SACS

Summary

SACS (sacsin molecular chaperone, HGNC:10519) is a protein-coding gene on chromosome 13q12.12, encoding Sacsin (Q9NZJ4). Co-chaperone which acts as a regulator of the Hsp70 chaperone machinery and may be involved in the processing of other ataxia-linked proteins.

This gene encodes the sacsin protein, which includes a UbL domain at the N-terminus, a DnaJ domain, and a HEPN domain at the C-terminus. The gene is highly expressed in the central nervous system, also found in skin, skeletal muscles and at low levels in the pancreas. This gene includes a very large exon spanning more than 12.8 kb. Mutations in this gene result in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a neurodegenerative disorder characterized by early-onset cerebellar ataxia with spasticity and peripheral neuropathy. The authors of a publication on the effects of siRNA-mediated sacsin knockdown concluded that sacsin protects against mutant ataxin-1 and suggest that “the large multi-domain sacsin protein is able to recruit Hsp70 chaperone action and has the potential to regulate the effects of other ataxia proteins” (Parfitt et al., PubMed: 19208651). A pseudogene associated with this gene is located on chromosome 11. Alternative splicing of this gene results in multiple transcript variants.

Source: NCBI Gene 26278 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Charlevoix-Saguenay spastic ataxia (Definitive, GenCC)
• GWAS associations: 6
• Clinical variants (ClinVar): 4,839 total — 322 pathogenic, 496 likely-pathogenic
• Phenotypes (HPO): 68
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_014363

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10519
Approved symbol	SACS
Name	sacsin molecular chaperone
Location	13q12.12
Locus type	gene with protein product
Status	Approved
Aliases	ARSACS, KIAA0730, DKFZp686B15167, DNAJC29, SPAX6, PPP1R138
Ensembl gene	ENSG00000151835
Ensembl biotype	protein_coding
OMIM	604490
Entrez	26278

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 15 protein_coding, 6 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000382292, ENST00000402364, ENST00000423156, ENST00000455470, ENST00000476776, ENST00000682244, ENST00000682354, ENST00000682547, ENST00000682775, ENST00000682944, ENST00000683154, ENST00000683210, ENST00000683270, ENST00000683367, ENST00000683489, ENST00000683638, ENST00000683680, ENST00000684053, ENST00000684163, ENST00000684196, ENST00000684325, ENST00000684385, ENST00000684497

RefSeq mRNA: 2 — MANE Select: NM_014363 NM_001278055, NM_014363

CCDS: CCDS9300

Canonical transcript exons

ENST00000382292 — 10 exons

Exon	Start	End
ENSE00001548892	23411220	23411740
ENSE00001749661	23371078	23371165
ENSE00003485164	23368402	23368487
ENSE00003509663	23375119	23375269
ENSE00003583465	23354519	23356007
ENSE00003586011	23358335	23358481
ENSE00003594781	23328830	23341690
ENSE00003651608	23353785	23353876
ENSE00003691212	23365166	23365277
ENSE00003820680	23433615	23433702

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 97.46.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.3609 / max 315.5645, expressed in 1777 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
136411	16.3546	1763
136413	6.4077	932
136412	2.0738	1175
136410	0.3594	168
136414	0.1385	79
136409	0.0269	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	97.46	gold quality
middle frontal gyrus	UBERON:0002702	96.34	gold quality
frontal pole	UBERON:0002795	95.91	gold quality
blood vessel layer	UBERON:0004797	95.83	gold quality
Brodmann (1909) area 10	UBERON:0013541	95.19	gold quality
diaphragm	UBERON:0001103	94.65	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	93.92	gold quality
lateral nuclear group of thalamus	UBERON:0002736	93.69	gold quality
middle temporal gyrus	UBERON:0002771	93.52	gold quality
biceps brachii	UBERON:0001507	93.48	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	92.63	gold quality
orbitofrontal cortex	UBERON:0004167	92.46	gold quality
gluteal muscle	UBERON:0002000	92.07	gold quality
CA1 field of hippocampus	UBERON:0003881	92.05	gold quality
choroid plexus epithelium	UBERON:0003911	92.03	gold quality
endothelial cell	CL:0000115	91.54	gold quality
postcentral gyrus	UBERON:0002581	90.68	gold quality
cauda epididymis	UBERON:0004360	90.66	gold quality
entorhinal cortex	UBERON:0002728	90.56	gold quality
Brodmann (1909) area 46	UBERON:0006483	90.30	gold quality
vastus lateralis	UBERON:0001379	90.22	gold quality
primary visual cortex	UBERON:0002436	90.06	gold quality
parietal lobe	UBERON:0001872	89.99	gold quality
quadriceps femoris	UBERON:0001377	89.81	gold quality
adrenal tissue	UBERON:0018303	89.45	gold quality
superior frontal gyrus	UBERON:0002661	89.13	gold quality
substantia nigra pars compacta	UBERON:0001965	89.03	gold quality
deltoid	UBERON:0001476	89.00	gold quality
body of tongue	UBERON:0011876	88.90	gold quality
pons	UBERON:0000988	88.80	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.49

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

120 targeting SACS, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AS-5P	99.94	71.22	3482

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Report of a reliable and inexpensive method to detect more than 95% of the ARSACS disease alleles. (PMID:11788093)
• The authors report a new mutation (1859insC), leading to a frameshift with a premature termination of the gene product sacsin, in two sisters from consanguineous parents. The phenotype is similar to previously described patients with ARSACS (PMID:14718706)
• The authors identified three new SACS mutations in two Italian patients whose phenotype closely matches that of Quebec cases, but without retinal striation. (PMID:14718707)
• A homozygous missense mutation (T7492C) in the SACS gene, which resulted in the substitution of arginine for tryptophan at amino acid residue 2498 (W2498R) was identified in two sibling Japanese early onset spastic ataxia patients (PMID:14718708)
• analysis of SACS mutations in autosomal recessive spastic ataxia of Charlevoix-Saguenay families (PMID:15156359)
• The authors describe two Japanese siblings with autosomal recessive spastic ataxia of Charlevoix-Saguenay without spasticity, usually a core feature of this disorder. They had a novel homozygous missense mutation (T987C) of the SACS gene. (PMID:15985586)
• The authors report here identical twin sisters with novel compound heterozygous mutations (c.[2951_2952delAG]+[3922delT]) in the SACS gene. (PMID:16198375)
• Japanese autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) patient with a compound heterozygous mutation in a new exon of the SACS gene. (PMID:16606928)
• report of Japanese siblings with a new missense mutation (C922T, L308F) in exon 7 of SACS (PMID:17290461)
• We describe four patients in a Belgian family with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). A novel homozygous missense mutation of the SACS gene was identified in the present family. (PMID:17716690)
• As more SACS mutations are identified worldwide, the clinical spectrum of ‘sacsinopathies’ will expand (PMID:17853117)
• Both point mutation and deletion associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay. (PMID:18398442)
• In a Dutch cohort of 43 index patients with ataxia onset before age 25, we identified 16 index patients (total 23 patients) with mutations in the SACS gene. Nine of them had homozygous mutations, and seven of them had compound heterozygous mutations. (PMID:18465152)
• The authors report a clinical and genetic analysis of a Japanese family with ARSACS with novel compound heterozygous mutations in the SACS gene (N161fsX175, L802P). The phenotype is similar to that of previously reported ARSACS patients. (PMID:18484239)
• Results report the identification of an unconventional SACS mutation, a large-scale deletion sized approximately 1.5 Mb encompassing the whole gene, in two unrelated patients. (PMID:19031088)
• Compares the GHKL-type-ATPase domain of this human protein to that of related plant, protozoan, yeast and bacterial proteins. (PMID:19880797)
• Our results expand the genotype phenotype correlation of mutations in the sacsin gene in ataxia patients (PMID:19892370)
• These data indicate that sacsin repeating regions necessitate nucleotide hydrolysis for their function, provided by the common Hsp90 ATPase domain, which may give rise to a novel activity related to protein quality control. (PMID:20488193)
• Data show that uniparental isodisomy of the paternal chromosome 13 carrying the mutated SACS gene played an etiologic role in a case of the disease. (PMID:20852969)
• This study, author enlargeg the ARSACS phenotype and the underlying genetic spectrum of SACS mutations. Patients with ARSACS are more common than previously known and risk underdiagnosis due to late onset age and unusual presentation. (PMID:20876471)
• novel insights into the oligomerization state of sacsin and functions that are lost in mutations that cause ARSACS. (PMID:21507954)
• This study demonistrated that Autosomal recessive spastic ataxia of Charlevoix-Saguenay with compound heterozygotes for nonsense mutations of the SACS gene. (PMID:21745802)
• Novel compound heterozygous frameshift mutations were detected in the SACS gene in two siblings with a sensorimotor neuropathy, ataxia, and spasticity (PMID:22751902)
• we describe two unrelated Autosomal recessive spastic ataxia of Charlevoix Saguenay patients from central Italy carrying two novel mutations in SACS (PMID:22805644)
• This study demonistrated that 16 novel SACS gene mutations in recessive spastic ataxia of Charlevoix-Saguenay showed Supratentorial and pontine abnormalitie. (PMID:22816526)
• We identified a new mutation in the SACS gene in Autosomal recessive cerebellar ataxia (PMID:23043354)
• the relative position of mutations in subrepeats will variably influence sacsin dysfunction (PMID:23280630)
• A novel missense mutation in sacsin, p.Arg272His, was identified in a patient with sacsin-related spastic ataxia. (PMID:23338241)
• Widespread tissue damage may be associated with extensive loss of sacsin protein in the brain and may explain a wide range of progressive neurologic abnormalities in patients with spastic ataxia of Charlevoix-Saguenay. (PMID:23598833)
• study reports an Italian family affected by an autosomal recessive form of hereditary spastic paraplegia (HSP) and peripheral neuropathy caused by a novel mutation in the SACS (PMID:23800155)
• To clarify the segregation pattern of the mutations found in this family, having excluded somatic mosaicism for the specific mutations, we fully reanalyzed the SACS gene (PMID:24164681)
• Whole-exome sequencing identified a hemizygous novel spastic ataxia of Charlevoix-Saguenay (SACS) stop-codon mutation in 2 brothers (PMID:24180463)
• Abnormal retinal thickening is a common feature in patients with SACS mutation phenotype. (PMID:24457356)
• Various SACS mutations have functional consequences on the mitochondrial compartment in ARSACS patients. (PMID:26288984)
• The results are consistent with the HEPN domain contributing to the functional activity of sacsin by binding to nucleotides or other multiply charged anionic compounds in neurons. (PMID:26366743)
• the twins described by Fitzsimmons had heterozygous mutations in the SACS gene, the gene responsible for autosomal recessive spastic ataxia of Charlevoix Saguenay as well as a heterozygous mutation in the TRPS1, the gene responsible in Trichorhinophalangeal syndrome type 1A TBL1XR1 mutation was identified in the patient described in 2009 as contributing to his cognitive impairment and autistic features.. (PMID:27133561)
• 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)
• This study provides a potential genetic diagnosis for the patient and expands the spectrum of SACS mutations. (PMID:28658676)
• we present the first Polish family with a comprehensive clinical and neuropsychological assessment, harboring two novel mutations in the SACS gene (PMID:28843771)
• Novel homozygous variants in ATCAY, MCOLN1, and SACS in a complex movement disorder in five consanguineous Pakistani families. (PMID:29449188)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	sacs	ENSDARG00000091042
mus_musculus	Sacs	ENSMUSG00000048279
rattus_norvegicus	Sacs	ENSRNOG00000014509

Protein

Protein identifiers

Sacsin — Q9NZJ4 (reviewed: Q9NZJ4)

Alternative names: DnaJ homolog subfamily C member 29

All UniProt accessions (15): Q9NZJ4, A0A804HHS6, A0A804HIG5, A0A804HIQ1, A0A804HIU0, A0A804HJS2, A0A804HK18, A0A804HK57, A0A804HKB3, A0A804HKY6, A0A804HL98, A0A804HLK7, A0A804HLL1, B2REB0, H0Y6M8

UniProt curated annotations — full annotation on UniProt →

Function. Co-chaperone which acts as a regulator of the Hsp70 chaperone machinery and may be involved in the processing of other ataxia-linked proteins.

Subcellular location. Cytoplasm.

Tissue specificity. Highly expressed in the central nervous system. Also found in skeletal muscle and at low levels in pancreas.

Disease relevance. Spastic ataxia Charlevoix-Saguenay type (SACS) [MIM:270550] A neurodegenerative disease characterized by early-onset cerebellar ataxia, spasticity, retinal hypermyelination, pyramidal signs, and both axonal and demyelinating neuropathy with loss of sensory nerve conduction and reduced motor conduction velocities. Other features include dysarthria, distal muscle wasting, nystagmus, defect in conjugate pursuit ocular movements, retinal striation (from prominent retinal nerves) obscuring the retinal blood vessels in places, and the frequent presence of mitral valve prolapse. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The ubiquitin-like domain mediates interaction with the proteasome. The J domain is functional and is shown to stimulate E.coli dnaK ATPase activity.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NZJ4-1	1	yes
Q9NZJ4-2	2

RefSeq proteins (2): NP_001264984, NP_055178* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000626	Ubiquitin-like_dom	Domain
IPR001623	DnaJ_domain	Domain
IPR007842	HEPN_dom	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR036869	J_dom_sf	Homologous_superfamily
IPR036890	HATPase_C_sf	Homologous_superfamily
IPR052972	Sacsin_chaperone_reg	Family
IPR058210	SACS/Nov_dom	Domain

Pfam: PF00240, PF05168, PF25794

UniProt features (103 total): sequence variant 37, helix 25, strand 16, modified residue 7, turn 4, domain 3, region of interest 3, sequence conflict 3, compositionally biased region 3, chain 1, splice variant 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
5V44	X-RAY DIFFRACTION	1.56
5V46	X-RAY DIFFRACTION	1.8
3O10	X-RAY DIFFRACTION	1.9
5V45	X-RAY DIFFRACTION	1.91
5VSX	X-RAY DIFFRACTION	2.1
5VSZ	X-RAY DIFFRACTION	2.4
1IUR	SOLUTION NMR

Predicted structure (AlphaFold)

No AlphaFold model available for Q9NZJ4 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

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): 943, 1779, 2511, 2516, 3435, 4261, 4264

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 382 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, BILD_SRC_ONCOGENIC_SIGNATURE, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_PROTEIN_MATURATION, ONKEN_UVEAL_MELANOMA_UP, LI_WILMS_TUMOR_VS_FETAL_KIDNEY_1_DN, GOBP_REGULATION_OF_INCLUSION_BODY_ASSEMBLY, GOBP_PROTEIN_FOLDING, DODD_NASOPHARYNGEAL_CARCINOMA_UP, SPIELMAN_LYMPHOBLAST_EUROPEAN_VS_ASIAN_UP, ACTTTAT_MIR1425P, GOCC_NEURON_PROJECTION, MARTINEZ_RESPONSE_TO_TRABECTEDIN_DN

GO Biological Process (2): protein folding (GO:0006457), negative regulation of inclusion body assembly (GO:0090084)

GO Molecular Function (6): Hsp70 protein binding (GO:0030544), identical protein binding (GO:0042802), low-density lipoprotein particle receptor binding (GO:0050750), protein-folding chaperone binding (GO:0051087), proteasome binding (GO:0070628), protein binding (GO:0005515)

GO Cellular Component (6): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), axon (GO:0030424), dendrite (GO:0030425), cell body fiber (GO:0070852)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
neuron projection	3
protein binding	2
intracellular membrane-bounded organelle	2
cellular process	1
protein maturation	1
negative regulation of cellular component organization	1
inclusion body assembly	1
regulation of inclusion body assembly	1
heat shock protein binding	1
protein-folding chaperone binding	1
lipoprotein particle receptor binding	1
protein-containing complex binding	1
binding	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytoplasm	1
dendritic tree	1

Protein interactions and networks

STRING

1322 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SACS	UBE3A	P78355	694
SACS	ATXN1	P54253	692
SACS	HSPA4	P34932	651
SACS	DNM1L	O00429	565
SACS	HSPA1A	P08107	542
SACS	DNAJB2	P25686	525
SACS	SGCG	Q13326	502
SACS	NWD2	Q9ULI1	478
SACS	DNAJC19	Q96DA6	472
SACS	SERTAD4	Q9NUC0	446
SACS	PICK1	Q9NRD5	446
SACS	PROSER1	Q86XN7	425
SACS	DNAJC13	O75165	423
SACS	NBEAL1	Q6ZS30	422
SACS	HSPA8	P11142	417

IntAct

54 interactions, top by confidence:

A	B	Type	Score
PLK1	EVI5	psi-mi:“MI:0914”(association)	0.660
SACS	SACS	psi-mi:“MI:0407”(direct interaction)	0.650
ENPP6	SCAMP1	psi-mi:“MI:0914”(association)	0.640
GYPA	TCAF2	psi-mi:“MI:0914”(association)	0.640
SPSB4	ARHGEF10	psi-mi:“MI:0914”(association)	0.530
	SACS	psi-mi:“MI:0407”(direct interaction)	0.440
SACS	PPP1CA	psi-mi:“MI:0407”(direct interaction)	0.440
SACS	P4HA2	psi-mi:“MI:0915”(physical association)	0.400
SACS	SOD1	psi-mi:“MI:0915”(physical association)	0.400
SACS	HNRNPA0	psi-mi:“MI:0915”(physical association)	0.400
SACS	ADRB2	psi-mi:“MI:0915”(physical association)	0.370
Naa10	MYO9A	psi-mi:“MI:0914”(association)	0.350
TRIM29	SEC16A	psi-mi:“MI:0914”(association)	0.350
ALB	SH3BP5	psi-mi:“MI:0914”(association)	0.350
MOCS3	HSPA6	psi-mi:“MI:0914”(association)	0.350
P		psi-mi:“MI:0914”(association)	0.350
TP63	HNRNPR	psi-mi:“MI:0914”(association)	0.350
MYC		psi-mi:“MI:0914”(association)	0.350
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
FKBP5	IFT56	psi-mi:“MI:0914”(association)	0.350
HNRNPH1	VWA8	psi-mi:“MI:0914”(association)	0.350

BioGRID (65): SACS (Affinity Capture-MS), SACS (Affinity Capture-MS), SACS (Synthetic Growth Defect), SACS (Affinity Capture-MS), SACS (Affinity Capture-MS), SACS (Affinity Capture-MS), SACS (Affinity Capture-MS), SACS (Affinity Capture-MS), SACS (Affinity Capture-MS), SACS (Affinity Capture-RNA), SACS (Affinity Capture-MS), SACS (Affinity Capture-RNA), SACS (Affinity Capture-MS), SACS (Proximity Label-MS), SACS (Proximity Label-MS)

ESM2 similar proteins: A4IF87, A9JRL3, E9PYK3, F1ND48, G1SPE9, O15228, O93479, O94952, O95870, P50747, P59764, P98192, Q08CZ0, Q09M05, Q1HAQ0, Q1JPD2, Q1LWG4, Q2KIX2, Q3TFD2, Q4R6Y8, Q4R8P0, Q4U2V3, Q5R5S1, Q5R6S0, Q5XGM5, Q641K1, Q6MG55, Q6PBN5, Q7L5N7, Q7ZU92, Q80U95, Q80V94, Q8BMD6, Q8BYI6, Q8K2I9, Q8N1I0, Q8NEC7, Q8NF37, Q8NFZ0, Q8NHU2

Diamond homologs: Q9JLC8, Q9NZJ4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

4839 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	322
Likely pathogenic	496
Uncertain significance	1080
Likely benign	2081
Benign	82

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068564	NM_014363.6(SACS):c.1555del (p.Glu519fs)	Pathogenic
1069091	NM_014363.6(SACS):c.1752del (p.Glu585fs)	Pathogenic
1069127	NM_014363.6(SACS):c.11606T>A (p.Leu3869Ter)	Pathogenic
1069733	NM_014363.6(SACS):c.3094G>T (p.Glu1032Ter)	Pathogenic
1069999	NM_014363.6(SACS):c.11674dup (p.Ser3892fs)	Pathogenic
1070056	NM_014363.6(SACS):c.12106A>T (p.Arg4036Ter)	Pathogenic
1070396	NM_014363.6(SACS):c.13156C>T (p.Arg4386Ter)	Pathogenic
1070558	NM_014363.6(SACS):c.6300T>A (p.Cys2100Ter)	Pathogenic
1072757	NM_014363.6(SACS):c.1014dup (p.Lys339Ter)	Pathogenic
1072798	NM_014363.6(SACS):c.5796_5809del (p.Thr1933fs)	Pathogenic
1073580	NM_014363.6(SACS):c.13064del (p.Leu4355fs)	Pathogenic
1075038	NM_014363.6(SACS):c.13208_13209del (p.Gln4403fs)	Pathogenic
1075545	NM_014363.6(SACS):c.1769_1770del (p.Val590fs)	Pathogenic
1076599	NM_014363.6(SACS):c.10671dup (p.Ile3558fs)	Pathogenic
1076877	NM_014363.6(SACS):c.2578C>T (p.Gln860Ter)	Pathogenic
1098923	NM_014363.6(SACS):c.9866C>G (p.Ser3289Ter)	Pathogenic
1098924	NM_014363.6(SACS):c.8132C>A (p.Ser2711Ter)	Pathogenic
1175062	NM_014363.6(SACS):c.13176C>G (p.Tyr4392Ter)	Pathogenic
1180639	NM_014363.6(SACS):c.7134T>G (p.Tyr2378Ter)	Pathogenic
1184884	NM_014363.6(SACS):c.11509del (p.Gln3837fs)	Pathogenic
1184885	NM_014363.6(SACS):c.1783C>T (p.Gln595Ter)	Pathogenic
1202576	NM_014363.6(SACS):c.4756_4760del (p.Asn1586fs)	Pathogenic
1256210	NM_014363.6(SACS):c.2593A>T (p.Lys865Ter)	Pathogenic
1256212	NM_014363.6(SACS):c.3168del (p.Asp1057fs)	Pathogenic
1297504	NM_014363.6(SACS):c.1925del (p.Gly642fs)	Pathogenic
1323550	NM_014363.6(SACS):c.7110C>G (p.Tyr2370Ter)	Pathogenic
1331499	NM_014363.6(SACS):c.6837dup (p.Glu2280fs)	Pathogenic
1343983	NM_014363.6(SACS):c.237dup (p.Ser80fs)	Pathogenic
1350577	NM_014363.6(SACS):c.4519_4522del (p.Glu1507fs)	Pathogenic
1357686	NM_014363.6(SACS):c.11848del (p.Tyr3950fs)	Pathogenic

SpliceAI

3055 predictions. Top by Δscore:

Variant	Effect	Δscore
13:23295411:TTA:T	acceptor_loss	1.0000
13:23295412:TAGG:T	acceptor_loss	1.0000
13:23295413:A:AG	acceptor_gain	1.0000
13:23295413:A:G	acceptor_loss	1.0000
13:23295413:AG:A	acceptor_gain	1.0000
13:23295414:G:GA	acceptor_gain	1.0000
13:23295414:GG:G	acceptor_gain	1.0000
13:23295414:GGGC:G	acceptor_gain	1.0000
13:23295488:G:GC	donor_loss	1.0000
13:23353775:A:C	donor_gain	1.0000
13:23353781:ATAC:A	donor_loss	1.0000
13:23353782:TAC:T	donor_loss	1.0000
13:23353783:A:C	donor_loss	1.0000
13:23353784:C:CA	donor_loss	1.0000
13:23353802:T:TA	donor_gain	1.0000
13:23353872:GGGAC:G	acceptor_gain	1.0000
13:23353877:C:CA	acceptor_loss	1.0000
13:23353877:C:CC	acceptor_gain	1.0000
13:23353878:T:A	acceptor_loss	1.0000
13:23365160:TCTTA:T	donor_loss	1.0000
13:23365161:CTTA:C	donor_loss	1.0000
13:23365162:TTA:T	donor_loss	1.0000
13:23365163:TAC:T	donor_loss	1.0000
13:23365164:A:AC	donor_gain	1.0000
13:23365164:AC:A	donor_gain	1.0000
13:23365164:ACCCT:A	donor_loss	1.0000
13:23365165:C:A	donor_loss	1.0000
13:23365165:C:CC	donor_gain	1.0000
13:23365165:CC:C	donor_gain	1.0000
13:23365275:TTC:T	acceptor_gain	1.0000

AlphaMissense

30352 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:23330233:G:C	P4548R	1.000
13:23330233:G:T	P4548Q	1.000
13:23330260:G:T	P4539H	1.000
13:23330359:G:T	A4506D	1.000
13:23330447:A:G	C4477R	1.000
13:23330460:C:A	W4472C	1.000
13:23330460:C:G	W4472C	1.000
13:23330462:A:G	W4472R	1.000
13:23330462:A:T	W4472R	1.000
13:23330494:G:T	A4461D	1.000
13:23330516:C:G	A4454P	1.000
13:23330528:A:G	W4450R	1.000
13:23330528:A:T	W4450R	1.000
13:23330675:A:G	W4401R	1.000
13:23330675:A:T	W4401R	1.000
13:23330865:A:C	H4337Q	1.000
13:23330865:A:T	H4337Q	1.000
13:23330866:T:C	H4337R	1.000
13:23330867:G:C	H4337D	1.000
13:23330870:A:G	W4336R	1.000
13:23330870:A:T	W4336R	1.000
13:23330884:C:G	R4331P	1.000
13:23330902:C:G	R4325P	1.000
13:23331142:A:G	F4245S	1.000
13:23331149:A:C	Y4243D	1.000
13:23331151:A:G	L4242P	1.000
13:23331151:A:T	L4242Q	1.000
13:23331196:A:C	I4227R	1.000
13:23331196:A:T	I4227K	1.000
13:23331265:G:T	A4204E	1.000

dbSNP variants (sampled 300 via entrez): RS1000039874 (13:23423222 T>C), RS1000060231 (13:23382825 A>G,T), RS1000067795 (13:23408440 A>G), RS1000083329 (13:23357980 C>G), RS1000199937 (13:23366031 A>G), RS1000219530 (13:23368534 G>A,T), RS1000317541 (13:23430737 T>C), RS1000390888 (13:23349751 T>A,C), RS1000409695 (13:23398548 A>G), RS1000424583 (13:23359375 A>G), RS1000460387 (13:23398315 C>A,T), RS1000480907 (13:23387394 G>A), RS1000492137 (13:23387197 C>A,G,T), RS1000511978 (13:23371522 T>A), RS1000534324 (13:23329200 A>C,G,T)

Disease associations

OMIM: gene MIM:604490 | disease phenotypes: MIM:270550, MIM:108600, MIM:118220, MIM:303350, MIM:253700, MIM:270500, MIM:302800, MIM:302900

GenCC curated gene-disease

Disease	Classification	Inheritance
Charlevoix-Saguenay spastic ataxia	Definitive	Autosomal recessive

Mondo (12): Charlevoix-Saguenay spastic ataxia (MONDO:0010041), spastic ataxia (MONDO:0017845), Charcot-Marie-Tooth disease (MONDO:0015626), hereditary spastic paraplegia (MONDO:0019064), autosomal recessive limb-girdle muscular dystrophy type 2C (MONDO:0009677), myoepithelial tumor (MONDO:0002380), autosomal recessive spastic ataxia (MONDO:0017847), intellectual disability (MONDO:0001071), ataxia, spastic, childhood-onset, autosomal recessive, with optic atrophy and intellectual disability (MONDO:0010040), hereditary ataxia (MONDO:0100309), Charcot-Marie-Tooth disease X-linked dominant 1 (MONDO:0010549), sarcoglycanopathy (MONDO:0016140)

Orphanet (10): Autosomal recessive spastic ataxia of Charlevoix-Saguenay (Orphanet:98), Spastic ataxia (Orphanet:316226), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), Hereditary spastic paraplegia (Orphanet:685), Gamma-sarcoglycan-related limb-girdle muscular dystrophy R5 (Orphanet:353), Autosomal recessive spastic ataxia (Orphanet:316240), Hereditary ataxia (Orphanet:183518), X-linked Charcot-Marie-Tooth disease type 1 (Orphanet:101075), Qualitative or quantitative defects of sarcoglycan (Orphanet:207052), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

68 total (30 of 68 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000012	Urinary urgency
HP:0000020	Urinary incontinence
HP:0000639	Nystagmus
HP:0000708	Atypical behavior
HP:0000802	Impotence
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001272	Cerebellar atrophy
HP:0001288	Gait disturbance
HP:0001310	Dysmetria
HP:0001317	Abnormal cerebellum morphology
HP:0001320	Cerebellar vermis hypoplasia
HP:0001324	Muscle weakness
HP:0001347	Hyperreflexia
HP:0001634	Mitral valve prolapse
HP:0001760	Abnormal foot morphology
HP:0001761	Pes cavus
HP:0001765	Hammertoe
HP:0002015	Dysphagia
HP:0002061	Lower limb spasticity
HP:0002064	Spastic gait
HP:0002066	Gait ataxia
HP:0002073	Progressive cerebellar ataxia
HP:0002079	Hypoplasia of the corpus callosum
HP:0002080	Intention tremor
HP:0002166	Impaired vibration sensation in the lower limbs
HP:0002168	Scanning speech

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST000189_5	Protein quantitative trait loci	4.000000e-06
GCST001474_4	Hypothyroidism	5.000000e-06
GCST001809_2	Type 2 diabetes	2.000000e-08
GCST002587_19	Blood pressure (smoking interaction)	4.000000e-07
GCST009391_1053	Metabolite levels	4.000000e-06
GCST009391_1661	Metabolite levels	6.000000e-07

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004753	interleukin 12 measurement
EFO:0006335	systolic blood pressure
EFO:0006526	pack-years measurement
EFO:0010363	lysophosphatidylcholine 20:4 measurement
EFO:0010470	carnosine measurement

MeSH disease descriptors (10)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D009208	Myoepithelioma	C04.557.435.585
D058088	Sarcoglycanopathies	C05.651.534.500.280.500; C08.618.923; C10.668.491.175.500.149.500; C14.280.238.812; C16.320.577.280.500
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820
C564446	Charcot-Marie-Tooth Peroneal Muscular Atrophy and Friedreich Ataxia, Combined (supp.)
C531684	Hereditary spinal ataxia (supp.)
C535900	Limb-girdle muscular dystrophy, type 2C (supp.)
C564815	Spastic Ataxia (supp.)
C536787	Spastic ataxia Charlevoix-Saguenay type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation	4
Estradiol	affects cotreatment, increases expression	4
sodium arsenite	affects methylation, decreases expression, increases abundance	3
Tobacco Smoke Pollution	affects expression, increases expression	3
Tretinoin	affects cotreatment, decreases expression	3
Aflatoxin B1	affects expression, increases expression	3
Resveratrol	affects cotreatment, increases expression	2
Arsenic Trioxide	affects cotreatment, decreases expression, increases expression	2
Acetaminophen	increases expression	2
Air Pollutants	affects cotreatment, affects expression, increases abundance, decreases expression	2
Cisplatin	affects cotreatment, decreases expression	2
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, affects expression, increases abundance	1
bisphenol A	affects cotreatment, decreases expression	1
sodium arsenate	decreases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	decreases expression, increases abundance	1
nickel sulfate	decreases expression	1
coumarin	affects phosphorylation	1
1-nitropyrene	increases expression	1
methacrylaldehyde	affects cotreatment, affects expression, increases abundance	1
tamibarotene	decreases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
MRK 003	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
MT19c compound	increases expression	1
Acrolein	affects cotreatment, affects expression, increases abundance	1
Arsenic	decreases expression, increases abundance	1
Cadmium	increases abundance, increases expression	1

Cellosaurus cell lines

2 cell lines: 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_UG20	ESi064-A	Induced pluripotent stem cell	Female
CVCL_VP83	ESi063-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00271635	PHASE2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT02561702	PHASE2	COMPLETED	Mexiletine for Muscle Cramps in Charcot Marie Tooth Disease
NCT02967679	PHASE2	COMPLETED	SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
NCT03124459	PHASE2	TERMINATED	Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
NCT03254199	PHASE2	TERMINATED	A Study to Assess the Safety and Effectiveness of FLX-787 in Subjects With Charcot-Marie-Tooth Disease Experiencing Muscle Cramps.
NCT03943290	PHASE2	TERMINATED	Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
NCT05777226	PHASE2	UNKNOWN	Research of SORD-CMT Natural History and Epalrestat Treatment
NCT06482437	PHASE2	COMPLETED	Safety and Efficacy of NMD670 in Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT01344798	PHASE1	COMPLETED	Clinical Study of AAV1-gamma-sarcoglycan Gene Therapy for Limb Girdle Muscular Dystrophy Type 2C
NCT05973630	PHASE1	ACTIVE_NOT_RECRUITING	ATA-200 Gene Therapy Trial in Patients With LGMDR5
NCT03600649	PHASE1	UNKNOWN	Clinical Trial of SP-2577 (Seclidemstat) in Patients With Relapsed or Refractory Ewing or Ewing-related Sarcomas
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT06596850	Not specified	NOT_YET_RECRUITING	Wheelchair Skills Training for People with ARSACS and DM1
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT04297891	Not specified	UNKNOWN	Phenotypes, Biomarkers and Pathophysiology in Spastic Ataxias
NCT01289704	PHASE2/PHASE3	UNKNOWN	Treadmill, Stretching and Proprioceptive Exercise (TreSPE) Rehabilitation Program for Charcot-Marie-Tooth Neuropathy Type 1A (CMT1A)
NCT00541164	PHASE1/PHASE2	COMPLETED	Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease
NCT05361031	PHASE1/PHASE2	COMPLETED	The Safety and Tolerability of Engensis (VM202) in Patients With Charcot-Marie-Tooth Disease Subtype 1A (CMT1A)
NCT07223632	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Treatment of Charcot-Marie-Tooth Disease, Axonal, Type 2S (CMT2S) in an Individual Patient
NCT00149045	Not specified	COMPLETED	Follow up and Observation of Charcot Marie Tooth Disease in Families
NCT01193075	Not specified	RECRUITING	Natural History Evaluation of Charcot Marie Tooth Disease (CMT) Types CMT1B, CMT2A, CMT4A, CMT4C, and Others