Cryohydrocytosis

Summary

Cryohydrocytosis (MONDO:0008494) is a disease caused by SLC4A1 (GenCC Strong), with 1 cohort gene and 1 clinical trial. Top therapeutic interventions include daclatasvir and vx-135.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC4A1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 164
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		53	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	cryohydrocytosis
Mondo ID	MONDO:0008494
MeSH	C535827
OMIM	185020
Orphanet	398088
UMLS	C1861453
MedGen	396137
GARD	0010184
Is cancer (heuristic)	no

Also known as: CHC · cryohydrocytosis · hereditary cryohydrocytosis with normal stomatin · stomatocytosis, cold-sensitive

Data availability: 164 ClinVar variants · 3 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 › cryohydrocytosis

Related subtypes (22): congenital nonspherocytic hemolytic anemia, elliptocytosis 2, southeast Asian ovalocytosis, overhydrated hereditary stomatocytosis, dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema, abetalipoproteinemia, hemolytic anemia due to diphosphoglycerate mutase deficiency, glycogen storage disease VII, cutaneous porphyria, hereditary cryohydrocytosis with reduced stomatin, familial pseudohyperkalemia, renal tubular acidosis, distal, 4, with hemolytic anemia, elliptocytosis 1, glycogen storage disease due to aldolase A deficiency, primary CD59 deficiency, triosephosphate isomerase deficiency, dehydrated hereditary stomatocytosis 2, Rh deficiency syndrome, hereditary spherocytosis, congenital dyserythropoietic anemia, X-linked congenital hemolytic anemia, hemolytic disease of fetus and newborn, RH-induced

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

164 retrieved; paginated sample, class counts are floors:

100 uncertain significance, 27 conflicting classifications of pathogenicity, 10 pathogenic/likely pathogenic, 9 benign/likely benign, 7 likely benign, 6 likely pathogenic, 5 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
17753	NM_000342.4(SLC4A1):c.1199_1225del (p.Ala400_Ala408del)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
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
17780	NM_000342.3(SLC4A1):c.2279G>A (p.Arg760Gln)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
218182	NM_000342.4(SLC4A1):c.2191T>C (p.Ser731Pro)	SLC4A1	Pathogenic	no assertion criteria provided
218184	NM_000342.4(SLC4A1):c.2060T>C (p.Leu687Pro)	SLC4A1	Pathogenic	no assertion criteria provided
235293	NM_000342.4(SLC4A1):c.1825G>A (p.Gly609Arg)	SLC4A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
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
620131	NM_000342.4(SLC4A1):c.1030C>T (p.Arg344Ter)	SLC4A1	Pathogenic/Likely 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
3780627	NC_000002.12:g.42108272_42108298del		Likely pathogenic	criteria provided, single submitter
1163104	NM_000342.4(SLC4A1):c.2260C>T (p.Gln754Ter)	SLC4A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1275803	NM_000342.4(SLC4A1):c.2716G>T (p.Glu906Ter)	SLC4A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2433471	NM_000342.4(SLC4A1):c.349+1G>C	SLC4A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3068136	NM_000342.4(SLC4A1):c.2115C>G (p.Asp705Glu)	SLC4A1	Likely pathogenic	criteria provided, single submitter
3068152	NM_000342.4(SLC4A1):c.2492G>A (p.Trp831Ter)	SLC4A1	Likely pathogenic	criteria provided, single submitter
1008971	NM_000342.4(SLC4A1):c.1181T>C (p.Leu394Pro)	SLC4A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1044950	NM_000342.4(SLC4A1):c.1160G>A (p.Arg387Gln)	SLC4A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1050262	NM_000342.4(SLC4A1):c.538C>T (p.Arg180Cys)	SLC4A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1162821	NM_000342.4(SLC4A1):c.277G>T (p.Ala93Ser)	SLC4A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1343087	NM_000342.4(SLC4A1):c.2656C>A (p.Leu886Met)	SLC4A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1420205	NM_000342.4(SLC4A1):c.2344C>T (p.Arg782Cys)	SLC4A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1495044	NM_000342.4(SLC4A1):c.523C>A (p.Pro175Thr)	SLC4A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1676955	NM_000342.4(SLC4A1):c.2116C>A (p.Leu706Met)	SLC4A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
17756	NM_000342.3(SLC4A1):c.118G>A (p.Glu40Lys)	SLC4A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 6 · 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	cryohydrocytosis	15

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

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
SLC4A1	HGNC:11027	ENSG00000004939	P02730	Band 3 anion transport protein	gencc,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.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC4A1	Other/Unknown	no		Anion_exchange, Anion_exchange_1, HCO3_transpt_euk

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
bone marrow	1
bone marrow cell	1
trabecular bone tissue	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC4A1	1,598

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC4A1	P02730	54

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Defective SLC4A1 causes hereditary spherocytosis type 4 (HSP4), distal renal tubular acidosis (dRTA) and dRTA with hemolytic anemia (dRTA-HA)	1	11420.0×	1e-03	SLC4A1
Erythrocytes take up oxygen and release carbon dioxide	1	1268.9×	0.002	SLC4A1
O2/CO2 exchange in erythrocytes	1	1268.9×	0.002	SLC4A1
Bicarbonate transporters	1	1142.0×	0.002	SLC4A1
Erythrocytes take up carbon dioxide and release oxygen	1	878.5×	0.003	SLC4A1
SLC transporter disorders	1	203.9×	0.009	SLC4A1
Disorders of transmembrane transporters	1	139.3×	0.011	SLC4A1
R-HSA-425393	1	129.8×	0.011	SLC4A1
SLC-mediated transmembrane transport	1	59.2×	0.021	SLC4A1
Transport of small molecules	1	25.1×	0.044	SLC4A1
Disease	1	13.1×	0.076	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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to increased oxygen levels	1	16852.0×	4e-04	SLC4A1
pH elevation	1	16852.0×	4e-04	SLC4A1
intracellular monoatomic ion homeostasis	1	4213.0×	9e-04	SLC4A1
negative regulation of urine volume	1	4213.0×	9e-04	SLC4A1
negative regulation of glycolytic process through fructose-6-phosphate	1	2808.7×	0.001	SLC4A1
plasma membrane phospholipid scrambling	1	1532.0×	0.002	SLC4A1
monoatomic anion transport	1	1404.3×	0.002	SLC4A1
bicarbonate transport	1	802.5×	0.002	SLC4A1
regulation of intracellular pH	1	601.9×	0.003	SLC4A1
erythrocyte development	1	526.6×	0.003	SLC4A1
chloride transport	1	455.5×	0.003	SLC4A1
chloride transmembrane transport	1	237.3×	0.005	SLC4A1
blood coagulation	1	173.7×	0.006	SLC4A1
transmembrane transport	1	168.5×	0.006	SLC4A1
protein localization to plasma membrane	1	108.7×	0.009	SLC4A1

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
SLC4A1	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	SLC4A1

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)
SLC4A1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01842451	PHASE2	COMPLETED	A Phase 2 Study to Evaluate the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of VX-135 and Daclatasvir in Subjects With Genotype 1 Chronic Hepatitis C Chronic Hepatitis C

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DACLATASVIR	4	1
VX-135	2	1
CHEMBL4442791	0	1