Hereditary spherocytosis type 5

Summary

Hereditary spherocytosis type 5 (MONDO:0012985) is a disease caused by EPB42 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: EPB42 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 148

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spherocytosis type 5
Mondo ID	MONDO:0012985
MeSH	C567202
OMIM	612690
DOID	DOID:0110920
UMLS	C2675192
MedGen	436371
GARD	0015578
Is cancer (heuristic)	no

Also known as: EPB42 hereditary spherocytosis · hereditary spherocytosis caused by mutation in EPB42 · hereditary spherocytosis type 5 · HS5 · SPH5 · spherocytosis, type 5

Data availability: 148 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 5

Related subtypes (4): hereditary spherocytosis type 2, hereditary spherocytosis type 1, hereditary spherocytosis type 3, hereditary spherocytosis type 4

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

148 retrieved; paginated sample, class counts are floors:

86 uncertain significance, 31 conflicting classifications of pathogenicity, 8 likely pathogenic, 8 likely benign, 6 pathogenic, 4 benign/likely benign, 3 benign, 1 not provided, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
13234	NM_001114134.2(EPB42):c.175del (p.Val59fs)	EPB42	Pathogenic	criteria provided, single submitter
13236	NM_000119.2(EPB42):c.922+1G>A	EPB42	Pathogenic	no assertion criteria provided
13237	NM_000119.2(EPB42):c.1747G>T (p.Glu583Ter)	EPB42	Pathogenic	no assertion criteria provided
132633	NM_001114134.2(EPB42):c.433G>T (p.Asp145Tyr)	EPB42	Pathogenic	criteria provided, single submitter
3577128	NM_001114134.2(EPB42):c.775C>T (p.Arg259Ter)	EPB42	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4078703	NM_001114134.2(EPB42):c.1423_1454del (p.Leu475fs)	EPB42	Pathogenic	criteria provided, single submitter
4685821	NM_001114134.2(EPB42):c.1305C>G (p.Tyr435Ter)	EPB42	Pathogenic	criteria provided, single submitter
13235	NM_000119.2(EPB42):c.929G>A (p.Arg310Gln)	EPB42	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324335	NM_001114134.2(EPB42):c.1501del (p.Ser501fs)	EPB42	Likely pathogenic	criteria provided, single submitter
2921044	NM_001114134.2(EPB42):c.1887del (p.Leu630fs)	EPB42	Likely pathogenic	criteria provided, single submitter
3577129	NM_001114134.2(EPB42):c.108dup (p.Gln37fs)	EPB42	Likely pathogenic	criteria provided, single submitter
4081372	NM_001114134.2(EPB42):c.1686del (p.Arg563fs)	EPB42	Likely pathogenic	criteria provided, single submitter
4081373	NM_001114134.2(EPB42):c.1350_1351del (p.Arg450fs)	EPB42	Likely pathogenic	criteria provided, single submitter
992935	NM_001114134.2(EPB42):c.832G>C (p.Val278Leu)	EPB42	Likely pathogenic	criteria provided, single submitter
992936	NM_001114134.2(EPB42):c.323C>T (p.Thr108Ile)	EPB42	Likely pathogenic	criteria provided, single submitter
1163092	NM_001114134.2(EPB42):c.620A>G (p.Gln207Arg)	EPB42	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1163095	NM_001114134.2(EPB42):c.256G>T (p.Asp86Tyr)	EPB42	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1163380	NM_001114134.2(EPB42):c.971+8_971+9delinsAA	EPB42	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
13233	NM_000119.2(EPB42):c.424G>A (p.Ala142Thr)	EPB42	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
132635	NM_001114134.2(EPB42):c.859C>T (p.Arg287Cys)	EPB42	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
132637	NM_001114134.2(EPB42):c.1609G>A (p.Ala537Thr)	EPB42	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1693639	NM_001114134.2(EPB42):c.1487C>T (p.Thr496Met)	EPB42	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2041913	NM_001114134.2(EPB42):c.2044G>A (p.Val682Ile)	EPB42	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2348551	NM_001114134.2(EPB42):c.1280G>A (p.Arg427His)	EPB42	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
255147	NM_001114134.2(EPB42):c.1032T>C (p.Asp344=)	EPB42	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
255148	NM_001114134.2(EPB42):c.1279C>T (p.Arg427Cys)	EPB42	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
255154	NM_001114134.2(EPB42):c.453T>C (p.Asn151=)	EPB42	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
255156	NM_001114134.2(EPB42):c.10+79G>A	EPB42	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
255158	NM_001114134.2(EPB42):c.894C>T (p.Thr298=)	EPB42	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
316007	NM_001114134.2(EPB42):c.2032A>G (p.Asn678Asp)	EPB42	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · 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
EPB42	Strong	Autosomal recessive	hereditary spherocytosis type 5	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EPB42	Orphanet:822	Hereditary spherocytosis

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
EPB42	HGNC:3381	ENSG00000166947	P16452	Protein 4.2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EPB42	Protein 4.2	Component of the ankyrin-1 complex, a multiprotein complex involved in the stability and shape of the erythrocyte membrane.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Antibody/Immunoglobulin	1	29.2×	0.034

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EPB42	Antibody/Immunoglobulin	yes	2.3.2.13	Transglutaminase_N, Transglutaminase-like, Transglutaminase_C

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	1
bone marrow	1
bone marrow cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EPB42	91	tissue_specific	marker	blood, bone marrow, bone marrow cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EPB42	923

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EPB42	P16452	13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
hemoglobin metabolic process	1	4213.0×	0.001	EPB42
erythrocyte maturation	1	842.6×	0.003	EPB42
multicellular organismal-level iron ion homeostasis	1	581.1×	0.003	EPB42
spleen development	1	401.2×	0.004	EPB42
cell morphogenesis	1	157.5×	0.008	EPB42
regulation of cell shape	1	123.0×	0.008	EPB42

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
EPB42	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
EPB42	2.3.2.13	protein-glutamine gamma-glutamyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	EPB42
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
EPB42	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.