Hereditary spherocytosis type 3

Summary

Hereditary spherocytosis type 3 (MONDO:0010053) is a disease caused by SPTA1 (GenCC Definitive), with 5 cohort genes.

At a glance

• Causal gene: SPTA1 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 304

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spherocytosis type 3
Mondo ID	MONDO:0010053
MeSH	C567489
OMIM	270970
DOID	DOID:0110918
UMLS	C2678338
MedGen	394798
GARD	0015236
Is cancer (heuristic)	no

Also known as: hereditary spherocytosis caused by mutation in SPTA1 · HS3 · SPH3 · spherocytosis, type 3 · SPTA1 hereditary spherocytosis

Data availability: 304 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › normocytic anemia › hemolytic anemia › familial hemolytic anemia › hereditary spherocytosis › hereditary spherocytosis type 3

Related subtypes (4): hereditary spherocytosis type 2, hereditary spherocytosis type 1, hereditary spherocytosis type 4, hereditary spherocytosis type 5

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

304 retrieved; paginated sample, class counts are floors:

128 conflicting classifications of pathogenicity, 98 uncertain significance, 38 benign, 15 benign/likely benign, 11 pathogenic, 8 likely pathogenic, 6 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1030630	NM_003126.4(SPTA1):c.4339-99C>T	SPTA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1033567	NM_003126.4(SPTA1):c.4180del (p.Cys1394fs)	SPTA1	Pathogenic	criteria provided, multiple submitters, no conflicts
1162868	NM_003126.4(SPTA1):c.3139C>T (p.Arg1047Ter)	SPTA1	Pathogenic	criteria provided, multiple submitters, no conflicts
1163172	NM_003126.4(SPTA1):c.178C>T (p.Arg60Ter)	SPTA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1163657	NM_003126.4(SPTA1):c.2671C>T (p.Arg891Ter)	SPTA1	Pathogenic	criteria provided, multiple submitters, no conflicts
1163757	NM_003126.4(SPTA1):c.660T>A (p.Tyr220Ter)	SPTA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12856	NM_003126.4(SPTA1):c.83G>A (p.Arg28His)	SPTA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12863	NM_003126.2(SPTA1):c.5190_5310del	SPTA1	Pathogenic	criteria provided, single submitter
1676967	NM_003126.4(SPTA1):c.27del (p.Val10fs)	SPTA1	Pathogenic	criteria provided, single submitter
1676968	NM_003126.4(SPTA1):c.4443-1G>A	SPTA1	Pathogenic	criteria provided, single submitter
496724	NM_003126.4(SPTA1):c.1850dup (p.Ser618fs)	SPTA1	Pathogenic	criteria provided, single submitter
561993	NM_003126.4(SPTA1):c.4975C>T (p.Arg1659Ter)	SPTA1	Pathogenic	criteria provided, multiple submitters, no conflicts
801565	NM_003126.4(SPTA1):c.1833+1G>A	SPTA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
915962	GRCh37/hg19 1q23.1(chr1:158655335-158667812)	SPTA1	Pathogenic	no assertion criteria provided
931603	NM_003126.4(SPTA1):c.2320C>T (p.Arg774Ter)	SPTA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
992925	NM_003126.4(SPTA1):c.3477+1G>C	SPTA1	Pathogenic	criteria provided, single submitter
996360	NM_003126.4(SPTA1):c.6788+11C>T	SPTA1	Pathogenic	criteria provided, multiple submitters, no conflicts
1676963	NM_003126.4(SPTA1):c.1700T>C (p.Leu567Pro)	SPTA1	Likely pathogenic	criteria provided, single submitter
1708148	NM_003126.4(SPTA1):c.2335_2352delinsGCTCTCA (p.Lys779fs)	SPTA1	Likely pathogenic	criteria provided, single submitter
3062300	NM_003126.4(SPTA1):c.6331del (p.Ala2111fs)	SPTA1	Likely pathogenic	criteria provided, single submitter
3062301	NM_003126.4(SPTA1):c.5581del (p.His1861fs)	SPTA1	Likely pathogenic	criteria provided, single submitter
3382312	NM_003126.4(SPTA1):c.2167C>T (p.Gln723Ter)	SPTA1	Likely pathogenic	criteria provided, single submitter
3776254	NM_003126.4(SPTA1):c.1112+2T>C	SPTA1	Likely pathogenic	criteria provided, single submitter
544822	NM_003126.4(SPTA1):c.2898G>A (p.Gln966=)	SPTA1	Likely pathogenic	criteria provided, single submitter
4280117	NM_001365999.1(SZT2):c.1627-1G>A	SZT2	Likely pathogenic	criteria provided, single submitter
292934	NM_003126.4(SPTA1):c.*68C>G	OR10Z1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
12859	NM_003126.4(SPTA1):c.2373C>A (p.Asp791Glu)	SPTA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1331112	NM_003126.4(SPTA1):c.3841C>T (p.Arg1281Cys)	SPTA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1676962	NM_003126.4(SPTA1):c.2768A>G (p.Asp923Gly)	SPTA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1676964	NM_003126.4(SPTA1):c.4823G>A (p.Arg1608His)	SPTA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SPTA1	Definitive	Autosomal recessive	hereditary spherocytosis type 3	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SPTA1	Orphanet:288	Hereditary elliptocytosis
SPTA1	Orphanet:822	Hereditary spherocytosis
SPTB	Orphanet:288	Hereditary elliptocytosis
SPTB	Orphanet:822	Hereditary spherocytosis
SYNE1	Orphanet:319332	Autosomal recessive myogenic arthrogryposis multiplex congenita
SYNE1	Orphanet:88644	Autosomal recessive ataxia, Beauce type
SYNE1	Orphanet:98853	Autosomal dominant Emery-Dreifuss muscular dystrophy
SZT2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SPTA1	HGNC:11272	ENSG00000163554	P02549	Spectrin alpha chain, erythrocytic 1	gencc,clinvar
SPTB	HGNC:11274	ENSG00000070182	P11277	Spectrin beta chain, erythrocytic	clinvar
OR10Z1	HGNC:14996	ENSG00000198967	Q8NGY1	Olfactory receptor 10Z1	clinvar
SYNE1	HGNC:17089	ENSG00000131018	Q8NF91	Nesprin-1	clinvar
SZT2	HGNC:29040	ENSG00000198198	Q5T011	KICSTOR complex protein SZT2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SPTA1	Spectrin alpha chain, erythrocytic 1	Spectrin is the major constituent of the cytoskeletal network underlying the erythrocyte plasma membrane.
SPTB	Spectrin beta chain, erythrocytic	Spectrin is the major constituent of the cytoskeletal network underlying the erythrocyte plasma membrane.
OR10Z1	Olfactory receptor 10Z1	Odorant receptor.
SYNE1	Nesprin-1	Multi-isomeric modular protein which forms a linking network between organelles and the actin cytoskeleton to maintain the subcellular spatial organization.
SZT2	KICSTOR complex protein SZT2	As part of the KICSTOR complex functions in the amino acid-sensing branch of the TORC1 signaling pathway.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.2

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
GPCR	1	4.8×	0.386
Scaffold/PPI	1	3.5×	0.386
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SPTA1	Scaffold/PPI	no		SH3_domain, Spectrin_repeat, EF_hand_dom
SPTB	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat
OR10Z1	GPCR	yes		GPCR_Rhodpsn, Olfact_rcpt, GPCR_Rhodpsn_7TM
SYNE1	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat
SZT2	Other/Unknown	no		SZT2

Expression context

Cohort genes with no expression data: 0.

5 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bone marrow	2
bone marrow cell	2
trabecular bone tissue	1
gastrocnemius	1
hindlimb stylopod muscle	1
muscle of leg	1
male germ line stem cell (sensu Vertebrata) in testis	1
calcaneal tendon	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
colonic epithelium	1
granulocyte	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SPTA1	147	tissue_specific	marker	trabecular bone tissue, bone marrow, bone marrow cell
SPTB	220	broad	marker	gastrocnemius, hindlimb stylopod muscle, muscle of leg
OR10Z1	36		marker	male germ line stem cell (sensu Vertebrata) in testis, bone marrow, bone marrow cell
SYNE1	275	ubiquitous	marker	cerebellar hemisphere, right hemisphere of cerebellum, calcaneal tendon
SZT2	238	ubiquitous	marker	colonic epithelium, sural nerve, granulocyte

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SYNE1	2,886
SPTA1	1,551
SPTB	1,079
SZT2	648
OR10Z1	132

Intra-cohort edges

A	B	Sources
OR10Z1	SPTA1	string_interaction
SPTA1	SPTB	intact, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SZT2	Q5T011	9
SPTB	P11277	6
SPTA1	P02549	3
SYNE1	Q8NF91	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
OR10Z1	Q8NGY1	85.94

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 27. Enrichment computed across 5 evidence-associated genes (5 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interaction between L1 and Ankyrins	2	147.3×	0.002	SPTA1, SPTB
NCAM signaling for neurite out-growth	2	108.8×	0.002	SPTA1, SPTB
ER to Golgi Anterograde Transport	2	53.1×	0.003	SPTA1, SPTB
MAPK1/MAPK3 signaling	2	52.5×	0.003	SPTA1, SPTB
L1CAM interactions	2	48.1×	0.003	SPTA1, SPTB
COPI-mediated anterograde transport	2	43.9×	0.003	SPTA1, SPTB
MAPK family signaling cascades	2	41.1×	0.003	SPTA1, SPTB
Transport to the Golgi and subsequent modification	2	41.1×	0.003	SPTA1, SPTB
RAF/MAP kinase cascade	2	24.4×	0.007	SPTA1, SPTB
Asparagine N-linked glycosylation	2	24.0×	0.007	SPTA1, SPTB
Axon guidance	2	18.1×	0.011	SPTA1, SPTB
Nervous system development	2	17.2×	0.012	SPTA1, SPTB
Membrane Trafficking	2	14.8×	0.014	SPTA1, SPTB
Vesicle-mediated transport	2	13.9×	0.015	SPTA1, SPTB
Meiosis	1	57.1×	0.031	SYNE1
Amino acids regulate mTORC1	1	40.1×	0.039	SZT2
Reproduction	1	38.1×	0.039	SYNE1
Post-translational protein modification	2	7.7×	0.039	SPTA1, SPTB
Cellular response to starvation	1	33.1×	0.042	SZT2
Meiotic synapsis	1	28.2×	0.047	SYNE1
Developmental Biology	2	5.8×	0.053	SPTA1, SPTB
Metabolism of proteins	2	5.0×	0.068	SPTA1, SPTB
Signal Transduction	2	4.1×	0.093	SPTA1, SPTB
Cellular responses to stress	1	7.4×	0.142	SZT2
Cell Cycle	1	7.2×	0.142	SYNE1
Cellular responses to stimuli	1	6.3×	0.155	SZT2
Expression and translocation of olfactory receptors	1	5.6×	0.166	OR10Z1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
actin filament capping	2	612.8×	1e-04	SPTA1, SPTB
regulation of superoxide dismutase activity	1	3370.4×	0.004	SZT2
nuclear matrix anchoring at nuclear membrane	1	1123.5×	0.007	SYNE1
porphyrin-containing compound biosynthetic process	1	842.6×	0.007	SPTA1
actin cytoskeleton organization	2	31.6×	0.008	SPTA1, SPTB
corpus callosum morphogenesis	1	481.5×	0.009	SZT2
lymphocyte homeostasis	1	374.5×	0.010	SPTA1
modification of postsynaptic actin cytoskeleton	1	280.9×	0.011	SPTB
protein localization to lysosome	1	210.7×	0.013	SZT2
plasma membrane organization	1	177.4×	0.013	SPTA1
muscle cell differentiation	1	168.5×	0.013	SYNE1
pigmentation	1	140.4×	0.015	SZT2
nucleus organization	1	112.3×	0.017	SYNE1
cellular response to glucose starvation	1	67.4×	0.024	SZT2
negative regulation of TORC1 signaling	1	64.8×	0.024	SZT2
cellular response to amino acid starvation	1	63.6×	0.024	SZT2
hemopoiesis	1	53.5×	0.027	SPTA1
positive regulation of T cell proliferation	1	51.9×	0.027	SPTA1
post-embryonic development	1	41.1×	0.032	SZT2
Golgi organization	1	26.8×	0.044	SYNE1
detection of chemical stimulus involved in sensory perception of smell	1	24.8×	0.044	OR10Z1
regulation of cell shape	1	24.6×	0.044	SPTA1
actin filament organization	1	23.7×	0.044	SPTA1
central nervous system development	1	23.1×	0.044	SZT2
spermatogenesis	1	7.0×	0.134	SYNE1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 0 of 5 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SPTA1	0	0
SPTB	0	0
OR10Z1	0	0
SYNE1	0	0
SZT2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	OR10Z1
E	Difficult family or no structure, no drug	4	SPTA1, SPTB, SYNE1, SZT2

Undrugged target profiles

5 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SPTA1	0	—
SPTB	0	—
OR10Z1	0	—
SYNE1	0	—
SZT2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.