phase 3 Study to Evaluate Efficacy and Safety in ALS
NCT00004771	Phase 2	COMPLETED	Phase II Study of Leuprolide and Testosterone for Men With Kennedy’s Disease or Other Motor Neuron Disease
NCT00005674	Phase 2	COMPLETED	Clinical Trial of Creatine in Amyotrophic Lateral Sclerosis [ALS]