SPTB

Summary

SPTB (spectrin beta, erythrocytic, HGNC:11274) is a protein-coding gene on chromosome 14q23.3, encoding Spectrin beta chain, erythrocytic (P11277). Spectrin is the major constituent of the cytoskeletal network underlying the erythrocyte plasma membrane.

This locus encodes a member of the spectrin gene family. Spectrin proteins, along with ankyrin, play a role in cell membrane organization and stability. The protein encoded by this locus functions in stability of erythrocyte membranes, and mutations in this gene have been associated with spherocytosis type 2, hereditary elliptocytosis, and neonatal hemolytic anemia. Alternatively spliced transcript variants have been described.

Source: NCBI Gene 6710 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary spherocytosis type 2 (Strong, GenCC) — +3 more curated relationships
• GWAS associations: 42
• Clinical variants (ClinVar): 1,713 total — 222 pathogenic, 291 likely-pathogenic
• Phenotypes (HPO): 46
• MANE Select transcript: NM_001355436

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11274
Approved symbol	SPTB
Name	spectrin beta, erythrocytic
Location	14q23.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000070182
Ensembl biotype	protein_coding
OMIM	182870
Entrez	6710

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 8 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000342835, ENST00000389720, ENST00000389722, ENST00000542694, ENST00000553938, ENST00000556227, ENST00000644917, ENST00000902733, ENST00000961380, ENST00000961381, ENST00000961382

RefSeq mRNA: 3 — MANE Select: NM_001355436 NM_001024858, NM_001355436, NM_001355437

CCDS: CCDS32099, CCDS32100

Canonical transcript exons

ENST00000644917 — 36 exons

Exon	Start	End
ENSE00000392073	64785537	64785627
ENSE00000392079	64774397	64774527
ENSE00000392084	64769034	64769118
ENSE00000658438	64767303	64767352
ENSE00000658448	64775125	64775403
ENSE00000867578	64784247	64784393
ENSE00000867584	64773220	64773424
ENSE00000867585	64772580	64772954
ENSE00000867589	64767663	64767859
ENSE00000902493	64769590	64769728
ENSE00000902494	64770885	64771129
ENSE00000902497	64779157	64779246
ENSE00001364447	64766726	64766801
ENSE00001506736	64779725	64779931
ENSE00001506737	64782290	64782553
ENSE00001592915	64801754	64801834
ENSE00001594267	64786404	64787160
ENSE00001597703	64785749	64785951
ENSE00001601006	64801285	64801400
ENSE00001604309	64791719	64791856
ENSE00001642694	64803607	64803780
ENSE00001643410	64799747	64799934
ENSE00001643743	64794467	64794617
ENSE00001647147	64802226	64802317
ENSE00001689221	64795337	64795639
ENSE00001692272	64804939	64805090
ENSE00001699666	64792997	64793867
ENSE00001786358	64796557	64796715
ENSE00001788289	64800756	64800868
ENSE00001793364	64797729	64797846
ENSE00002263831	64822947	64823145
ENSE00003487173	64746283	64749473
ENSE00003496785	64749981	64750154
ENSE00003615523	64753537	64753793
ENSE00003615947	64749654	64749696
ENSE00003815581	64879792	64879907

Expression profiles

Bgee: expression breadth ubiquitous, 220 present calls, max score 97.99.

FANTOM5 (CAGE): breadth broad, TPM avg 9.3075 / max 1206.9188, expressed in 572 samples.

FANTOM5 promoters (20 alternative TSS)

Promoter ID	TPM avg	Samples expressed
143665	4.1035	399
143669	1.3477	322
143650	1.1943	279
143647	0.4568	164
143664	0.3260	95
143659	0.2841	121
143649	0.2240	88
143640	0.2099	101
143667	0.2089	69
143666	0.1766	82

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	97.99	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.95	gold quality
muscle of leg	UBERON:0001383	96.42	gold quality
apex of heart	UBERON:0002098	95.71	gold quality
muscle organ	UBERON:0001630	95.06	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	94.96	gold quality
tibialis anterior	UBERON:0001385	94.77	gold quality
triceps brachii	UBERON:0001509	94.29	gold quality
cerebellar hemisphere	UBERON:0002245	93.44	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.42	gold quality
cerebellar cortex	UBERON:0002129	93.36	gold quality
gluteal muscle	UBERON:0002000	92.93	gold quality
skeletal muscle tissue	UBERON:0001134	92.54	gold quality
cerebellum	UBERON:0002037	92.45	gold quality
right atrium auricular region	UBERON:0006631	92.41	gold quality
heart left ventricle	UBERON:0002084	92.21	gold quality
diaphragm	UBERON:0001103	91.74	silver quality
cardiac ventricle	UBERON:0002082	91.68	gold quality
quadriceps femoris	UBERON:0001377	91.01	gold quality
cardiac atrium	UBERON:0002081	90.71	gold quality
vastus lateralis	UBERON:0001379	90.42	gold quality
deltoid	UBERON:0001476	90.02	gold quality
biceps brachii	UBERON:0001507	89.28	gold quality
heart	UBERON:0000948	89.11	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	88.34	gold quality
muscle tissue	UBERON:0002385	88.28	gold quality
paraflocculus	UBERON:0005351	87.14	gold quality
sural nerve	UBERON:0015488	85.25	gold quality
buccal mucosa cell	CL:0002336	84.00	gold quality
trabecular bone tissue	UBERON:0002483	83.97	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	40.89
E-ANND-3	yes	4.69
E-MTAB-9067	yes	4.40
E-MTAB-6379	no	3.90
E-MTAB-6678	no	3.67
E-MTAB-9801	no	2.73
E-GEOD-124858	no	1.40

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA1, KLF1

miRNA regulators (miRDB)

135 targeting SPTB, 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-5196-5P	100.00	67.98	2761
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6079	99.84	68.54	1170
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6785-5P	99.82	68.68	4428

Literature-anchored findings (GeneRIF, showing 40)

• Important region in the beta-spectrin C-terminus for association with the alpha chain and for spectrin tetramer formation is defined. (PMID:12038451)
• The spectrin-ankyrin skeleton controls CD45 surface display and interleukin-2 production (PMID:12354383)
• the repeats of five human beta-spectrins have been analysed (PMID:12655374)
• This study identifies the precise sites of all significant phosphorylation events on beta-spectrin and has determined that these phosphorylation events apparently occur in a tightly regulated sequential order. (PMID:15065869)
• analysis of erythroid alpha and beta spectrin chaperone activity and prodan binding (PMID:15492010)
• Binding sites for both protein 4.1R and actin are located in both of the beta I-spectrin calponin homology domains, (CH1 and CH2). (PMID:16060676)
• analysis of conformational stabilities of the structural repeats of erythroid spectrin (PMID:16476728)
• The results indicate that the whole ankyrin-sensitive lipid-binding site of beta-spectrin exhibits a helical conformation revealing a distinct 3(10)-helix contribution at its N-terminus. (PMID:17520478)
• This model supports the hypothesis that initial docking of the correct alpha and beta repeats from among many very similar repeats in both subunits is driven primarily by long range electrostatic interactions. (PMID:17977835)
• The spectrin tetramer can be modeled as a soft polymer with a unique flat force-extension profile over the range of biologically important lengths. (PMID:18202182)
• The structure of the ankyrin ZU5 domain shows a novel structure containing a beta core. (PMID:19141864)
• The putative coupling of flexibility and ligand binding suggests a mechanism by which spectrin might participate in mechanosensory regulation. (PMID:19168783)
• DNA analysis of SPTB in hereditary spherocytosis subjects with decreased SPTB mRNA levels revealed the presence of 5 previously undescribed mutations: R1756X, 781delT and IVS22nt-4G>A, 1502insA & IVS20nt-2A>G (PMID:19538529)
• CD45 lateral mobility is regulated by the spectrin-ankyrin cytoskeleton of T cells (PMID:20164196)
• through the use of an ATP-driven phospholipid translocase (flippase), erythrocytes have evolved a protective mechanism against spectrin glycation and thus maintain their optimal membrane function during their long circulatory life span (PMID:20724481)
• Results suggest that it is possible for cellular proteins to differentially associate with the C-termini of different beta-spectrin isoforms to regulate alpha- and beta-spectrin association to form functional spectrin tetramers. (PMID:21412925)
• Data postulate that direct interactions between spectrin ankBDn and PE-rich domains play an important role in stabilizing the structure of the spectrin-based membrane skeleton. (PMID:21738695)
• analysis of glycosylation of erythrocyte spectrin and its modification in visceral leishmaniasis (PMID:22164239)
• A protein encoded by this locus was found to be differentially expressed in postmortem brains from patients with atypical frontotemporal lobar degeneration. (PMID:22360420)
• 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)
• Mutational characteristics of ANK1 and SPTB genes in Korean hereditary spherocytosis have been described. (PMID:26830532)
• Using Next-Generation sequencing, we identified the causative genetic mutations in fifteen patients with clinically suspected hereditary elliptocytosis and hereditary pyropoikilocytosis and correlated the identified mutations with the clinical phenotype and ektacytometry profile. (PMID:27667160)
• a new mutation in the SPTB gene (466insG) leading to a frameshift and a premature stop codon 29 codons downstream in the region encoding the C-terminal part of the dimerization domain; instability of mutant mRNA results in spectrin deficiency and clinically moderate to serious hereditary spherocytosis (PMID:27709257)
• two sex-specific loci(SPTB in females and IZUMO3 in males), yielding associations that were particularly strong at a specific skeletal site, were identified. (PMID:28181694)
• Targeted next generation sequencing identifies a novel beta-spectrin gene mutation A2059P in two Omani children with hereditary pyropoikilocytosis (PMID:28699249)
• These findings suggest that band 3 and spectrin are potential targets of autoantibodies that may be relevant for P. vivax malaria-associated anemia. (PMID:29884876)
• Next-generation sequencing identified a novel SPTB frameshift insertion causing hereditary spherocytosis in China. (PMID:29961904)
• Novel mutations in SPTA1 and SPTB identified by whole exome sequencing in eight Thai families with hereditary pyropoikilocytosis presenting with severe fetal and neonatal anaemia. (PMID:30198572)
• Study found that betaI spectrin was only weakly stained or lost in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) cases while at least moderately stained in normal hepatocytes and all focal nodular hyperplasia (FNH) and hepatic adenoma (HA) cases. These findings suggest, for the first time, that betaI spectrins could be helpful in differentiating HCC from FNH or HA. (PMID:30798076)
• Patient 4 had c.318delGExon3 mutation in the SPTB gene (PMID:31014431)
• proband with Hereditary spherocytosis was found to carry a c.5798+1G>A variant of the SPTB gene (PMID:31922588)
• SPTB related spherocytosis in a three-generation family presenting with kidney failure in adulthood due to co-occurrence of UMOD disease causing variant. (PMID:32113667)
• A clinical and experimental study of adult hereditary spherocytosis in the Chinese population. (PMID:32133777)
• Clinical manifestation and phenotypic analysis of novel gene mutation in 28 Chinese children with hereditary spherocytosis. (PMID:33620149)
• A novel essential splice site variant in SPTB in a large hereditary spherocytosis family. (PMID:33943044)
• A novel SPTB frameshift deletion causing hereditary spherocytosis identified by next-generation sequencing in a Chinese family. (PMID:33974364)
• The updated beta-spectrin mutations in patients with hereditary spherocytosis by targeted next-generation sequencing. (PMID:34140613)
• A novel SPTB mutation causes hereditary spherocytosis via loss-of-function of beta-spectrin. (PMID:35099593)
• Whole exome sequencing identifies a novel SPTB frameshift mutation causing hereditary spherocytosis in the Chinese population. (PMID:35726106)
• [Genetic Analysis of a Chinese Pedigree with Hereditary Spherocytosis Caused by Copy Number Variation Deletion of SPTB Gene]. (PMID:36765497)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	sptb	ENSDARG00000030490
mus_musculus	Sptb	ENSMUSG00000021061
rattus_norvegicus	Sptb	ENSRNOG00000006911
caenorhabditis_elegans		WBGENE00006803

Paralogs (36): SYNE2 (ENSG00000054654), 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), SPTAN1 (ENSG00000197694), DMD (ENSG00000198947), PKHD1L1 (ENSG00000205038), DYTN (ENSG00000232125), MICAL3 (ENSG00000243156), ACTN3 (ENSG00000248746), EPPK1 (ENSG00000261150), GAS2L2 (ENSG00000270765)

Protein

Protein identifiers

Spectrin beta chain, erythrocytic — P11277 (reviewed: P11277)

Alternative names: Beta-I spectrin

All UniProt accessions (2): P11277, H0YJE6

UniProt curated annotations — full annotation on UniProt →

Function. Spectrin is the major constituent of the cytoskeletal network underlying the erythrocyte plasma membrane. It associates with band 4.1 and actin to form the cytoskeletal superstructure of the erythrocyte plasma membrane.

Subunit / interactions. Composed of nonhomologous chains, alpha and beta, which aggregate to form dimers, tetramers, and higher polymers. Interacts with BCAM.

Subcellular location. Cytoplasm. Cytoskeleton. Cell cortex.

Post-translational modifications. The first phosphorylation event occurs on Ser-2114, followed by Ser-2125, Ser-2123, Ser-2128, Ser-2117, and Thr-2110. (Microbial infection) Probably cleaved by P.falciparum SERA6; the cleavage results in SPTB solubilization causing the disruption of the actin cytoskeleton and the rupture of the erythrocyte cell membrane releasing the merozoites.

Disease relevance. Elliptocytosis 3 (EL3) [MIM:617948] A Rhesus-unlinked form of hereditary elliptocytosis, a genetically heterogeneous hematologic disorder characterized by variable hemolytic anemia and elliptical or oval red cell shape. Inheritance can be autosomal dominant or autosomal recessive. The disease is caused by variants affecting the gene represented in this entry. Spherocytosis 2 (SPH2) [MIM:616649] An autosomal dominant form of hereditary spherocytosis, a group of hematologic disorders characterized by numerous abnormally shaped erythrocytes which are generally spheroidal. Clinical manifestations include chronic hemolytic anemia, jaundice, and splenomegaly, with variable severity. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. This complex is anchored to the cytoplasmic face of the plasma membrane via another protein, ankyrin, which binds to beta-spectrin and mediates the binding of the whole complex to a transmembrane protein band 3. The interaction of erythrocyte spectrin with other proteins through specific binding domains lead to the formation of an extensive subplasmalemmal meshwork which is thought to be responsible for the maintenance of the biconcave shape of human erythrocytes, for the regulation of plasma membrane components and for the maintenance of the lipid asymmetry of the plasma membrane. Due to exon skipping.

Similarity. Belongs to the spectrin family.

Isoforms (3)

UniProt ID	Names	Canonical?
P11277-1	1	yes
P11277-2	2, Muscle-specific
P11277-3	3

RefSeq proteins (3): NP_001020029, NP_001342365, NP_001342366 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001589	Actinin_actin-bd_CS	Conserved_site
IPR001715	CH_dom	Domain
IPR002017	Spectrin_repeat	Repeat
IPR016343	Spectrin_bsu	Family
IPR018159	Spectrin/alpha-actinin	Repeat
IPR036872	CH_dom_sf	Homologous_superfamily

Pfam: PF00307, PF00435

UniProt features (80 total): helix 18, repeat 17, sequence variant 14, modified residue 11, sequence conflict 6, region of interest 3, domain 2, compositionally biased region 2, site 2, splice variant 2, initiator methionine 1, chain 1, strand 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
3EDU	X-RAY DIFFRACTION	2.1
1S35	X-RAY DIFFRACTION	2.4
3KBT	X-RAY DIFFRACTION	2.75
3KBU	X-RAY DIFFRACTION	2.75
3LBX	X-RAY DIFFRACTION	2.8
3F57	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P11277-F1	79.55	0.13

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 (2): 165–166 ((microbial infection) cleavage; by p.falciparum sera6); 167–168 ((microbial infection) cleavage; by p.falciparum sera6)

Post-translational modifications (11): 36, 104, 1297, 2043, 2073, 2110, 2114, 2117, 2123, 2125, 2128

Function

Pathways and Gene Ontology

Reactome pathways

18 pathways

ID	Pathway
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-6807878	COPI-mediated anterograde transport
R-HSA-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
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-5653656	Vesicle-mediated transport
R-HSA-5683057	MAPK family signaling cascades
R-HSA-5684996	MAPK1/MAPK3 signaling
R-HSA-597592	Post-translational protein modification
R-HSA-948021	Transport to the Golgi and subsequent modification
R-HSA-9675108	Nervous system development

MSigDB gene sets: 352 (showing top): MORF_RAGE, E2F_Q4, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, AGGAAGC_MIR5163P, CREL_01, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, BENPORATH_ES_WITH_H3K27ME3, MYOGENIN_Q6, GNF2_PRDX2, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, E2F4DP1_01, GCANCTGNY_MYOD_Q6, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_POLYMERIZATION, GOCC_CELL_SURFACE, REACTOME_NCAM_SIGNALING_FOR_NEURITE_OUT_GROWTH

GO Biological Process (4): actin cytoskeleton organization (GO:0030036), actin filament capping (GO:0051693), modification of postsynaptic actin cytoskeleton (GO:0098885), synapse organization (GO:0050808)

GO Molecular Function (6): actin binding (GO:0003779), structural constituent of cytoskeleton (GO:0005200), ankyrin binding (GO:0030506), actin filament binding (GO:0051015), protein binding (GO:0005515), phospholipid binding (GO:0005543)

GO Cellular Component (19): cytosol (GO:0005829), plasma membrane (GO:0005886), spectrin (GO:0008091), cytoplasmic side of plasma membrane (GO:0009898), cell surface (GO:0009986), spectrin-associated cytoskeleton (GO:0014731), actin cytoskeleton (GO:0015629), cell junction (GO:0030054), cortical actin cytoskeleton (GO:0030864), protein-containing complex (GO:0032991), cell projection (GO:0042995), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), cell cortex (GO:0005938), membrane (GO:0016020), cortical cytoskeleton (GO:0030863), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Axon guidance	2
L1CAM interactions	1
MAPK1/MAPK3 signaling	1
ER to Golgi Anterograde Transport	1
Membrane Trafficking	1
Transport to the Golgi and subsequent modification	1
Vesicle-mediated transport	1
Nervous system development	1
Post-translational protein modification	1
Signal Transduction	1
MAPK family signaling cascades	1
Metabolism of proteins	1
Asparagine N-linked glycosylation	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
cytoskeleton	4
cytoskeleton organization	2
cytoskeletal protein binding	2
cytoplasm	2
cell periphery	2
synapse	2
actin filament-based process	1
negative regulation of actin filament depolymerization	1
negative regulation of actin filament polymerization	1
modification of postsynaptic structure	1
cell junction organization	1
structural molecule activity	1
actin binding	1
protein-containing complex binding	1
binding	1
lipid binding	1
membrane	1
cortical actin cytoskeleton	1
protein-containing complex	1
plasma membrane	1
cytoplasmic side of membrane	1
actin cytoskeleton	1
cortical cytoskeleton	1
cellular_component	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
cell cortex	1
cell junction	1

Protein interactions and networks

STRING

898 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPTB	EPB41	P11171	972
SPTB	ANK1	P16157	926
SPTB	ANK2	Q01484	834
SPTB	SPTAN1	Q13813	805
SPTB	ANK3	Q12955	801
SPTB	SPTA1	P02549	800
SPTB	TPM3	P06753	753
SPTB	SLC1A6	P48664	633
SPTB	ARHGEF11	O15085	597
SPTB	TSPAN16	Q9UKR8	582
SPTB	COPB1	P53618	544
SPTB	GYPC	P04921	526
SPTB	ADD2	P35612	490
SPTB	RHO	P08100	476
SPTB	PLEK2	Q9NYT0	464

IntAct

70 interactions, top by confidence:

A	B	Type	Score
SPTA1	SPTB	psi-mi:“MI:0407”(direct interaction)	0.790
SPTA1	SPTB	psi-mi:“MI:0915”(physical association)	0.790
SPTB	SPTA1	psi-mi:“MI:0407”(direct interaction)	0.790
CDK9	AIP	psi-mi:“MI:0914”(association)	0.730
DIDO1	OGT	psi-mi:“MI:0914”(association)	0.670
RHOD	PLXNB2	psi-mi:“MI:0914”(association)	0.640
Csrp3	SPTB	psi-mi:“MI:0915”(physical association)	0.570
Csrp3	SPTB	psi-mi:“MI:0914”(association)	0.570
APP	SPTB	psi-mi:“MI:0915”(physical association)	0.560
SLC4A1	FLOT1	psi-mi:“MI:0914”(association)	0.530
CRP	QSOX1	psi-mi:“MI:0914”(association)	0.530
PAPOLG	ZFC3H1	psi-mi:“MI:0914”(association)	0.530
MRPL38	DUSP14	psi-mi:“MI:0914”(association)	0.530
RAB40AL	VSIG8	psi-mi:“MI:0914”(association)	0.530
GLB1L2	HSPA5	psi-mi:“MI:0914”(association)	0.530
BOLA1	PLSCR1	psi-mi:“MI:0914”(association)	0.530
SH2D2A	SPTB	psi-mi:“MI:0915”(physical association)	0.490
SPTB	STAT1	psi-mi:“MI:0915”(physical association)	0.490
STAT1	SPTB	psi-mi:“MI:0915”(physical association)	0.490

BioGRID (111): SPTB (Affinity Capture-MS), SPTB (Affinity Capture-MS), SPTB (Affinity Capture-MS), ACTA1 (Reconstituted Complex), SPTB (Two-hybrid), SPTB (Two-hybrid), SPTB (Affinity Capture-MS), SPTB (Affinity Capture-MS), SPTB (Affinity Capture-MS), SPTB (Affinity Capture-MS), SPTB (Affinity Capture-MS), SPTB (Affinity Capture-MS), SPTB (Affinity Capture-MS), SPTB (Affinity Capture-MS), SPTB (Affinity Capture-MS)

ESM2 similar proteins: A0A8M2BID5, A2CG49, D3ZEY0, D3ZHV2, E9Q557, E9Q8Q6, F1LMV6, F1M0Z1, G3V7L1, O15068, O60229, O60437, O75962, O97592, P02549, P10911, P11277, P11530, P11531, P11532, P11533, P15508, P15924, P30427, P46939, P97924, Q03001, Q0KL02, Q15149, Q1LUA6, Q4FZC9, Q5GN48, Q63406, Q64096, Q6ZMZ3, Q6ZP82, Q6ZWQ0, Q6ZWR6, Q86YR7, Q8NF91

Diamond homologs: A5D7D1, D3ZEN0, D3ZHA0, D3ZHV2, D3ZQL6, E1BBG2, F1MF74, F1RA39, F6QZ15, G3MWR8, G3V7L1, L7UZ85, M9MRD1, O13728, O15020, O43707, O75369, O76329, O88990, O94851, O97592, P05094, P05095, P07751, P11277, P11530, P11531, P11532, P11533, P12814, P13395, P13466, P15508, P16086, P16546, P18091, P20111, P21333, P30427, P35609

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
“Ankyrin complex”	“up-regulates activity”	SPTB	binding
SPTB	“form complex”	“Erythrocytic spectrin”	binding
“4.1 complex”	“up-regulates activity”	SPTB	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

1713 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	222
Likely pathogenic	291
Uncertain significance	744
Likely benign	178
Benign	57

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1163553	NM_001355436.2(SPTB):c.1912C>T (p.Arg638Ter)	Pathogenic
12832	NM_001355436.2(SPTB):c.6269+3G>T	Pathogenic
12833	NM_001355436.2(SPTB):c.6135_6136dup (p.Lys2046fs)	Pathogenic
12834	NM_001355436.2(SPTB):c.6177del (p.Ser2060fs)	Pathogenic
12835	NM_001355436.2(SPTB):c.604T>C (p.Trp202Arg)	Pathogenic
12836	NM_001355436.2(SPTB):c.6053C>G (p.Ala2018Gly)	Pathogenic
12838	NG_016202.2:g.(105169_105646)_(109769_110365)del	Pathogenic
12840	NM_001355436.2(SPTB):c.6191G>C (p.Arg2064Pro)	Pathogenic
12842	NM_001355436.2(SPTB):c.1912del (p.Arg638fs)	Pathogenic
12843	NM_001355436.2(SPTB):c.5266C>T (p.Arg1756Ter)	Pathogenic
1325138	NM_001355436.2(SPTB):c.1801C>T (p.Gln601Ter)	Pathogenic
1330685	NM_001355436.2(SPTB):c.1182_1182+9del	Pathogenic
1330780	NM_001355436.2(SPTB):c.4407_4410del (p.Lys1471fs)	Pathogenic
1330827	NM_001355436.2(SPTB):c.5528_5535del (p.Arg1843fs)	Pathogenic
1330961	NM_001355436.2(SPTB):c.1530G>A (p.Trp510Ter)	Pathogenic
1331020	NM_001355436.2(SPTB):c.281dup (p.Leu95fs)	Pathogenic
1331052	NM_001355436.2(SPTB):c.5494G>T (p.Glu1832Ter)	Pathogenic
1339570	NM_001355436.2(SPTB):c.3818_3832delinsGT (p.Asn1273fs)	Pathogenic
1376530	NM_001355436.2(SPTB):c.5329G>T (p.Glu1777Ter)	Pathogenic
1385339	NM_001355436.2(SPTB):c.3850C>T (p.Gln1284Ter)	Pathogenic
1414107	NM_001355436.2(SPTB):c.2274G>A (p.Trp758Ter)	Pathogenic
1433577	NM_001355436.2(SPTB):c.1510del (p.Asp504fs)	Pathogenic
1451678	NM_001355436.2(SPTB):c.2782_2783dup (p.Gln929fs)	Pathogenic
1453666	NM_001355436.2(SPTB):c.4873C>T (p.Arg1625Ter)	Pathogenic
1454599	NM_001355436.2(SPTB):c.5038G>T (p.Glu1680Ter)	Pathogenic
1456574	NC_000014.8:g.(?65270305)(65271828_?)del	Pathogenic
1676970	NM_001355436.2(SPTB):c.3841C>T (p.Gln1281Ter)	Pathogenic
1676971	NM_001355436.2(SPTB):c.493C>T (p.Gln165Ter)	Pathogenic
1676972	NM_001355436.2(SPTB):c.6059_6060del (p.Val2020fs)	Pathogenic
1676973	NM_001355436.2(SPTB):c.5464G>T (p.Glu1822Ter)	Pathogenic

SpliceAI

5770 predictions. Top by Δscore:

Variant	Effect	Δscore
14:64749469:TCCTC:T	acceptor_gain	1.0000
14:64749470:CCTCC:C	acceptor_gain	1.0000
14:64749471:CTC:C	acceptor_gain	1.0000
14:64749473:CCTG:C	acceptor_loss	1.0000
14:64749474:C:CC	acceptor_gain	1.0000
14:64749474:CTGCG:C	acceptor_loss	1.0000
14:64749475:T:G	acceptor_loss	1.0000
14:64749976:CTCA:C	donor_loss	1.0000
14:64749978:CAC:C	donor_loss	1.0000
14:64749979:A:AC	donor_gain	1.0000
14:64749980:C:CC	donor_gain	1.0000
14:64749980:CCT:C	donor_gain	1.0000
14:64749985:G:C	donor_gain	1.0000
14:64750150:AGGAC:A	acceptor_gain	1.0000
14:64750151:GGAC:G	acceptor_gain	1.0000
14:64750152:GAC:G	acceptor_gain	1.0000
14:64750152:GACC:G	acceptor_loss	1.0000
14:64750154:CCT:C	acceptor_loss	1.0000
14:64750155:C:CA	acceptor_loss	1.0000
14:64750155:C:CC	acceptor_gain	1.0000
14:64750158:C:CT	acceptor_gain	1.0000
14:64767349:CAAG:C	acceptor_gain	1.0000
14:64767353:C:CC	acceptor_gain	1.0000
14:64767658:CTCA:C	donor_loss	1.0000
14:64767659:TCACC:T	donor_loss	1.0000
14:64767660:CA:C	donor_loss	1.0000
14:64767661:A:AC	donor_gain	1.0000
14:64767661:A:C	donor_loss	1.0000
14:64767662:C:CC	donor_gain	1.0000
14:64769026:GTACT:G	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000005353 (14:64804039 A>C,G), RS1000015681 (14:64748658 C>T), RS1000022748 (14:64829265 T>C), RS1000035216 (14:64748857 C>A), RS1000044830 (14:64869168 G>A), RS1000052270 (14:64878906 G>C), RS1000093700 (14:64789760 G>A,T), RS1000154900 (14:64828485 G>T), RS1000167430 (14:64789540 G>A), RS1000202783 (14:64804268 G>A), RS1000234455 (14:64759510 C>G), RS1000243871 (14:64833427 T>A), RS1000267856 (14:64765576 C>G), RS1000268040 (14:64817029 G>T), RS1000272586 (14:64875792 C>T)

Disease associations

OMIM: gene MIM:182870 | disease phenotypes: MIM:616649, MIM:617948, MIM:604213, MIM:266140, MIM:270970

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary spherocytosis type 2	Strong	Autosomal dominant
elliptocytosis 3	Strong	Autosomal recessive
hereditary elliptocytosis	Supportive	Autosomal dominant
hereditary spherocytosis	Supportive	Autosomal dominant

Mondo (10): hereditary spherocytosis type 2 (MONDO:0000913), elliptocytosis 3 (MONDO:0054780), Chudley-McCullough syndrome (MONDO:0011411), pyropoikilocytosis, hereditary (MONDO:0009948), hereditary spherocytosis (MONDO:0019350), anemia (MONDO:0002280), hemolytic anemia (MONDO:0003664), familial hemolytic anemia (MONDO:0003689), hereditary spherocytosis type 3 (MONDO:0010053), hereditary elliptocytosis (MONDO:0017319)

Orphanet (3): Hereditary spherocytosis (Orphanet:822), Chudley-McCullough syndrome (Orphanet:314597), Hereditary pyropoikilocytosis (Orphanet:98867)

HPO phenotypes

46 total (30 of 46 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000952	Jaundice
HP:0000980	Pallor
HP:0001046	Intermittent jaundice
HP:0001081	Cholelithiasis
HP:0001251	Ataxia
HP:0001324	Muscle weakness
HP:0001510	Growth delay
HP:0001723	Restrictive cardiomyopathy
HP:0001744	Splenomegaly
HP:0001789	Hydrops fetalis
HP:0001877	Abnormal erythrocyte morphology
HP:0001878	Hemolytic anemia
HP:0001903	Anemia
HP:0001923	Reticulocytosis
HP:0001927	Acanthocytosis
HP:0001945	Fever
HP:0001978	Extramedullary hematopoiesis
HP:0001997	Gout
HP:0002007	Frontal bossing
HP:0002027	Abdominal pain
HP:0002240	Hepatomegaly
HP:0002904	Hyperbilirubinemia
HP:0003265	Neonatal hyperbilirubinemia
HP:0003270	Abdominal distention
HP:0003326	Myalgia
HP:0003546	Exercise intolerance
HP:0004444	Spherocytosis
HP:0004445	Elliptocytosis
HP:0004446	Stomatocytosis

GWAS associations

42 associations (top):

Study	Trait	p-value
GCST001762_262	Obesity-related traits	1.000000e-06
GCST001762_594	Obesity-related traits	6.000000e-06
GCST003518_66	Daytime sleep phenotypes	4.000000e-06
GCST004176_13	Pediatric areal bone mineral density (radius)	8.000000e-06
GCST004176_7	Pediatric areal bone mineral density (radius)	6.000000e-09
GCST004605_2	Mean corpuscular hemoglobin concentration	2.000000e-11
GCST004611_197	High light scatter reticulocyte count	9.000000e-12
GCST004612_131	High light scatter reticulocyte percentage of red cells	1.000000e-11
GCST004619_95	Reticulocyte fraction of red cells	3.000000e-21
GCST004621_68	Red cell distribution width	9.000000e-12
GCST004621_69	Red cell distribution width	1.000000e-21
GCST004622_128	Reticulocyte count	5.000000e-21
GCST006804_133	Red cell distribution width	9.000000e-10
GCST006804_86	Red cell distribution width	3.000000e-26
GCST008114_10	Type 2 diabetes	7.000000e-06
GCST90002385_27	High light scatter reticulocyte count	8.000000e-34
GCST90002386_171	High light scatter reticulocyte percentage of red cells	3.000000e-32
GCST90002388_134	Lymphocyte count	7.000000e-09
GCST90002391_256	Mean corpuscular hemoglobin concentration	8.000000e-09
GCST90002391_257	Mean corpuscular hemoglobin concentration	3.000000e-27
GCST90002396_561	Mean reticulocyte volume	1.000000e-35
GCST90002396_562	Mean reticulocyte volume	3.000000e-09
GCST90002396_563	Mean reticulocyte volume	3.000000e-78
GCST90002396_564	Mean reticulocyte volume	2.000000e-32
GCST90002396_565	Mean reticulocyte volume	2.000000e-18
GCST90002396_566	Mean reticulocyte volume	3.000000e-20
GCST90002397_352	Mean spheric corpuscular volume	1.000000e-12
GCST90002397_353	Mean spheric corpuscular volume	5.000000e-18
GCST90002397_354	Mean spheric corpuscular volume	8.000000e-72
GCST90002397_355	Mean spheric corpuscular volume	1.000000e-215

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0005000	leptin measurement
EFO:0007828	daytime rest measurement
EFO:0007933	radius bone mineral density
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0007986	reticulocyte count
EFO:0009188	Red cell distribution width
EFO:0004587	lymphocyte count
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (9)

Descriptor	Name	Tree numbers
D000740	Anemia	C15.378.050
D000743	Anemia, Hemolytic	C15.378.050.141
D000745	Anemia, Hemolytic, Congenital	C15.378.050.141.150; C16.320.070
D004612	Elliptocytosis, Hereditary	C15.378.050.141.150.365; C16.320.070.365
D013103	Spherocytosis, Hereditary	C15.378.050.141.150.785; C16.320.070.785
C535459	Chudley-Mccullough syndrome (supp.)
C566678	Elliptocytosis 3 (supp.)
C563004	Pyropoikilocytosis, Hereditary (supp.)
C567489	Spherocytosis, Type 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, increases mutagenesis, affects methylation, decreases methylation, increases expression	3
sodium arsenite	decreases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
sotorasib	affects cotreatment, decreases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects expression, affects response to substance	1
ethyl-p-hydroxybenzoate	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	increases reaction, affects binding	1
pentabrominated diphenyl ether 100	increases expression	1
hexabrominated diphenyl ether 153	increases expression	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic Trioxide	increases expression	1
Fulvestrant	increases methylation	1
Cannabidiol	decreases expression	1
Copper	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects binding, increases reaction	1
Ivermectin	decreases expression	1
Lead	affects expression	1
Rifampin	increases expression	1
Silicon Dioxide	decreases expression	1
Tretinoin	decreases expression	1
Triclosan	decreases expression	1
Valproic Acid	increases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00003398	PHASE4	COMPLETED	Bone Marrow Transplantation in Treating Patients With Hematologic Cancer
NCT00022386	PHASE4	COMPLETED	Epoetin Alfa in Treating Chemotherapy-Related Anemia in Women With Stage I, Stage II, or Stage III Breast Cancer
NCT00046969	PHASE4	COMPLETED	Epoetin Beta in Treating Anemia in Patients With Cervical Cancer
NCT00111995	PHASE4	COMPLETED	Evaluating Aranesp® for the Treatment of Anemia in African-American Subjects With Chronic Renal Failure (CRF) Receiving Hemodialysis
NCT00117039	PHASE4	COMPLETED	A Study to Evaluate the Effectiveness of Aranesp® for Cancer Patients With Anemia
NCT00117065	PHASE4	COMPLETED	Study of Transplant Related Anemia Treated With Aranesp® (STRATA)
NCT00117117	PHASE4	COMPLETED	A Study to Assess Symptom Burden in Subjects With Nonmyeloid Malignancies Receiving Chemotherapy and Aranesp®
NCT00126334	PHASE4	COMPLETED	Conservative Versus Liberal Red Cell Transfusion in Myocardial Infarction Trial: The CRIT Pilot
NCT00153868	PHASE4	COMPLETED	A Web-based Study of Quality of Life Benefits Associated Aranesp in Anemic Patients With Cancer
NCT00168948	PHASE4	UNKNOWN	Intermittent Antimalaria Treatment With SP in African Children
NCT00173706	PHASE4	UNKNOWN	Evaluation of the Effects of L-Carnitine Injection in Patients Undergoing Hemodialysis
NCT00194857	PHASE4	TERMINATED	Treatment of Anemia and Neutropenia in HIV/HCV Coinfected Patients Treated With Pegylated Interferon and Ribavirin
NCT00204334	PHASE4	COMPLETED	Effects of Anemia Correction on Vascular and Monocyte Function in Renal Transplant Recipients
NCT00206739	PHASE4	COMPLETED	Intermittent Treatment With Sulfadoxine-pyrimethamine for Malaria Control in Infants
NCT00211120	PHASE4	TERMINATED	Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR)
NCT00216541	PHASE4	COMPLETED	A Study of the Safety and Effectiveness of Epoetin Alfa on Hemoglobin Levels and Blood Transfusions in Cancer Patients Receiving Chemotherapy
NCT00223938	PHASE4	TERMINATED	Study of the Efficacy and Safety of Ferrlecit in the Maintenance Dosing in Hemodialysis Patients.
NCT00223964	PHASE4	COMPLETED	Study of the Efficacy of Two Doses of Ferrlecit in the Treatment of Iron Deficiency in Pediatric Hemodialysis Patients
NCT00224003	PHASE4	COMPLETED	Study of the Safety and Efficacy of Ferrlecit® Maintenance Dosing in Pediatric Hemodialysis Patients
NCT00224068	PHASE4	COMPLETED	Effect of Iron Therapy as an Adjunct to Epoetin Alfa in the Anemia of Cancer Chemotherapy
NCT00239642	PHASE4	COMPLETED	Safety and Efficacy of Iron Sucrose in Children
NCT00247507	PHASE4	UNKNOWN	The Effects of Acetylcysteine on Alleviating Damage of Oxidative Stress in Hemodialysis Patients
NCT00248716	PHASE4	UNKNOWN	Treatment of Anemia in the 2nd Year of Life. Comparison of the Efficacy of Two Different Iron Preparations.
NCT00283465	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Treatment With Epoetin Alfa on Hemoglobin Levels, Red Blood Cell Transfusions, and Quality of Life in Patients With Cancer Receiving Platinum-containing Chemotherapy
NCT00312871	PHASE4	TERMINATED	Effects of Early Correction of Anemia in Patients With Chronic Renal Insufficiency
NCT00315484	PHASE4	COMPLETED	Hematologic Response of Epoetin Alfa (PROCRIT) Versus Darbepoetin Alfa (ARANESP) in Chemotherapy Induced Anemia
NCT00317902	PHASE4	COMPLETED	An Open-Label Study to Evaluate the Effect of Every Other Week PROCRIT� (Epoetin Alfa) Dosing (40,000-60,000 Units) On Maintaining Quality of Life and Target Hemoglobin Levels in Anemic HIV-Infected Patients (CHAMPS II)
NCT00335023	PHASE4	COMPLETED	Well Being of Obstetric Patients on Minimal Blood Transfusions
NCT00338468	PHASE4	TERMINATED	A Study to Assess Disability in Anemic Elderly Patients With Kidney Disease Receiving PROCRIT (Epoetin Alfa)
NCT00377481	PHASE4	COMPLETED	COMFORT Study: A Crossover Study of NeoRecormon (Epoetin Beta) and Darbepoetin Alfa in Patients With Renal Anemia.
NCT00396435	PHASE4	COMPLETED	Correction of Anaemia and Progression of Renal Failure on Transplanted Patients
NCT00401869	PHASE4	COMPLETED	The Effect of PROCRIT (Epoetin Alfa) on Postoperative Vigor and Handgrip Strength (VIGOR Study)
NCT00413101	PHASE4	COMPLETED	A Study of NeoRecormon (Epoetin Beta) in Patients With End Stage Renal Disease.
NCT00431496	PHASE4	COMPLETED	A Study of Cinacalcet to Improve Achievement of National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) Targets in Patients With End Stage Renal Disease (ESRD)
NCT00437723	PHASE4	COMPLETED	A Study of NeoRecormon in Patients With Chronic Kidney Disease.
NCT00440063	PHASE4	TERMINATED	A Study of NeoRecormon (Epoetin Beta) in Patients With Renal Anemia.
NCT00470158	PHASE4	COMPLETED	Delivery of Iron and Zinc Supplements: Evaluation of Interaction Effect on Biochemical and Clinical Outcomes
NCT00479102	PHASE4	UNKNOWN	Prevention of Iron Deficiency in 2nd Year of Life
NCT00495365	PHASE4	TERMINATED	A Dose Conversion Study of Epoetin Alfa in Subjects With the Anemia of Chronic Kidney Disease.
NCT00495378	PHASE4	TERMINATED	RAPID-2. A Study to Evaluate the Effectiveness of Alternate Dosing of PROCRIT (Epoetin Alfa) in Maintaining Hemoglobin Levels in Patients With Chemotherapy Related Anemia