Hereditary spherocytosis type 4

Summary

Hereditary spherocytosis type 4 (MONDO:0012981) is a disease caused by variants in SLC4A1 and SLC4A2, with 3 cohort genes.

At a glance

• Causal genes: SLC4A1 (GenCC Strong), SLC4A2 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 300

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spherocytosis type 4
Mondo ID	MONDO:0012981
MeSH	C567208
OMIM	612653
DOID	DOID:0110919
UMLS	C2675212
MedGen	436375
GARD	0015576
Is cancer (heuristic)	no

Also known as: hereditary spherocytosis caused by mutation in SLC4A1 · HS4 · SLC4A1 hereditary spherocytosis · SPH4 · spherocytosis, type 4

Data availability: 300 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 4

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

300 retrieved; paginated sample, class counts are floors:

145 uncertain significance, 63 conflicting classifications of pathogenicity, 28 benign/likely benign, 15 pathogenic/likely pathogenic, 15 pathogenic, 15 benign, 12 likely pathogenic, 7 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1162816	NM_000342.4(SLC4A1):c.1468C>T (p.Arg490Cys)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1676953	NM_000342.4(SLC4A1):c.370C>T (p.Gln124Ter)	SLC4A1	Pathogenic	criteria provided, single submitter
1676959	NM_000342.4(SLC4A1):c.910C>T (p.Arg304Ter)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1676960	NM_000342.4(SLC4A1):c.1610dup (p.Ser538fs)	SLC4A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1676961	NM_000342.4(SLC4A1):c.1267_1268insG (p.Phe423fs)	SLC4A1	Pathogenic	criteria provided, single submitter
17753	NM_000342.4(SLC4A1):c.1199_1225del (p.Ala400_Ala408del)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17758	NM_000342.3(SLC4A1):c.2464_2465insCACCCAGATG (p.Val822Alafs)	SLC4A1	Pathogenic	no assertion criteria provided
17761	NM_000342.3(SLC4A1):c.988C>T (p.Gln330Ter)	SLC4A1	Pathogenic	no assertion criteria provided
17762	NM_000342.3(SLC4A1):c.448C>T (p.Arg150Ter)	SLC4A1	Pathogenic	criteria provided, multiple submitters, no conflicts
17763	NM_000342.4(SLC4A1):c.1766G>A (p.Arg589His)	SLC4A1	Pathogenic	criteria provided, multiple submitters, no conflicts
17764	NM_000342.4(SLC4A1):c.1765C>T (p.Arg589Cys)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17767	NM_000342.4(SLC4A1):c.2102G>A (p.Gly701Asp)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17771	NM_000342.4(SLC4A1):c.2573C>A (p.Ala858Asp)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17773	NM_000342.3(SLC4A1):c.1462G>A (p.Val488Met)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17776	NM_000342.3(SLC4A1):c.2608C>T (p.Arg870Trp)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17780	NM_000342.3(SLC4A1):c.2279G>A (p.Arg760Gln)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
235293	NM_000342.4(SLC4A1):c.1825G>A (p.Gly609Arg)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
323504	NM_000342.4(SLC4A1):c.2210C>T (p.Ala737Val)	SLC4A1	Pathogenic	criteria provided, single submitter
3382897	NM_000342.4(SLC4A1):c.2020del (p.Val674fs)	SLC4A1	Pathogenic	criteria provided, single submitter
3582115	NM_000342.4(SLC4A1):c.1242del (p.Phe414fs)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4530604	NM_000342.4(SLC4A1):c.111del (p.His37fs)	SLC4A1	Pathogenic	criteria provided, single submitter
520435	NM_000342.3(SLC4A1):c.(1094_1375)_(2057+11_2058-41)del	SLC4A1	Pathogenic	criteria provided, single submitter
544805	NM_000342.4(SLC4A1):c.1458C>G (p.Tyr486Ter)	SLC4A1	Pathogenic	criteria provided, single submitter
544806	NM_000342.4(SLC4A1):c.486-2A>G	SLC4A1	Pathogenic	criteria provided, single submitter
544809	NM_000342.4(SLC4A1):c.2423G>A (p.Arg808His)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
620131	NM_000342.4(SLC4A1):c.1030C>T (p.Arg344Ter)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
803425	NM_000342.4(SLC4A1):c.2278C>T (p.Arg760Trp)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
811391	NM_000342.4(SLC4A1):c.1469G>A (p.Arg490His)	SLC4A1	Pathogenic	criteria provided, multiple submitters, no conflicts
971626	NM_000342.4(SLC4A1):c.2726T>C (p.Met909Thr)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
992922	NM_000342.4(SLC4A1):c.2269A>T (p.Lys757Ter)	SLC4A1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 7 · 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
SLC4A1	Strong	Autosomal dominant	hereditary spherocytosis type 4	15
SLC4A2	Strong	Autosomal dominant	hereditary spherocytosis type 4	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC4A1	Orphanet:3202	Dehydrated hereditary stomatocytosis
SLC4A1	Orphanet:398088	Hereditary cryohydrocytosis with normal stomatin
SLC4A1	Orphanet:822	Hereditary spherocytosis
SLC4A1	Orphanet:93608	Autosomal dominant distal renal tubular acidosis
SLC4A1	Orphanet:93610	Distal renal tubular acidosis with anemia
SLC4A1	Orphanet:98868	Southeast Asian ovalocytosis
SLC7A7	Orphanet:470	Lysinuric protein intolerance

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC4A1	HGNC:11027	ENSG00000004939	P02730	Band 3 anion transport protein	gencc,clinvar
SLC4A2	HGNC:11028	ENSG00000164889	P04920	Anion exchange protein 2	gencc
SLC7A7	HGNC:11065	ENSG00000155465	Q9UM01	Y+L amino acid transporter 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC4A1	Band 3 anion transport protein	Functions both as a transporter that mediates electroneutral anion exchange across the cell membrane and as a structural protein.
SLC4A2	Anion exchange protein 2	Sodium-independent anion exchanger which mediates the electroneutral exchange of chloride for bicarbonate ions across the cell membrane.
SLC7A7	Y+L amino acid transporter 1	Heterodimer with SLC3A2, that functions as an antiporter which operates as an efflux route by exporting cationic amino acids from inside the cells in exchange with neutral amino acids plus sodium ions and may participate in nitric oxide sy…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Transporter	1	25.9×	0.076
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC4A1	Other/Unknown	no		Anion_exchange, Anion_exchange_1, HCO3_transpt_euk
SLC4A2	Other/Unknown	no		Anion_exchange, Anion_exchange_2, HCO3_transpt_euk
SLC7A7	Transporter	yes		AA/rel_permease1, AminoAcid_Transporter

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bone marrow	1
bone marrow cell	1
trabecular bone tissue	1
body of stomach	1
metanephros cortex	1
muscle layer of sigmoid colon	1
monocyte	1
mononuclear cell	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC4A1	161	tissue_specific	marker	trabecular bone tissue, bone marrow, bone marrow cell
SLC4A2	261	ubiquitous	marker	body of stomach, metanephros cortex, muscle layer of sigmoid colon
SLC7A7	215	ubiquitous	marker	secondary oocyte, monocyte, mononuclear cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC4A1	1,598
SLC7A7	1,584
SLC4A2	1,580

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC4A1	P02730	54
SLC4A2	P04920	10
SLC7A7	Q9UM01	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Bicarbonate transporters	2	761.3×	3e-05	SLC4A1, SLC4A2
Defective SLC4A1 causes hereditary spherocytosis type 4 (HSP4), distal renal tubular acidosis (dRTA) and dRTA with hemolytic anemia (dRTA-HA)	1	3806.7×	0.001	SLC4A1
R-HSA-425393	2	86.5×	0.001	SLC4A1, SLC4A2
Defective amino acid transport by SLC7A7 causes lysinuric protein intolerance (LPI)	1	1903.3×	0.002	SLC7A7
SLC-mediated transmembrane transport	2	39.5×	0.002	SLC4A1, SLC4A2
Erythrocytes take up oxygen and release carbon dioxide	1	423.0×	0.005	SLC4A1
O2/CO2 exchange in erythrocytes	1	423.0×	0.005	SLC4A1
Erythrocytes take up carbon dioxide and release oxygen	1	292.8×	0.006	SLC4A1
Transport of small molecules	2	16.8×	0.007	SLC4A1, SLC4A2
Basigin interactions	1	146.4×	0.010	SLC7A7
Amino acid transport across the plasma membrane	1	100.2×	0.013	SLC7A7
SLC transporter disorders	1	68.0×	0.017	SLC4A1
Disorders of transmembrane transporters	1	46.4×	0.023	SLC4A1
Disease	1	4.4×	0.212	SLC4A1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
monoatomic anion transport	2	936.2×	4e-05	SLC4A1, SLC4A2
bicarbonate transport	2	535.0×	6e-05	SLC4A1, SLC4A2
regulation of intracellular pH	2	401.2×	8e-05	SLC4A1, SLC4A2
response to increased oxygen levels	1	5617.3×	7e-04	SLC4A1
pH elevation	1	5617.3×	7e-04	SLC4A1
basic amino acid transmembrane transport	1	5617.3×	7e-04	SLC7A7
transmembrane transport	2	112.3×	7e-04	SLC4A1, SLC4A2
obsolete regulation of arginine metabolic process	1	2808.7×	0.001	SLC7A7
negative regulation of CD8-positive, alpha-beta T cell proliferation	1	2808.7×	0.001	SLC4A2
negative regulation of CD8-positive, alpha-beta T cell differentiation	1	1872.4×	0.002	SLC4A2
intracellular monoatomic ion homeostasis	1	1404.3×	0.002	SLC4A1
negative regulation of urine volume	1	1404.3×	0.002	SLC4A1
positive regulation of enamel mineralization	1	1123.5×	0.002	SLC4A2
negative regulation of glycolytic process through fructose-6-phosphate	1	936.2×	0.002	SLC4A1
L-leucine transport	1	510.7×	0.003	SLC7A7
plasma membrane phospholipid scrambling	1	510.7×	0.003	SLC4A1
regulation of bone resorption	1	510.7×	0.003	SLC4A2
amelogenesis	1	468.1×	0.003	SLC4A2
L-arginine transmembrane transport	1	468.1×	0.003	SLC7A7
amino acid transmembrane transport	1	244.2×	0.006	SLC7A7
digestive tract development	1	175.5×	0.007	SLC4A2
erythrocyte development	1	175.5×	0.007	SLC4A1
chloride transport	1	151.8×	0.008	SLC4A1
osteoclast differentiation	1	114.6×	0.011	SLC4A2
chloride transmembrane transport	1	79.1×	0.015	SLC4A1
blood coagulation	1	57.9×	0.019	SLC4A1
regulation of actin cytoskeleton organization	1	52.5×	0.020	SLC4A2
protein localization to plasma membrane	1	36.2×	0.028	SLC4A1
spermatogenesis	1	11.7×	0.083	SLC4A2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
SLC4A1	0	0
SLC4A2	0	0
SLC7A7	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	SLC7A7
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SLC4A1, SLC4A2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC4A1	0	—
SLC4A2	0	—
SLC7A7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.