Hereditary spherocytosis type 2

Summary

Hereditary spherocytosis type 2 (MONDO:0000913) is a disease caused by SPTB (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: SPTB (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 169

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spherocytosis type 2
Mondo ID	MONDO:0000913
OMIM	616649
DOID	DOID:0110917
UMLS	C2674219
MedGen	436112
GARD	0016149
Is cancer (heuristic)	no

Also known as: hereditary spherocytosis caused by mutation in SPTB · hereditary spherocytosis type 2 · HS2 · SPH2 · spherocytosis, type 2 · SPTB hereditary spherocytosis

Data availability: 169 ClinVar variants · 2 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 2

Related subtypes (4): hereditary spherocytosis type 1, hereditary spherocytosis type 3, 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

169 retrieved; paginated sample, class counts are floors:

48 pathogenic, 38 likely pathogenic, 37 uncertain significance, 18 pathogenic/likely pathogenic, 14 benign/likely benign, 10 conflicting classifications of pathogenicity, 4 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
520434	Single allele		Pathogenic	criteria provided, single submitter
1163075	NM_001355436.2(SPTB):c.4291C>T (p.Arg1431Ter)	SPTB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1163553	NM_001355436.2(SPTB):c.1912C>T (p.Arg638Ter)	SPTB	Pathogenic	criteria provided, multiple submitters, no conflicts
12835	NM_001355436.2(SPTB):c.604T>C (p.Trp202Arg)	SPTB	Pathogenic	no assertion criteria provided
12837	NM_001355436.2(SPTB):c.6055T>C (p.Ser2019Pro)	SPTB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12838	NG_016202.2:g.(105169_105646)_(109769_110365)del	SPTB	Pathogenic	no assertion criteria provided
12841	NM_001355436.2(SPTB):c.1A>G (p.Met1Val)	SPTB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12842	NM_001355436.2(SPTB):c.1912del (p.Arg638fs)	SPTB	Pathogenic	no assertion criteria provided
12843	NM_001355436.2(SPTB):c.5266C>T (p.Arg1756Ter)	SPTB	Pathogenic	criteria provided, multiple submitters, no conflicts
1453666	NM_001355436.2(SPTB):c.4873C>T (p.Arg1625Ter)	SPTB	Pathogenic	criteria provided, multiple submitters, no conflicts
1676970	NM_001355436.2(SPTB):c.3841C>T (p.Gln1281Ter)	SPTB	Pathogenic	criteria provided, single submitter
1676971	NM_001355436.2(SPTB):c.493C>T (p.Gln165Ter)	SPTB	Pathogenic	criteria provided, single submitter
1676972	NM_001355436.2(SPTB):c.6059_6060del (p.Val2020fs)	SPTB	Pathogenic	criteria provided, single submitter
1676973	NM_001355436.2(SPTB):c.5464G>T (p.Glu1822Ter)	SPTB	Pathogenic	criteria provided, single submitter
1676974	NM_001355436.2(SPTB):c.2423del (p.Gly808fs)	SPTB	Pathogenic	criteria provided, single submitter
1676975	NM_001355436.2(SPTB):c.472C>T (p.Gln158Ter)	SPTB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1676976	NM_001355436.2(SPTB):c.2092del (p.Gln698fs)	SPTB	Pathogenic	criteria provided, single submitter
1676977	NM_001355436.2(SPTB):c.3351C>A (p.Tyr1117Ter)	SPTB	Pathogenic	criteria provided, single submitter
1676978	NM_001355436.2(SPTB):c.467G>C (p.Arg156Pro)	SPTB	Pathogenic	criteria provided, single submitter
1676979	NM_001355436.2(SPTB):c.6536_6537del (p.Val2179fs)	SPTB	Pathogenic	criteria provided, single submitter
1676980	NM_001355436.2(SPTB):c.2659C>T (p.Gln887Ter)	SPTB	Pathogenic	criteria provided, single submitter
1676981	NM_001355436.2(SPTB):c.1630dup (p.Met544fs)	SPTB	Pathogenic	criteria provided, single submitter
1676982	NM_001355436.2(SPTB):c.5737dup (p.Arg1913fs)	SPTB	Pathogenic	criteria provided, single submitter
1676983	NM_001355436.2(SPTB):c.4417C>T (p.Gln1473Ter)	SPTB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1676984	NM_001355436.2(SPTB):c.999_1000del (p.Leu334fs)	SPTB	Pathogenic	criteria provided, single submitter
1676986	NM_001355436.2(SPTB):c.85G>T (p.Glu29Ter)	SPTB	Pathogenic	criteria provided, multiple submitters, no conflicts
1676987	NM_001355436.2(SPTB):c.3986_4001del (p.Leu1329fs)	SPTB	Pathogenic	criteria provided, single submitter
1676988	NM_001355436.2(SPTB):c.2165C>A (p.Ser722Ter)	SPTB	Pathogenic	criteria provided, single submitter
1676989	NM_001355436.2(SPTB):c.5099del (p.Asp1700fs)	SPTB	Pathogenic	criteria provided, single submitter
1676990	NM_001355436.2(SPTB):c.4969G>T (p.Glu1657Ter)	SPTB	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 12 · 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
SPTB	Strong	Autosomal dominant	hereditary spherocytosis type 2	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SPTB	Orphanet:288	Hereditary elliptocytosis
SPTB	Orphanet:822	Hereditary spherocytosis
SPTA1	Orphanet:288	Hereditary elliptocytosis
SPTA1	Orphanet:822	Hereditary spherocytosis
TBX1	Orphanet:1727	22q11.2 duplication syndrome
TBX1	Orphanet:3303	Tetralogy of Fallot
TBX1	Orphanet:567	22q11.2 deletion syndrome
TBX1	Orphanet:665044	Common arterial trunk with aortic dominance
TBX1	Orphanet:665058	Common arterial trunk with pulmonary dominance and interrupted aortic arch
TBX1	Orphanet:685017	Combined immunodeficiency due to TBX1 deficiency
MYH2	Orphanet:363677	Childhood-onset autosomal recessive myopathy with external ophthalmoplegia
MYH2	Orphanet:79091	Hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SPTB	HGNC:11274	ENSG00000070182	P11277	Spectrin beta chain, erythrocytic	gencc,clinvar
SPTA1	HGNC:11272	ENSG00000163554	P02549	Spectrin alpha chain, erythrocytic 1	clinvar
TBX1	HGNC:11592	ENSG00000184058	O43435	T-box transcription factor TBX1	clinvar
MYH2	HGNC:7572	ENSG00000125414	Q9UKX2	Myosin-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SPTB	Spectrin beta chain, erythrocytic	Spectrin is the major constituent of the cytoskeletal network underlying the erythrocyte plasma membrane.
SPTA1	Spectrin alpha chain, erythrocytic 1	Spectrin is the major constituent of the cytoskeletal network underlying the erythrocyte plasma membrane.
TBX1	T-box transcription factor TBX1	Transcription factor that plays a key role in cardiovascular development by promoting pharyngeal arch segmentation during embryonic development.
MYH2	Myosin-2	Myosins are actin-based motor molecules with ATPase activity essential for muscle contraction.

Protein-family classification

Druggable: 0 · Difficult: 3 · Unknown: 1 · Druggable fraction: 0.0

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
Scaffold/PPI	2	8.6×	0.056
Transcription factor	1	2.1×	0.605
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SPTB	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat
SPTA1	Scaffold/PPI	no		SH3_domain, Spectrin_repeat, EF_hand_dom
TBX1	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS
MYH2	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	2
hindlimb stylopod muscle	2
muscle of leg	2
bone marrow	1
bone marrow cell	1
trabecular bone tissue	1
biceps brachii	1
skeletal muscle tissue of biceps brachii	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SPTB	220	broad	marker	gastrocnemius, hindlimb stylopod muscle, muscle of leg
SPTA1	147	tissue_specific	marker	trabecular bone tissue, bone marrow, bone marrow cell
TBX1	220	broad	marker	hindlimb stylopod muscle, gastrocnemius, muscle of leg
MYH2	163	tissue_specific	marker	skeletal muscle tissue of rectus abdominis, biceps brachii, skeletal muscle tissue of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MYH2	2,008
SPTA1	1,551
TBX1	1,256
SPTB	1,079

Intra-cohort edges

A	B	Sources
SPTA1	SPTB	intact, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SPTB	P11277	6
SPTA1	P02549	3
TBX1	O43435	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MYH2	Q9UKX2	73.51

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 30. Enrichment computed across 4 evidence-associated genes (4 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 4 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	184.2×	0.001	SPTB, SPTA1
NCAM signaling for neurite out-growth	2	135.9×	0.001	SPTB, SPTA1
ER to Golgi Anterograde Transport	2	66.4×	0.002	SPTB, SPTA1
MAPK1/MAPK3 signaling	2	65.6×	0.002	SPTB, SPTA1
L1CAM interactions	2	60.1×	0.002	SPTB, SPTA1
COPI-mediated anterograde transport	2	54.9×	0.002	SPTB, SPTA1
MAPK family signaling cascades	2	51.4×	0.002	SPTB, SPTA1
Transport to the Golgi and subsequent modification	2	51.4×	0.002	SPTB, SPTA1
Developmental Biology	3	10.8×	0.004	SPTB, SPTA1, TBX1
RAF/MAP kinase cascade	2	30.5×	0.004	SPTB, SPTA1
Asparagine N-linked glycosylation	2	30.1×	0.004	SPTB, SPTA1
Axon guidance	2	22.6×	0.007	SPTB, SPTA1
Nervous system development	2	21.5×	0.007	SPTB, SPTA1
Membrane Trafficking	2	18.5×	0.009	SPTB, SPTA1
Vesicle-mediated transport	2	17.4×	0.009	SPTB, SPTA1
Cardiogenesis	1	105.7×	0.018	TBX1
Parasite infection	1	86.5×	0.019	MYH2
Leishmania phagocytosis	1	86.5×	0.019	MYH2
Fcgamma receptor (FCGR) dependent phagocytosis	1	69.6×	0.023	MYH2
Post-translational protein modification	2	9.6×	0.023	SPTB, SPTA1
FCGR3A-mediated phagocytosis	1	46.8×	0.029	MYH2
Regulation of actin dynamics for phagocytic cup formation	1	46.0×	0.029	MYH2
Leishmania infection	1	40.8×	0.030	MYH2
Parasitic Infection Pathways	1	40.8×	0.030	MYH2
Metabolism of proteins	2	6.2×	0.042	SPTB, SPTA1
Signal Transduction	2	5.1×	0.058	SPTB, SPTA1
Innate Immune System	1	6.4×	0.162	MYH2
Infectious disease	1	6.2×	0.162	MYH2
Disease	1	3.3×	0.275	MYH2
Immune System	1	3.2×	0.275	MYH2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 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	766.0×	2e-04	SPTB, SPTA1
regulation of animal organ morphogenesis	1	4213.0×	0.009	TBX1
vagus nerve morphogenesis	1	2106.5×	0.009	TBX1
positive regulation of tongue muscle cell differentiation	1	2106.5×	0.009	TBX1
porphyrin-containing compound biosynthetic process	1	1053.2×	0.009	SPTA1
ear morphogenesis	1	1053.2×	0.009	TBX1
tongue morphogenesis	1	842.6×	0.009	TBX1
soft palate development	1	842.6×	0.009	TBX1
muscle cell fate commitment	1	702.2×	0.009	TBX1
semicircular canal morphogenesis	1	601.9×	0.009	TBX1
parathyroid gland development	1	601.9×	0.009	TBX1
muscle tissue morphogenesis	1	601.9×	0.009	TBX1
negative regulation of mesenchymal cell apoptotic process	1	601.9×	0.009	TBX1
lymph vessel development	1	468.1×	0.009	TBX1
lymphocyte homeostasis	1	468.1×	0.009	SPTA1
muscle organ morphogenesis	1	468.1×	0.009	TBX1
coronary artery morphogenesis	1	468.1×	0.009	TBX1
actin cytoskeleton organization	2	39.6×	0.009	SPTB, SPTA1
embryonic viscerocranium morphogenesis	1	421.3×	0.009	TBX1
outer ear morphogenesis	1	383.0×	0.009	TBX1
mesenchymal cell apoptotic process	1	383.0×	0.009	TBX1
modification of postsynaptic actin cytoskeleton	1	351.1×	0.009	SPTB
enamel mineralization	1	300.9×	0.010	TBX1
muscle filament sliding	1	263.3×	0.011	MYH2
plasma membrane organization	1	221.7×	0.012	SPTA1
aorta morphogenesis	1	221.7×	0.012	TBX1
blood vessel morphogenesis	1	200.6×	0.013	TBX1
pharyngeal system development	1	200.6×	0.013	TBX1
middle ear morphogenesis	1	175.5×	0.014	TBX1
artery morphogenesis	1	168.5×	0.014	TBX1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SPTB	0	0
SPTA1	0	0
TBX1	0	0
MYH2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MYH2	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	0
E	Difficult family or no structure, no drug	4	SPTB, SPTA1, TBX1, MYH2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SPTB	0	—
SPTA1	0	—
TBX1	0	—
MYH2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.