SPTAN1

Summary

SPTAN1 (spectrin alpha, non-erythrocytic 1, HGNC:11273) is a protein-coding gene on chromosome 9q34.11, encoding Spectrin alpha chain, non-erythrocytic 1 (Q13813). Fodrin, which seems to be involved in secretion, interacts with calmodulin in a calcium-dependent manner and is thus candidate for the calcium-dependent movement of the cytoskeleton at the membrane. It is haploinsufficient (ClinGen: sufficient evidence).

Spectrins are a family of filamentous cytoskeletal proteins that function as essential scaffold proteins that stabilize the plasma membrane and organize intracellular organelles. Spectrins are composed of alpha and beta dimers that associate to form tetramers linked in a head-to-head arrangement. This gene encodes an alpha spectrin that is specifically expressed in nonerythrocytic cells. The encoded protein has been implicated in other cellular functions including DNA repair and cell cycle regulation. Mutations in this gene are the cause of early infantile epileptic encephalopathy-5. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 6709 — RefSeq curated summary.

At a glance

• Gene–disease (curated): genetic developmental and epileptic encephalopathy (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 3,252 total — 53 pathogenic, 68 likely-pathogenic
• Phenotypes (HPO): 104
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001130438

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11273
Approved symbol	SPTAN1
Name	spectrin alpha, non-erythrocytic 1
Location	9q34.11
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000197694
Ensembl biotype	protein_coding
OMIM	182810
Entrez	6709

Gene structure

Transcript identifiers

Ensembl transcripts: 58 — 31 protein_coding, 20 retained_intron, 4 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay

ENST00000358161, ENST00000372731, ENST00000372739, ENST00000461855, ENST00000472211, ENST00000475367, ENST00000476825, ENST00000491712, ENST00000497216, ENST00000625282, ENST00000625980, ENST00000627441, ENST00000627809, ENST00000628614, ENST00000628867, ENST00000629047, ENST00000629089, ENST00000629137, ENST00000629378, ENST00000630147, ENST00000630763, ENST00000630804, ENST00000630866, ENST00000630981, ENST00000631121, ENST00000631315, ENST00000635806, ENST00000635853, ENST00000636010, ENST00000636257, ENST00000636337, ENST00000636483, ENST00000636939, ENST00000637032, ENST00000637434, ENST00000637820, ENST00000637867, ENST00000637903, ENST00000672130, ENST00000704202, ENST00000704203, ENST00000704204, ENST00000704205, ENST00000704206, ENST00000704207, ENST00000706487, ENST00000853878, ENST00000853879, ENST00000853880, ENST00000853881, ENST00000853882, ENST00000853883, ENST00000853884, ENST00000924806, ENST00000946108, ENST00000946109, ENST00000946110, ENST00000946111

RefSeq mRNA: 11 — MANE Select: NM_001130438 NM_001130438, NM_001195532, NM_001363759, NM_001363765, NM_001375310, NM_001375311, NM_001375312, NM_001375313, NM_001375314, NM_001375318, NM_003127

CCDS: CCDS48036, CCDS6905, CCDS75914, CCDS87695, CCDS87696, CCDS94500, CCDS94501

Canonical transcript exons

ENST00000372739 — 57 exons

Exon	Start	End
ENSE00000730476	128632572	128632718
ENSE00000730493	128632431	128632484
ENSE00000730509	128632127	128632323
ENSE00000730520	128630321	128630375
ENSE00000730551	128626391	128626687
ENSE00000730564	128625769	128625978
ENSE00000730575	128625103	128625179
ENSE00000730597	128624328	128624487
ENSE00000730702	128617987	128618108
ENSE00000730706	128618871	128619003
ENSE00000806992	128617640	128617760
ENSE00000806993	128621158	128621256
ENSE00000806994	128632808	128632955
ENSE00001215160	128627386	128627498
ENSE00001597357	128579637	128579738
ENSE00001611067	128584282	128584525
ENSE00001612670	128584721	128584843
ENSE00001613637	128582479	128582556
ENSE00001627456	128574675	128574815
ENSE00001627979	128588809	128588943
ENSE00001628507	128592983	128593042
ENSE00001636184	128600080	128600115
ENSE00001644730	128611714	128611845
ENSE00001651430	128581782	128581892
ENSE00001654893	128608874	128608977
ENSE00001679538	128578110	128578245
ENSE00001683382	128583077	128583281
ENSE00001693277	128577129	128577273
ENSE00001697185	128615632	128615840
ENSE00001697865	128594175	128594373
ENSE00001704186	128583788	128583969
ENSE00001720104	128608130	128608276
ENSE00001729156	128609122	128609284
ENSE00001740794	128580922	128581059
ENSE00001742935	128598963	128598986
ENSE00001749734	128607852	128608049
ENSE00001750205	128576823	128576956
ENSE00001752389	128627925	128627942
ENSE00001767008	128575199	128575345
ENSE00001768241	128591477	128591625
ENSE00001771137	128612109	128612246
ENSE00001776409	128587606	128587698
ENSE00001777576	128585748	128585965
ENSE00001783018	128609651	128609665
ENSE00001783994	128568772	128568897
ENSE00001790966	128582694	128582849
ENSE00001796301	128577352	128577506
ENSE00002729979	128566738	128566977
ENSE00003475630	128603543	128603590
ENSE00003507452	128598400	128598504
ENSE00003545564	128605034	128605178
ENSE00003578991	128605296	128605477
ENSE00003589349	128604326	128604417
ENSE00003658618	128607604	128607703
ENSE00003679449	128613381	128613485
ENSE00003899158	128552587	128552696
ENSE00003901332	128633209	128633662

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 99.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 165.7116 / max 3387.4530, expressed in 1820 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
98805	163.8205	1820
98810	0.9310	532
98809	0.3548	146
98814	0.2702	94
98813	0.1285	36
98807	0.1200	51
98806	0.0867	38

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	99.76	gold quality
cerebellar hemisphere	UBERON:0002245	99.72	gold quality
cerebellar cortex	UBERON:0002129	99.64	gold quality
cortical plate	UBERON:0005343	99.64	gold quality
right frontal lobe	UBERON:0002810	99.62	gold quality
cerebellum	UBERON:0002037	99.53	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.37	gold quality
amygdala	UBERON:0001876	99.33	gold quality
right uterine tube	UBERON:0001302	99.31	gold quality
prefrontal cortex	UBERON:0000451	99.30	gold quality
nucleus accumbens	UBERON:0001882	99.30	gold quality
Brodmann (1909) area 10	UBERON:0013541	99.29	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.28	gold quality
tibial nerve	UBERON:0001323	99.25	gold quality
cingulate cortex	UBERON:0003027	99.25	gold quality
inferior olivary complex	UBERON:0002127	99.24	gold quality
anterior cingulate cortex	UBERON:0009835	99.23	gold quality
putamen	UBERON:0001874	99.22	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.22	gold quality
frontal cortex	UBERON:0001870	99.21	gold quality
neocortex	UBERON:0001950	99.20	gold quality
hypothalamus	UBERON:0001898	99.19	gold quality
dorsal root ganglion	UBERON:0000044	99.18	gold quality
caudate nucleus	UBERON:0001873	99.16	gold quality
ganglionic eminence	UBERON:0004023	99.15	gold quality
colonic epithelium	UBERON:0000397	99.13	gold quality
apex of heart	UBERON:0002098	99.13	gold quality
substantia nigra pars compacta	UBERON:0001965	99.12	gold quality
sural nerve	UBERON:0015488	99.12	gold quality
cerebral cortex	UBERON:0000956	99.11	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-75140	yes	1334.69
E-HCAD-5	yes	44.18
E-GEOD-137537	yes	12.77
E-CURD-112	yes	4.16
E-GEOD-93593	no	14.81
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKB

miRNA regulators (miRDB)

27 targeting SPTAN1, 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-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-4690-5P	99.65	66.24	813
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-1264	99.25	66.81	1317
HSA-MIR-7109-5P	99.18	66.13	1057
HSA-MIR-5190	99.15	67.76	1234
HSA-MIR-625-5P	99.02	68.64	2031
HSA-MIR-511-5P	98.97	70.94	2268
HSA-MIR-6830-3P	98.62	68.07	1760
HSA-MIR-4665-5P	97.91	67.69	1536
HSA-MIR-503-5P	97.87	66.83	575
HSA-MIR-134-5P	97.11	66.52	976
HSA-MIR-3118	97.11	66.58	984
HSA-MIR-3616-3P	96.96	65.45	983

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 39)

• Review. 120 kDa alpha-fodrin is an important autoantigen in both animal models and Sjogren syndrome patients. Increased caspase cascade activity may be involved in the progression of alpha-fodrin proteolysis and tissue destruction. (PMID:12630566)
• High affinity and slow overall kinetics of association/dissociation of alpha II-spectrin may suit it well to a role in strengthening cell junctions and providing stable anchorage for transmembrane proteins at points specified by cell-adhesion molecules. (PMID:12820899)
• Fanconi anemia cell lines deficient in alphaII spectrin express normal levels of alphaII spectrin mRNA. (PMID:12893251)
• These observations indicate that calpain is activated and reacts with alpha-fodrin as a substrate at the sarcolemma, and plays a key role in modulating sarcolemmal proteins to adapt to the specific conditions in each myopathy. (PMID:15948206)
• The in vivo role of alpha-fodrin autoantigen in primary Sjogren’s syndrome was analyzed. (PMID:16192640)
• These studies indicate that alphaSpIISigma( *) may play a role in a number of diverse and important processes in the nucleus and that a deficiency in this protein, as occurs in Fanconi’s anemia, could affect a number of critical cellular pathways. (PMID:16889989)
• provide novel insights into spectrin functions by demonstrating the involvement of alphaII-spectrin in cell cycle regulation and actin organization (PMID:18978357)
• This protein has been found differentially expressed in the temporal lobe from patients with schizophrenia. (PMID:19034380)
• The SH3 domain of SPTAN1 is a target for the Fanconi anemia protein, FANCG. (PMID:19102630)
• depletion of alphaIISp in normal cells leads to a number of defects observed in Fanconi anemia cells, such as chromosome instability and a deficiency in cross-link repair. (PMID:19217883)
• fodrin degradation occurs during galectin-1 T cell death and CD45 is essential for fodrin degradation to occur (PMID:19454697)
• SigA binds to epithelial HEp-2 cells as well as being able to induce fodrin degradation in vitro and in situ, further extending its documented role in the pathogenesis of Shigella infections. (PMID:20011051)
• This protein has been found differentially expressed in the anterior cingulate cortex from patients with schizophrenia (PMID:20381070)
• Analysis of alphaII-spectrin breakdown products in cerebrospinal fluid predicts mortality and injury severity in adults following traumatic brain injury. (PMID:20408766)
• findings suggest that pathological aggregation of alpha/beta spectrin heterodimers and abnormal axon initial segment(AIS) integrity resulting from SPTAN1 mutations were involved in pathogenesis of infantile epilepsy (PMID:20493457)
• Fanconi anemia proteins may play an important role in maintaining the stability of alphaIISp in the cell by regulating its cleavage by mu-calpain. (PMID:20518497)
• These results suggest that ubiquitin C-terminal hydrolase and alphaII-spectrin breakdown product 145 kDa may be useful in assessing outcome after pediatric traumatic brain injury. (PMID:22022780)
• organization of a spectrin-like cytoskeleton is associated with keratinocyte differentiation, and cytoskeleton disruption is mediated by either PKCdelta(Thr505) phosphorylation associated with phosphorylated adducin or due to reduction of endogenous adducin (PMID:22163289)
• In-frame mutations in the C-terminus of SPTAN1 cause a core set of manifestations that include severe intellectual disability, generalized epilepsy, and pontocerebellar atrophy. (PMID:22258530)
• hypomyelination of the cerebral white matter was revealed at the age of 1 year, and a de novo heterozygous mutation in the SPTAN1 gene was confirmed (PMID:22656320)
• loss of SPTAN1 switches TGF-beta signaling from tumor suppression to tumor promotion by engaging Notch signaling and activating SOX9 in esophageal adenocarcinoma. (PMID:23536563)
• Variations in both alpha-spectrin (SPTA1) and beta-spectrin ( SPTB ) were found in a neonate with prolonged jaundice in a family where nine individuals had hereditary elliptocytosis. (PMID:24193021)
• aggressiveness of MLH1-positive colorectal cancers might be related to SPTAN1. (PMID:24456667)
• Studies demonstrate that alpha-IISp plays a critical role in maintaining chromosome stability in cells after DNA interstrand cross-links damage by repairing damage that occurs in both genomic and telomeric DNA. (PMID:25757157)
• Alpha-spectrin is critical for recruitment of non-ubiquitinated FANCD2 to sites of damage, which has an important role in the repair response and interstrand cross-link repair. (PMID:26297932)
• SPTAN1-related disorders comprise a wide spectrum of neurodevelopmental phenotypes ranging from mild to severe and progressive. Spectrin aggregate formation in fibroblasts with mutations in the alpha/beta heterodimerization domain seems to be associated with a severe neurodegenerative course. (PMID:29050398)
• Spectrin may be engaged in regulation of distinct events necessary for the establishment and maturity of the immunological synapse. (PMID:29244882)
• alphaII spectrin has a role in critical aspects of dendritic and axonal development and synaptogenesis, and there is a dominant-negative mechanism of SPTAN1 mutations in epileptic encephalopathy (PMID:29337302)
• we present two patients with novel SPTAN1 variants who exhibit potentially important differences from other published cases and expand the SPTAN1 encephalopathy phenotype. (PMID:30548380)
• Compared with the surrounding normal mucosa, SPTAN1 expression was reduced in MLH1-deficient colorectal cancers (CRCs), whereas MLH1-proficient CRCs showed a significant upregulation of SPTAN1. We conclude that SPTAN1 is a candidate molecule explaining the tumor progression and metastasis of MLH1-deficient CRCs. (PMID:30856214)
• The 150-kDa (calpain-mediated) cleavage product of SPTAN1 was significantly increased in ischemic and nonischemic heart failure. (PMID:31064843)
• Patients with nonsense mutations in SPTAN1 were identified, in hereditary motor neuropathy families. (PMID:31332438)
• alpha-Fodrin is required for the organization of functional microtubules during mitosis. (PMID:31455186)
• Our results further suggest that SPTAN1 may cause autosomal recessive hereditary spastic paraplegia (HSP), and that it should be included in genetic screening panels for genetically undiagnosed HSP patients. (PMID:31515523)
• Expression and secretion of the proinflammatory cytokine IL8 is increased in colorectal cancer cells following the knockdown of nonerythroid spectrin alphaII. (PMID:32236629)
• Intrafamilial variability in SPTAN1-related disorder: From benign convulsions with mild gastroenteritis to developmental encephalopathy. (PMID:32811770)
• alpha-Fodrin in Cytoskeletal Organization and the Activity of Certain Key Microtubule Kinesins. (PMID:34067543)
• De Novo and Dominantly Inherited SPTAN1 Mutations Cause Spastic Paraplegia and Cerebellar Ataxia. (PMID:35150594)
• Expanding SPTAN1 monoallelic variant associated disorders: From epileptic encephalopathy to pure spastic paraplegia and ataxia. (PMID:36331550)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	sptan1	ENSDARG00000019231
mus_musculus	Sptan1	ENSMUSG00000057738
rattus_norvegicus	Sptan1	ENSRNOG00000015396
drosophila_melanogaster	alpha-Spec	FBGN0250789

Paralogs (36): SYNE2 (ENSG00000054654), SPTB (ENSG00000070182), ACTN1 (ENSG00000072110), ACTN2 (ENSG00000077522), DSP (ENSG00000096696), DRP2 (ENSG00000102385), SPTBN1 (ENSG00000115306), MACF1 (ENSG00000127603), FLNC (ENSG00000128591), ACTN4 (ENSG00000130402), SYNE1 (ENSG00000131018), MICAL2 (ENSG00000133816), DTNA (ENSG00000134769), MICAL1 (ENSG00000135596), FLNB (ENSG00000136068), SPTBN5 (ENSG00000137877), DTNB (ENSG00000138101), GAS2L3 (ENSG00000139354), DST (ENSG00000151914), UTRN (ENSG00000152818), SPTBN4 (ENSG00000160460), SPTA1 (ENSG00000163554), CLMN (ENSG00000165959), PKHD1 (ENSG00000170927), SPTBN2 (ENSG00000173898), SYNE3 (ENSG00000176438), PLEC (ENSG00000178209), SMTNL2 (ENSG00000188176), FLNA (ENSG00000196924), DMD (ENSG00000198947), PKHD1L1 (ENSG00000205038), DYTN (ENSG00000232125), MICAL3 (ENSG00000243156), ACTN3 (ENSG00000248746), EPPK1 (ENSG00000261150), GAS2L2 (ENSG00000270765)

Protein

Protein identifiers

Spectrin alpha chain, non-erythrocytic 1 — Q13813 (reviewed: Q13813)

Alternative names: Alpha-II spectrin, Fodrin alpha chain, Spectrin, non-erythroid alpha subunit

All UniProt accessions (18): A0A0D9SF54, A0A0D9SFF6, A0A0D9SFH4, A0A0D9SGF6, A0A1B0GTB7, A0A1B0GTD1, A0A1B0GUH3, A0A1B0GV13, A0A1B0GW19, A0A1B0GWE2, A0A384P5S9, A0A5F9ZHC3, A0A994J498, A0A994J4G5, A0A994J6W3, A0A994J6W6, A0A994J7B0, Q13813

UniProt curated annotations — full annotation on UniProt →

Function. Fodrin, which seems to be involved in secretion, interacts with calmodulin in a calcium-dependent manner and is thus candidate for the calcium-dependent movement of the cytoskeleton at the membrane.

Subunit / interactions. Like erythrocyte spectrin, the spectrin-like proteins are capable of forming dimers which can further associate to tetramers. Interacts (via C-terminal spectrin repeats) with TRPC4. Interacts with CALM and EMD. Interacts with isoform 1 of ACP1. Identified in a complex with ACTN4, CASK, IQGAP1, MAGI2, NPHS1 and SPTBN1. Interacts with SHANK3 (via ANK repeats). Interacts with CLN3; this interaction regulates the fodrin localization at the plasma membrane.

Subcellular location. Cytoplasm. Cytoskeleton. Cell cortex.

Post-translational modifications. Phosphorylation of Tyr-1176 decreases sensitivity to cleavage by calpain in vitro.

Disease relevance. Developmental and epileptic encephalopathy 5 (DEE5) [MIM:613477] A disorder characterized by seizures associated with hypsarrhythmia, profound intellectual disability with lack of visual attention and speech development, as well as spastic quadriplegia. The disease is caused by variants affecting the gene represented in this entry. Developmental delay with or without epilepsy (DEVEP) [MIM:620540] An autosomal dominant neurodevelopmental disorder apparent from infancy or early childhood, and characterized by impaired intellectual development, speech delay, motor delay, and behavioral abnormalities. About half of patients develop various types of seizures. Some affected individuals have cerebellar atrophy and ataxia. The disease is caused by variants affecting the gene represented in this entry. Neuronopathy, distal hereditary motor, autosomal dominant 11 (HMND11) [MIM:620528] A form of distal hereditary motor neuronopathy, a heterogeneous group of neuromuscular diseases caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. HMND11 is an autosomal dominant form with incomplete penetrance, characterized by juvenile or young-adult onset of distal limb muscle weakness and atrophy mainly affecting the lower limbs, resulting in gait instability and walking difficulties. Some affected individuals may have distal upper limb and hand involvement or mild distal sensory abnormalities, but motor symptoms dominate the clinical picture. The disease is caused by variants affecting the gene represented in this entry. Spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia (SPG91) [MIM:620538] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG91 is an autosomal dominant form characterized by gait abnormalities, sometimes associated with cerebellar ataxia. Additional features may include sensory abnormalities, peripheral neuropathy, optic neuropathy, developmental delay, impaired intellectual development, and seizures. Most patients have symptoms onset in the first decade of life, although age at onset is highly variable and ranges from birth to young adulthood. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the spectrin family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q13813-1	1	yes
Q13813-2	2
Q13813-3	3

RefSeq proteins (11): NP_001123910, NP_001182461, NP_001350688, NP_001350694, NP_001362239, NP_001362240, NP_001362241, NP_001362242, NP_001362243, NP_001362247, NP_003118 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR002017	Spectrin_repeat	Repeat
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR014837	EF-hand_Ca_insen	Domain
IPR018159	Spectrin/alpha-actinin	Repeat
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR035825	Alpha_Spectrin_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily

Pfam: PF00018, PF00435, PF08726, PF13499

UniProt features (134 total): sequence variant 36, modified residue 27, repeat 20, helix 14, sequence conflict 11, binding site 10, strand 7, domain 4, splice variant 2, chain 1, turn 1, site 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
6ZEH	X-RAY DIFFRACTION	1.3
5FWC	X-RAY DIFFRACTION	1.4
5FWB	X-RAY DIFFRACTION	1.5
5FW9	X-RAY DIFFRACTION	1.55
3F31	X-RAY DIFFRACTION	2.3
3FB2	X-RAY DIFFRACTION	2.3
2FOT	X-RAY DIFFRACTION	2.45

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13813-F1	77.05	0.04

Functional residue map

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

Catalytic / active sites (1): 1176–1177 (cleavage; by mu-calpain)

Ligand- & substrate-binding residues (10): 2336; 2338; 2340; 2342; 2347; 2379; 2381; 2383; 2385; 2390

Post-translational modifications (27): 1, 587, 637, 803, 924, 982, 999, 1029, 1031, 1041, 1176, 1190, 1207, 1217, 1291, 1306, 1323, 1338, 1519, 1550 …

Function

Pathways and Gene Ontology

Reactome pathways

37 pathways

ID	Pathway
R-HSA-264870	Caspase-mediated cleavage of cytoskeletal proteins
R-HSA-373753	Nephrin family interactions
R-HSA-375165	NCAM signaling for neurite out-growth
R-HSA-445095	Interaction between L1 and Ankyrins
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-6798695	Neutrophil degranulation
R-HSA-6807878	COPI-mediated anterograde transport
R-HSA-9013420	RHOU GTPase cycle
R-HSA-9013424	RHOV GTPase cycle
R-HSA-9662360	Sensory processing of sound by inner hair cells of the cochlea
R-HSA-9662361	Sensory processing of sound by outer hair cells of the cochlea
R-HSA-109581	Apoptosis
R-HSA-111465	Apoptotic cleavage of cellular proteins
R-HSA-1266738	Developmental Biology
R-HSA-1500931	Cell-Cell communication
R-HSA-162582	Signal Transduction
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-194315	Signaling by Rho GTPases
R-HSA-199977	ER to Golgi Anterograde Transport
R-HSA-199991	Membrane Trafficking
R-HSA-373760	L1CAM interactions
R-HSA-392499	Metabolism of proteins
R-HSA-422475	Axon guidance
R-HSA-446203	Asparagine N-linked glycosylation
R-HSA-5357801	Programmed Cell Death
R-HSA-5653656	Vesicle-mediated transport
R-HSA-5683057	MAPK family signaling cascades
R-HSA-5684996	MAPK1/MAPK3 signaling
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 496 (showing top): TAKEDA_TARGETS_OF_NUP98_HOXA9_FUSION_6HR_DN, TGGTGCT_MIR29A_MIR29B_MIR29C, RNGTGGGC_UNKNOWN, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, REACTOME_INNATE_IMMUNE_SYSTEM, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, PAX4_01, RORA1_01, GOCC_SECRETORY_GRANULE, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_POLYMERIZATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN

GO Biological Process (3): actin cytoskeleton organization (GO:0030036), actin filament capping (GO:0051693), cytoskeleton organization (GO:0007010)

GO Molecular Function (8): actin binding (GO:0003779), structural constituent of cytoskeleton (GO:0005200), calcium ion binding (GO:0005509), calmodulin binding (GO:0005516), cadherin binding (GO:0045296), actin filament binding (GO:0051015), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (17): extracellular region (GO:0005576), cytosol (GO:0005829), plasma membrane (GO:0005886), spectrin (GO:0008091), microtubule cytoskeleton (GO:0015630), membrane (GO:0016020), cell junction (GO:0030054), cortical actin cytoskeleton (GO:0030864), specific granule lumen (GO:0035580), cell projection (GO:0042995), extracellular exosome (GO:0070062), extracellular vesicle (GO:1903561), tertiary granule lumen (GO:1904724), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), cell cortex (GO:0005938), organelle (GO:0043226)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
RHO GTPase cycle	2
Sensory processing of sound	2
Apoptotic cleavage of cellular proteins	1
Cell-Cell communication	1
Axon guidance	1
L1CAM interactions	1
MAPK1/MAPK3 signaling	1
Innate Immune System	1
ER to Golgi Anterograde Transport	1
Programmed Cell Death	1
Apoptotic execution phase	1
Immune System	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Membrane Trafficking	1
Transport to the Golgi and subsequent modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
cytoskeleton organization	2
cytoskeleton	2
cytoplasm	2
cell periphery	2
actin filament-based process	1
negative regulation of actin filament depolymerization	1
negative regulation of actin filament polymerization	1
organelle organization	1
cytoskeletal protein binding	1
structural molecule activity	1
metal ion binding	1
protein binding	1
cell adhesion molecule binding	1
actin binding	1
protein-containing complex binding	1
binding	1
cation binding	1
membrane	1
cortical actin cytoskeleton	1
protein-containing complex	1
actin cytoskeleton	1
cortical cytoskeleton	1
secretory granule lumen	1
specific granule	1
extracellular vesicle	1
extracellular region	1
vesicle	1
extracellular membrane-bounded organelle	1
intracellular organelle lumen	1
tertiary granule	1
intracellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

2104 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPTAN1	ANK2	Q01484	990
SPTAN1	SPTBN1	Q01082	986
SPTAN1	ANK3	Q12955	889
SPTAN1	STXBP1	P61764	887
SPTAN1	ANK1	P16157	815
SPTAN1	SPTB	P11277	805
SPTAN1	EPB41	P11171	787
SPTAN1	CAST	P20810	786
SPTAN1	SLC25A22	Q9H936	782
SPTAN1	PCDH19	Q8TAB3	761
SPTAN1	CAPN2	P17655	757
SPTAN1	SPTBN5	Q9NRC6	747
SPTAN1	VASP	P50552	736
SPTAN1	SPTBN4	Q9H254	736
SPTAN1	SHANK1	Q9Y566	731

IntAct

322 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
MED20	MED19	psi-mi:“MI:0914”(association)	0.840
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
PAK5	AURKA	psi-mi:“MI:0914”(association)	0.640
SPTAN1	SPTBN1	psi-mi:“MI:0407”(direct interaction)	0.610
SPTBN1	SPTAN1	psi-mi:“MI:0407”(direct interaction)	0.610
SPTBN1	SPTAN1	psi-mi:“MI:0915”(physical association)	0.610
TJP1	ACTN4	psi-mi:“MI:0914”(association)	0.600
SPTAN1	MLH1	psi-mi:“MI:0915”(physical association)	0.600
MLH1	SPTAN1	psi-mi:“MI:0915”(physical association)	0.600
MLH1	SPTAN1	psi-mi:“MI:0403”(colocalization)	0.600
CALD1	SPTAN1	psi-mi:“MI:0915”(physical association)	0.560
GATA2	BANF1	psi-mi:“MI:0914”(association)	0.530
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
SPTB	SPTAN1	psi-mi:“MI:0407”(direct interaction)	0.440
SPTBN1	SPTAN1	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (657): KIAA0368 (Co-fractionation), SPTAN1 (Co-fractionation), SPTAN1 (Co-fractionation), SPTAN1 (Co-fractionation), SPTAN1 (Co-fractionation), SPTAN1 (Co-fractionation), SPTAN1 (Co-fractionation), SPTAN1 (Co-fractionation), SPTAN1 (Co-fractionation), SPTAN1 (Co-fractionation), SPTBN1 (Co-fractionation), SPTBN5 (Co-fractionation), SPTAN1 (Affinity Capture-MS), PDE4D (Far Western), SPTAN1 (Reconstituted Complex)

ESM2 similar proteins: A2CG49, D3ZHV2, F1M0Z1, L7UZ85, O13728, O15020, O15068, O60229, O75962, O88990, P02549, P05095, P07751, P08032, P11277, P11533, P13395, P15508, P16086, P16546, P18091, P20111, P30427, P35609, P97924, Q00963, Q01082, Q08043, Q0III9, Q0KL02, Q13813, Q15149, Q1LUA6, Q3ZC55, Q62261, Q7PKQ5, Q86VI3, Q8R307, Q90734, Q99PK0

Diamond homologs: A0JNJ1, A1CEK6, A1DFN5, A2QW93, A4RF61, A6QLK6, A7A261, F1LRS8, O35179, O35964, O43307, O74749, O75791, O75886, O88811, O89100, O93436, P02549, P07751, P09215, P09216, P10830, P13395, P16054, P16086, P16546, P23298, P24723, P28867, P29355, P32793, P34885, P38753, P43603, P53281, P62993, P62994, P70297, P87379, P97306

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
“Caspase 3 complex”	down-regulates	SPTAN1	cleavage
FANCG	“up-regulates quantity by stabilization”	SPTAN1
SPTAN1	“form complex”	“Non-erythrocytic spectrin”	binding
CASP3	down-regulates	SPTAN1	cleavage
SPTAN1	up-regulates	Membrane_blebbing
SRC	up-regulates	SPTAN1	phosphorylation
SPTAN1	“up-regulates activity”	ERCC4

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 198 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Signaling by FLT3 fusion proteins	6	25.8×	2e-05
Downstream signal transduction	5	14.3×	2e-03
Signaling by high-kinase activity BRAF mutants	5	11.9×	3e-03
Sensory processing of sound	5	11.6×	3e-03
Signaling by ALK fusions and activated point mutants	10	11.3×	8e-06
Signaling by FGFR1 in disease	5	11.0×	4e-03
MAP2K and MAPK activation	5	10.7×	4e-03
RHOV GTPase cycle	5	10.7×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
epidermal growth factor receptor signaling pathway	7	10.3×	2e-03
actin filament organization	9	6.4×	5e-03
actin cytoskeleton organization	13	6.1×	2e-04
negative regulation of gene expression	11	4.5×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

3252 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	53
Likely pathogenic	68
Uncertain significance	1293
Likely benign	1320
Benign	152

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1014849	NC_000009.11:g.(?131360669)(131367766_?)del	Pathogenic
1038134	NM_001130438.3(SPTAN1):c.2961del (p.Thr987_Met988insTer)	Pathogenic
1053546	NM_001130438.3(SPTAN1):c.1367G>A (p.Trp456Ter)	Pathogenic
1308193	NM_001130438.3(SPTAN1):c.133C>T (p.Arg45Ter)	Pathogenic
1356630	NM_001130438.3(SPTAN1):c.6100C>T (p.Gln2034Ter)	Pathogenic
1360796	NM_001130438.3(SPTAN1):c.2860del (p.Gln954fs)	Pathogenic
1400602	NM_001130438.3(SPTAN1):c.889_896del (p.His297fs)	Pathogenic
1414392	NM_001130438.3(SPTAN1):c.6956C>A (p.Ala2319Asp)	Pathogenic
1458679	NM_001130438.3(SPTAN1):c.3251_3252del (p.Lys1084fs)	Pathogenic
1686228	NM_001130438.3(SPTAN1):c.6905_6946dup (p.Leu2302_Gln2315dup)	Pathogenic
1701629	NM_001130438.3(SPTAN1):c.7229C>T (p.Ser2410Phe)	Pathogenic
1707716	NC_000009.11:g.(?131382516)(131393966_?)del	Pathogenic
1804130	NM_001130438.3(SPTAN1):c.6924_6929dup (p.Met2309_Gln2310insHisMet)	Pathogenic
2034072	NM_001130438.3(SPTAN1):c.58dup (p.Gln20fs)	Pathogenic
2095342	NM_001130438.3(SPTAN1):c.6975_6995delinsTC (p.Thr2326fs)	Pathogenic
2106992	NM_001130438.3(SPTAN1):c.3292del (p.Arg1098fs)	Pathogenic
2111062	NM_001130438.3(SPTAN1):c.7225_7228dup (p.Ser2410Ter)	Pathogenic
2117994	NM_001130438.3(SPTAN1):c.6937dup (p.Leu2313fs)	Pathogenic
2571338	NM_001130438.3(SPTAN1):c.1006C>T (p.Arg336Ter)	Pathogenic
2581094	NM_001130438.3(SPTAN1):c.4615C>T (p.Gln1539Ter)	Pathogenic
2581095	NM_001130438.3(SPTAN1):c.6367del (p.Val2123fs)	Pathogenic
2583070	NM_001130438.3(SPTAN1):c.1642C>T (p.Arg548Ter)	Pathogenic
2659537	NM_001130438.3(SPTAN1):c.315_316insA (p.Gly106fs)	Pathogenic
2702325	NM_001130438.3(SPTAN1):c.1339G>T (p.Glu447Ter)	Pathogenic
2746967	NM_001130438.3(SPTAN1):c.5425A>T (p.Lys1809Ter)	Pathogenic
2786148	NM_001130438.3(SPTAN1):c.5531_5532del (p.Glu1844fs)	Pathogenic
3322409	NM_001130438.3(SPTAN1):c.6460C>T (p.Gln2154Ter)	Pathogenic
3341008	NM_001130438.3(SPTAN1):c.6923G>A (p.Arg2308His)	Pathogenic
3341043	NM_001130438.3(SPTAN1):c.6263dup (p.Ser2089fs)	Pathogenic
3359083	NM_001130438.3(SPTAN1):c.1033C>T (p.Gln345Ter)	Pathogenic

SpliceAI

7113 predictions. Top by Δscore:

Variant	Effect	Δscore
9:128566731:A:AG	acceptor_gain	1.0000
9:128566733:TTCAG:T	acceptor_loss	1.0000
9:128566735:CAGAA:C	acceptor_loss	1.0000
9:128566736:A:AG	acceptor_gain	1.0000
9:128566736:A:T	acceptor_loss	1.0000
9:128566737:G:GA	acceptor_gain	1.0000
9:128566737:GA:G	acceptor_gain	1.0000
9:128566737:GAA:G	acceptor_gain	1.0000
9:128566737:GAAA:G	acceptor_gain	1.0000
9:128566737:GAAAA:G	acceptor_gain	1.0000
9:128566975:CAGG:C	donor_loss	1.0000
9:128566977:GGTA:G	donor_loss	1.0000
9:128566978:G:C	donor_loss	1.0000
9:128566979:T:G	donor_loss	1.0000
9:128574669:TTTCA:T	acceptor_loss	1.0000
9:128574670:TTCA:T	acceptor_loss	1.0000
9:128574672:CA:C	acceptor_loss	1.0000
9:128574673:A:AG	acceptor_gain	1.0000
9:128574673:A:AT	acceptor_loss	1.0000
9:128574674:G:GC	acceptor_gain	1.0000
9:128574674:GA:G	acceptor_gain	1.0000
9:128574674:GAC:G	acceptor_gain	1.0000
9:128574674:GACC:G	acceptor_gain	1.0000
9:128574674:GACCC:G	acceptor_gain	1.0000
9:128574789:G:GT	donor_gain	1.0000
9:128574827:G:GT	donor_gain	1.0000
9:128574827:G:T	donor_gain	1.0000
9:128575184:AT:A	acceptor_gain	1.0000
9:128575185:T:TA	acceptor_gain	1.0000
9:128575186:G:A	acceptor_gain	1.0000

AlphaMissense

16522 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:128576890:T:C	L240P	1.000
9:128577254:T:C	L304P	1.000
9:128581004:T:C	L469P	1.000
9:128581010:T:C	L471P	1.000
9:128581019:G:C	R474P	1.000
9:128581042:T:A	W482R	1.000
9:128581042:T:C	W482R	1.000
9:128581044:G:C	W482C	1.000
9:128581044:G:T	W482C	1.000
9:128581789:T:C	L490P	1.000
9:128581834:T:C	L505P	1.000
9:128581867:T:C	L516P	1.000
9:128582504:T:C	L533P	1.000
9:128582749:T:C	L569P	1.000
9:128582805:T:A	W588R	1.000
9:128582805:T:C	W588R	1.000
9:128582807:G:C	W588C	1.000
9:128582807:G:T	W588C	1.000
9:128582830:C:A	A596D	1.000
9:128583125:G:C	A619P	1.000
9:128583132:T:C	L621P	1.000
9:128583258:T:C	L663P	1.000
9:128583797:T:C	L674P	1.000
9:128583805:G:C	A677P	1.000
9:128583830:G:C	R685P	1.000
9:128583853:T:A	W693R	1.000
9:128583853:T:C	W693R	1.000
9:128583923:T:C	L716P	1.000
9:128584427:T:C	L780P	1.000
9:128584483:T:A	W799R	1.000

dbSNP variants (sampled 300 via entrez): RS1000077448 (9:128560436 A>G), RS1000086103 (9:128566240 T>G), RS1000095719 (9:128602852 T>C), RS1000159647 (9:128616022 C>T), RS1000206858 (9:128609399 A>G), RS1000224471 (9:128573248 C>A), RS1000254334 (9:128565995 G>C), RS1000258192 (9:128603059 C>A), RS1000261748 (9:128621871 C>G), RS1000353801 (9:128573140 T>C), RS1000359183 (9:128616290 G>A,T), RS1000387894 (9:128586851 T>A,C), RS1000422998 (9:128627097 G>A), RS1000458102 (9:128566502 G>A), RS1000488052 (9:128572814 C>G)

Disease associations

OMIM: gene MIM:182810 | disease phenotypes: MIM:613477, MIM:108600, MIM:620540, MIM:620538, MIM:620528, MIM:303350, MIM:117100, MIM:253300, MIM:300799, MIM:213000, MIM:615633

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy, 5	Definitive	Autosomal dominant
genetic developmental and epileptic encephalopathy	Definitive	Autosomal dominant
neuronopathy, distal hereditary motor, autosomal dominant 11	Strong	Autosomal dominant
spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia	Strong	Autosomal dominant
infantile spasms	Supportive	Autosomal dominant
hereditary spastic paraplegia	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
genetic developmental and epileptic encephalopathy	Definitive	AD

Mondo (26): developmental and epileptic encephalopathy (MONDO:0100620), early-infantile DEE (MONDO:0800491), developmental and epileptic encephalopathy, 5 (MONDO:0013277), spastic ataxia (MONDO:0017845), developmental delay with or without epilepsy (MONDO:0957815), neurodevelopmental disorder (MONDO:0700092), spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia (MONDO:0957813), neuronopathy, distal hereditary motor, autosomal dominant 11 (MONDO:0957875), intellectual disability (MONDO:0001071), distal hereditary motor neuropathy (MONDO:0018894), neuromuscular disease (MONDO:0019056), hereditary spastic paraplegia (MONDO:0019064), self-limited epilepsy with centrotemporal spikes (MONDO:0007295), undetermined early-onset epileptic encephalopathy (MONDO:0018614), Landau-Kleffner syndrome (MONDO:0009509)

Orphanet (19): Early infantile developmental and epileptic encephalopathy (Orphanet:1934), West syndrome (Orphanet:3451), Spastic ataxia (Orphanet:316226), Distal hereditary motor neuropathy (Orphanet:53739), Neuromuscular disease (Orphanet:68381), Hereditary spastic paraplegia (Orphanet:685), Self-limited epilepsy with centrotemporal spikes (Orphanet:1945), Non-specific early-onset epileptic encephalopathy (Orphanet:442835), Developmental and epileptic encephalopathy with spike-wave activation in sleep (Orphanet:725), Landau-Kleffner syndrome (Orphanet:98818), Proximal spinal muscular atrophy type 1 (Orphanet:83330), Isolated cerebellar agenesis (Orphanet:1398), Cerebellar hypoplasia-tapetoretinal degeneration syndrome (Orphanet:2246), Jeune syndrome (Orphanet:474), Short rib-polydactyly syndrome, Verma-Naumoff type (Orphanet:93271)

HPO phenotypes

104 total (30 of 104 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000098	Tall stature
HP:0000189	Narrow palate
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000486	Strabismus
HP:0000639	Nystagmus
HP:0000707	Abnormality of the nervous system
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0000768	Pectus carinatum
HP:0001138	Optic neuropathy
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001258	Spastic paraplegia
HP:0001260	Dysarthria
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001332	Dystonia
HP:0001336	Myoclonus
HP:0001347	Hyperreflexia
HP:0001382	Joint hypermobility
HP:0001761	Pes cavus
HP:0001763	Pes planus

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002115_14	Axial length	6.000000e-06
GCST005951_65	Body mass index	5.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005318	axial length measurement
EFO:0004340	body mass index

MeSH disease descriptors (10)

Descriptor	Name	Tree numbers
D004828	Epilepsies, Partial	C10.228.140.490.360
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D018887	Landau-Kleffner Syndrome	C10.228.140.490.493.500
D008209	Lymphedema	C15.604.496
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D065886	Neurodevelopmental Disorders	F03.625
D009468	Neuromuscular Diseases	C10.668
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
C562568	Cerebellar Hypoplasia (supp.)
C564815	Spastic Ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725058 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2297771	SPTAN1		0.00	0

ChEMBL bioactivities

5 potent at pChembl≥5 of 5 total, top 5 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.10	Kd	79.95	nM	CHEMBL3752910
7.10	ED50	79.95	nM	CHEMBL3752910
6.92	Kd	120.3	nM	CHEMBL5653589
6.92	ED50	120.3	nM	CHEMBL5653589
5.98	IC50	1040	nM	MOLIBRESIB

PubChem BioAssay actives

3 with measured affinity, of 10 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149474: Binding affinity to human SPTAN1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0799	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149474: Binding affinity to human SPTAN1 incubated for 45 mins by Kinobead based pull down assay	kd	0.1203	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178830: Inhibition of SPTAN1 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	1.0400	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, affects cotreatment, decreases expression, increases abundance	4
Acetaminophen	decreases expression, increases expression	3
Tretinoin	increases cleavage, decreases expression, affects cotreatment	3
Valproic Acid	affects expression, decreases expression, increases expression	3
bisphenol F	increases expression, affects cotreatment	2
(+)-JQ1 compound	increases expression	2
Resveratrol	decreases reaction, increases cleavage, affects cotreatment, increases expression	2
Arsenic Trioxide	increases expression	2
Aspirin	decreases expression	2
Cisplatin	increases cleavage, decreases expression	2
Dexamethasone	increases cleavage, affects cotreatment, increases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Cyclosporine	decreases expression	2
Particulate Matter	increases abundance, increases expression, decreases expression, affects cotreatment	2
cyclopiazonic acid	increases cleavage	1
FR900359	increases phosphorylation	1
TAK-243	decreases sumoylation	1
dicrotophos	increases expression	1
dimethyl maleate	increases cleavage	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	increases expression	1
methylselenic acid	increases expression	1
pyrogallol 1,3-dimethyl ether	decreases expression, affects cotreatment, affects localization	1
styrene oxide	increases cleavage	1
diethyl maleate	increases cleavage	1
arsenite	affects binding, increases reaction	1
chelerythrine	increases cleavage	1
cobaltous chloride	increases expression	1
acetylenedicarboxylic acid dimethyl ester	increases cleavage	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652516	Binding	Binding affinity to human SPTAN1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01413711	PHASE4	WITHDRAWN	An Open-Label, Single and Multiple Oral Dose Pharmacokinetic Study of Vigabatrin in Infants With Infantile Spasms
NCT02092883	PHASE4	COMPLETED	Evaluation of Neuroinflammation in Children With Infantile Spasms
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
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
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT01575639	PHASE3	COMPLETED	Prednisolone in Infantile Spasms- High Dose Versus Usual Dose
NCT01828437	PHASE3	COMPLETED	Addition of Pyridoxine to Prednisolone in Infantile Spasms
NCT02299115	PHASE3	WITHDRAWN	Prednisolone Versus Vigabatrin in the First-line Treatment of Infantile Spasms
NCT02953548	PHASE3	COMPLETED	Trial of Cannabidiol (CBD; GWP42003-P) for Infantile Spasms (GWPCARE7)
NCT02954887	PHASE3	COMPLETED	Phase 3 Trial of Cannabidiol (CBD; GWP42003-P) for Infantile Spasms: Open-label Extension Phase (GWPCARE7)
NCT03347526	PHASE3	SUSPENDED	A Novel Approach to Infantile Spasms
NCT03421496	PHASE3	TERMINATED	A Study to Assess Cannabidiol Oral Solution With Vigabatrin as Initial Therapy in Participants With Infantile Spasms
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
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
NCT05626634	PHASE2	COMPLETED	Open-label, Long-term Safety Study of LP352 in Subjects With Developmental and Epileptic Encephalopathy
NCT00441896	PHASE2	COMPLETED	A Randomized, Controlled Trial of Ganaxolone in Patients With Infantile Spasms
NCT00442104	PHASE2	TERMINATED	Open-label Extension to Protocol 1042-0500
NCT02829827	PHASE2	TERMINATED	A Phase 2 Study of Radiprodil in Subjects With Drug-resistant Infantile Spasms (IS)
NCT03976076	PHASE2	TERMINATED	A Study of Orally Administered JBPOS0101 in Refractory Infantile Spasms Patients
NCT06819670	PHASE2	RECRUITING	A Study to Prevent Infantile Spasms Relapse
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT04289467	PHASE2	RECRUITING	Treatment of Refractory Infantile Spasms With Fenfluramine
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
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
NCT06700811	PHASE1	RECRUITING	Ketogenic Diet for Prevention of Epileptic Spasms in Infantile Onset Genetic Epilepsies