Hereditary spherocytosis type 1

Summary

Hereditary spherocytosis type 1 (MONDO:0008447) is a disease caused by ANK1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: ANK1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 865

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spherocytosis type 1
Mondo ID	MONDO:0008447
OMIM	182900
DOID	DOID:0110916
UMLS	C2674218
MedGen	382302
GARD	0024621
Is cancer (heuristic)	no

Also known as: ANK1 hereditary spherocytosis · hereditary spherocytosis caused by mutation in ANK1 · HS1 · SPH1 · spherocytosis, type 1

Data availability: 865 ClinVar variants · 5 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 1

Related subtypes (4): hereditary spherocytosis type 2, 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

600 retrieved; paginated sample, class counts are floors:

245 uncertain significance, 125 likely pathogenic, 69 pathogenic, 63 conflicting classifications of pathogenicity, 31 pathogenic/likely pathogenic, 27 likely benign, 21 benign/likely benign, 19 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1163881	NM_000037.4(ANK1):c.4000C>T (p.Arg1334Ter)	ANK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1198634	NM_000037.4(ANK1):c.2390_2393del	ANK1	Pathogenic	criteria provided, multiple submitters, no conflicts
1299404	NM_000037.4(ANK1):c.382_386del (p.Lys128fs)	ANK1	Pathogenic	criteria provided, multiple submitters, no conflicts
1299406	NM_000037.4(ANK1):c.3850del (p.Asp1284fs)	ANK1	Pathogenic	criteria provided, single submitter
1299410	NM_000037.4(ANK1):c.2393_2403del (p.Val798fs)	ANK1	Pathogenic	criteria provided, single submitter
1299413	NM_000037.4(ANK1):c.3269del (p.Leu1090fs)	ANK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1299414	NM_000037.4(ANK1):c.3629+2T>C	ANK1	Pathogenic	criteria provided, single submitter
1300176	NM_000037.4(ANK1):c.2098-1G>T	ANK1	Pathogenic	criteria provided, single submitter
1300177	NM_000037.4(ANK1):c.4098C>A (p.Cys1366Ter)	ANK1	Pathogenic	no assertion criteria provided
1323138	NM_000037.4(ANK1):c.2394_2397del (p.Ser799fs)	ANK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323892	NM_000037.4(ANK1):c.2961-2A>G	ANK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323896	NM_000037.4(ANK1):c.3157C>T (p.Arg1053Ter)	ANK1	Pathogenic	criteria provided, multiple submitters, no conflicts
1330541	NM_000037.4(ANK1):c.1124T>G (p.Leu375Ter)	ANK1	Pathogenic	criteria provided, single submitter
1330553	NM_000037.4(ANK1):c.2102del (p.Gly701fs)	ANK1	Pathogenic	criteria provided, single submitter
1330761	NM_000037.4(ANK1):c.2803C>T (p.Arg935Ter)	ANK1	Pathogenic	criteria provided, multiple submitters, no conflicts
1330914	NM_000037.4(ANK1):c.409C>T (p.Gln137Ter)	ANK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1331044	NM_000037.4(ANK1):c.5436_5437insCAGGG (p.Glu1813fs)	ANK1	Pathogenic	criteria provided, single submitter
1331095	NM_000037.4(ANK1):c.1702-2A>G	ANK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1333460	NM_000037.4(ANK1):c.5108G>A (p.Trp1703Ter)	ANK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1393753	NM_000037.4(ANK1):c.4414C>T (p.Gln1472Ter)	ANK1	Pathogenic	criteria provided, multiple submitters, no conflicts
1406324	NM_000037.4(ANK1):c.358C>T (p.Gln120Ter)	ANK1	Pathogenic	criteria provided, multiple submitters, no conflicts
1455153	NM_000037.4(ANK1):c.856C>T (p.Arg286Ter)	ANK1	Pathogenic	criteria provided, multiple submitters, no conflicts
1676944	NM_000037.4(ANK1):c.5192C>G (p.Ser1731Ter)	ANK1	Pathogenic	criteria provided, single submitter
1676945	NM_000037.4(ANK1):c.4157dup (p.Tyr1386Ter)	ANK1	Pathogenic	criteria provided, single submitter
1676946	NM_000037.4(ANK1):c.5071C>T (p.Gln1691Ter)	ANK1	Pathogenic	criteria provided, single submitter
1676947	NM_000037.4(ANK1):c.1305+1G>A	ANK1	Pathogenic	criteria provided, multiple submitters, no conflicts
1676948	NM_000037.4(ANK1):c.1405-9G>A	ANK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1676949	NM_000037.4(ANK1):c.1602+1G>C	ANK1	Pathogenic	criteria provided, single submitter
1676950	NM_000037.4(ANK1):c.3629+1G>C	ANK1	Pathogenic	criteria provided, multiple submitters, no conflicts
1676951	NM_000037.4(ANK1):c.886del (p.Ala296fs)	ANK1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 2 · 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
ANK1	Definitive	Autosomal dominant	hereditary spherocytosis	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ANK1	Orphanet:251066	8p11.2 deletion syndrome
ANK1	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
ANK1	HGNC:492	ENSG00000029534	P16157	Ankyrin-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ANK1	Ankyrin-1	Component of the ankyrin-1 complex, a multiprotein complex involved in the stability and shape of the erythrocyte membrane.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ANK1	Scaffold/PPI	no		Death_dom, ZU5_dom, Ankyrin_rpt

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
body of tongue	1
skeletal muscle tissue of rectus abdominis	1
triceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ANK1	226	broad	marker	skeletal muscle tissue of rectus abdominis, triceps brachii, body of tongue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ANK1	5,705

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ANK1	P16157	21

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
NrCAM interactions	1	1631.4×	0.004	ANK1
Neurofascin interactions	1	1427.5×	0.004	ANK1
CHL1 interactions	1	1268.9×	0.004	ANK1
Interaction between L1 and Ankyrins	1	368.4×	0.011	ANK1
ER to Golgi Anterograde Transport	1	132.8×	0.019	ANK1
L1CAM interactions	1	120.2×	0.019	ANK1
COPI-mediated anterograde transport	1	109.8×	0.019	ANK1
Transport to the Golgi and subsequent modification	1	102.9×	0.019	ANK1
Asparagine N-linked glycosylation	1	60.1×	0.030	ANK1
Axon guidance	1	45.1×	0.034	ANK1
Nervous system development	1	42.9×	0.034	ANK1
Membrane Trafficking	1	37.1×	0.035	ANK1
Vesicle-mediated transport	1	34.8×	0.035	ANK1
Post-translational protein modification	1	19.2×	0.060	ANK1
Developmental Biology	1	14.5×	0.074	ANK1
Metabolism of proteins	1	12.4×	0.081	ANK1

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
maintenance of epithelial cell apical/basal polarity	1	2407.4×	0.002	ANK1
exocytosis	1	151.8×	0.011	ANK1
endoplasmic reticulum to Golgi vesicle-mediated transport	1	135.9×	0.011	ANK1
cytoskeleton organization	1	132.7×	0.011	ANK1
protein localization to plasma membrane	1	108.7×	0.011	ANK1
signal transduction	1	16.1×	0.062	ANK1

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
ANK1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ANK1

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)
ANK1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.