SPTBN2

protein-coding

spectrin beta, non-erythrocytic 2, the group of Spectrins|Pleckstrin homology domain containing

Gene summary

Spectrins are principle components of a cell's membrane-cytoskeleton and are composed of two alpha and two beta spectrin subunits. The protein encoded by this gene (SPTBN2), is called spectrin beta non-erythrocytic 2 or beta-III spectrin. It is related to, but distinct from, the beta-II spectrin gene which is also known as spectrin beta non-erythrocytic 1 (SPTBN1). SPTBN2 regulates the glutamate signaling pathway by stabilizing the glutamate transporter EAAT4 at the surface of the plasma membrane. Mutations in this gene cause a form of spinocerebellar ataxia, SCA5, that is characterized by neurodegeneration, progressive locomotor incoordination, dysarthria, and uncoordinated eye movements. [provided by RefSeq, Dec 2009]

Previous symbols:

SCA5

MANE transcript

NM_006946.4

Inheritance

AR, AD

ClinVar variants

P:65U:700B:514

Top phenotype

Spinocerebellar ataxia 5, autosomal dominant; Spinocerebellar ataxia 14, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.27

Max pathogenic AF

—

Genomic locus

chr11:66,682,496-66,744,670

External References & Databases

Ensembl (ENSG00000173898)

Transcript & Mutation Effects

hg38 • Region Span ~62.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive spinocerebellar ataxia 14DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014159

Submitter: G2P

spinocerebellar ataxia type 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010848

Submitter: PanelApp Australia

autosomal recessive spinocerebellar ataxia 14DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014159

Submitter: ClinGen

Nonerythrocytic beta spectrin (SPTBN2) was first reported in relation to autosomal recessive spinocerebellar ataxia 14 in 2012 (Lise et al., PMID: 23236289). *SPTBN2* can involve but is not limited to: ataxia, developmental delay, cerebellar atrophy and intellectual disability. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found a difference in the molecular mechanism and inheritance pattern. Therefore, the following disease entities have been split into multiple disease entities: spinocerebellar ataxia 5 (OMIM:600224), and spinocerebellar ataxia recessive 14 (OMIM:615386). The split curation for autosomal dominant spinocerebellar ataxia 5 has been curated separately. Four variants (1 missense, 1 nonsense, 1 frameshift and 1 splice-site) that have been reported in four probands in four publications (PMIDs: 23236289, 23838597, 28636205, 31692161) are included in this curation. Case evidence includes segregation in a family with 7 genotyped affected homozygous carriers and 3 unaffected heterozygous carriers. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by expression data and a knockout mouse model (PMIDs: 20371805, 9826670). The mouse model showed features consistent with ataxia in mouse models and further supports the proposed loss of function mechanism by lack of phenotype in the heterozygous mice. In summary, there is definitive evidence to support the relationship between *SPTBN2* and autosomal recessive spinocerebellar ataxia 14. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Cerebellar Ataxia GCEP on the meeting date May 13, 2026 (SOP Version 12).

autosomal recessive spinocerebellar ataxia 14STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014159

Submitter: PanelApp Australia

autosomal recessive spinocerebellar ataxia 14STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014159

Submitter: Labcorp Genetics (formerly Invitae)

spinocerebellar ataxia type 5DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010848

Submitter: ClinGen

Nonerythrocytic spectrin beta (SPTBN2) was first reported in relation to autosomal dominant spinocerebellar ataxia in 2006 (Ikeda et al., PMID: 16429157). Features of autosomal dominant *SPTBN2* related disease include but are not limited to: cerebellar ataxia, nystagmus, developmental delay, and cerebellar atrophy. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found a difference in the molecular mechanism and inheritance pattern. Therefore, the following disease entities have been split into two disease entities: spinocerebellar ataxia 5 (OMIM:600224), spinocerebellar ataxia recessive 14 (OMIM:615386). The split curation for autosomal recessive *SPTBN2* related spinocerebellar ataxia has been curated separately. 16 variants (14 missense and 2 in-frame indels that have been reported in 18 probands in 9 publications (PMIDs: 16429157, 25981959, 22914369, 31617442, 31066025, 31721007, 30898343, 29915382, 33801522) are included in this curation. Segregation in a large well phenotyped family with extensive genotyping yielded approximately 90 affected with consistent features and all affected members genotyped, carried the familial variant (PMID 16429157). More evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism of pathogenicity appears to be gain-of-function, though the precise nature of the altered function is unclear. This gene-disease relationship is also supported by an animal model, expression study and functional alteration assay (PMIDs: 9826670, 20603325, 25057192). Expression of a human patient derived variant nearly fully recapitulated the ataxia and cerebellar atrophy features in a mouse model and a cell-culture model in a mouse neuronal cell line (Neuro2a) showed disruption to sub-cellular localization. Further functional evidence was used to weight case-level evidence and suggested that at least one mechanism for disease could be related to an increase in variant *SPTBN2* binding affinity for actin (PMID: 37626910). In summary, there is definitive evidence supporting the relationship between *SPTBN2* and autosomal dominant spinocerebellar ataxia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Cerebellar Ataxia GCEP on the meeting date Wednesday Sepetember 10, 2025 (SOP Version 11).

spinocerebellar ataxia type 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010848

Submitter: Illumina

autosomal recessive spinocerebellar ataxia 14SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014159

Submitter: Orphanet

spinocerebellar ataxia type 5SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010848

Submitter: Orphanet

spinocerebellar ataxia type 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010848

Submitter: G2P

spinocerebellar ataxia type 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010848

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Spinocerebellar ataxia 5, autosomal dominant; Spinocerebellar ataxia 14, autosomal recessiveAD/AR

Manifestation: Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 16429157; 23236289; 23838597

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SPTBN2 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 1138

Inborn genetic diseasesTotal: 350

not specifiedTotal: 221

Spinocerebellar ataxia type 5Total: 115

Autosomal recessive spinocerebellar ataxia 14Total: 70

SPTBN2-related disorderTotal: 66

See casesTotal: 4

Hereditary ataxiaTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006946.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			18 clinvar	301 clinvar	28 clinvar	347
missense	4 clinvar	31 clinvar	664 clinvar	179 clinvar	6 clinvar	884
nonsense	10 clinvar	3 clinvar	3 clinvar			16
start loss						0
frameshift	4 clinvar	5 clinvar	3 clinvar			12
splice donor/acceptor (+/-2bp)	5 clinvar	3 clinvar	12 clinvar			20
Total	23	42	700	480	34	1279

Highest pathogenic variant AF is 0.0000830572

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 45 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006946.4	RefSeq	NP_008877.2	36	MANE Select
ENST00000533211.6	Ensembl	ENSP00000432568.1	36	MANE Select
NM_001411025.1	RefSeq	NP_001397954.1	36	Standard
NM_001437541.1	RefSeq	NP_001424470.1	36	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Developmental Biology
Signal Transduction
Vesicle-mediated transport
Membrane Trafficking
Post-translational protein modification

Biological Process

MAPK cascade
endoplasmic reticulum to Golgi vesicle-mediated transport
cytoskeleton organization
axon guidance
synapse assembly

Molecular Function

actin binding
Ras guanyl-nucleotide exchange factor activity
structural constituent of cytoskeleton
phospholipid binding
cadherin binding

Cellular Component

extracellular space
cytosol
spectrin
apical plasma membrane
cell junction

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000533211
Coding exons: 36
Length: 43979
Individuals with no LoFs: 125695
Homozygous LoFs: 0
Heterozygous LoFs: 53
Defined: 125748
p: 0.000211

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.63	1209	1.50e+3	0.808	0.000111	15347
Missense (PolyPhen)		459	664.15	0.69111		6992
Synonymous	-0.589	653	634	1.03	0.0000470	4851
Loss of Function	7.64	34	127	0.268	0.00000763	1257

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.00047	0.00040	rare
East Asian	0.00033	0.00033	rare
Finnish	0.00029	0.00023	rare
European (Non-Finnish)	0.00017	0.00017	rare
South Asian	0.00036	0.00036	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probably plays an important role in neuronal membrane skeleton.;
Disease: DISEASE: Spinocerebellar ataxia, autosomal recessive, 14 (SCAR14) [MIM:615386]: Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR14 is characterized by delayed psychomotor development, severe early onset gait ataxia, eye movement abnormalities, cerebellar atrophy on brain imaging, and intellectual disability. {ECO:0000269|PubMed:23236289, ECO:0000269|PubMed:23838597}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.205

Intolerance Scores

LoFtool: 0.469
RVIS EVS: -4.23
RVIS percentile EVS: 0.14

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.816

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium