Hereditary folate malabsorption

Summary

Hereditary folate malabsorption (MONDO:0009238) is a disease caused by SLC46A1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC46A1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 149
• Phenotypes (HPO): 25

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		30	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0000206	Glossitis	Very frequent (80-99%)
HP:0000980	Pallor	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0001889	Megaloblastic anemia	Very frequent (80-99%)
HP:0002014	Diarrhea	Very frequent (80-99%)
HP:0002017	Nausea and vomiting	Very frequent (80-99%)
HP:0002039	Anorexia	Very frequent (80-99%)
HP:0002715	Abnormality of the immune system	Very frequent (80-99%)
HP:0004313	Decreased circulating antibody level	Very frequent (80-99%)
HP:0100022	Abnormality of movement	Very frequent (80-99%)
HP:0100825	Cheilitis	Very frequent (80-99%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0002020	Gastroesophageal reflux	Frequent (30-79%)
HP:0009830	Peripheral neuropathy	Frequent (30-79%)
HP:0000010	Recurrent urinary tract infections	Occasional (5-29%)
HP:0001347	Hyperreflexia	Occasional (5-29%)
HP:0001873	Thrombocytopenia	Occasional (5-29%)
HP:0001876	Pancytopenia	Occasional (5-29%)
HP:0001880	Eosinophilia	Occasional (5-29%)
HP:0002205	Recurrent respiratory infections	Occasional (5-29%)
HP:0002514	Cerebral calcification	Occasional (5-29%)
HP:0002721	Immunodeficiency	Occasional (5-29%)
HP:0003202	Skeletal muscle atrophy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary folate malabsorption
Mondo ID	MONDO:0009238
MeSH	C562799
OMIM	229050
Orphanet	90045
DOID	DOID:0111678
ICD-11	773545237
NCIT	C156424
SNOMED CT	62578003
UMLS	C0342705
MedGen	83348
GARD	0012983
Is cancer (heuristic)	no

Also known as: congenital defect of folate absorption · congenital folate malabsorption · folic acid transport defect

Data availability: 149 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › macrocytic anemia › megaloblastic anemia › hereditary folate malabsorption

Related subtypes (5): pernicious anemia, formiminoglutamic aciduria, Imerslund-Grasbeck syndrome, constitutional megaloblastic anemia with severe neurologic disease, vitamin B12- and folate-independent constitutional megaloblastic anemia

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

149 retrieved; paginated sample, class counts are floors:

81 uncertain significance, 22 benign, 14 conflicting classifications of pathogenicity, 11 pathogenic, 11 likely benign, 4 likely pathogenic, 4 benign/likely benign, 1 not provided, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
30922	NM_080669.6(SLC46A1):c.23dup (p.Glu9fs)	LOC130060550	Pathogenic	no assertion criteria provided
3254553	NM_080669.6(SLC46A1):c.1253del (p.Leu418fs)	SARM1	Pathogenic	criteria provided, single submitter
850	NM_080669.6(SLC46A1):c.1082-1G>A	SARM1	Pathogenic	criteria provided, multiple submitters, no conflicts
854	NM_080669.6(SLC46A1):c.1126C>T (p.Arg376Trp)	SARM1	Pathogenic	no assertion criteria provided
30924	NM_080669.6(SLC46A1):c.204_205del (p.Asn68fs)	SLC46A1	Pathogenic	no assertion criteria provided
30925	NM_080669.6(SLC46A1):c.1012G>C (p.Gly338Arg)	SLC46A1	Pathogenic	no assertion criteria provided
3366387	NM_080669.6(SLC46A1):c.487_493del (p.Ala163fs)	SLC46A1	Pathogenic	criteria provided, single submitter
801406	NM_080669.6(SLC46A1):c.981_982del (p.Tyr327_Cys328delinsTer)	SLC46A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
851	NM_080669.6(SLC46A1):c.194del (p.Gly65fs)	SLC46A1	Pathogenic	criteria provided, single submitter
852	NM_080669.6(SLC46A1):c.337C>A (p.Arg113Ser)	SLC46A1	Pathogenic	no assertion criteria provided
853	NM_080669.6(SLC46A1):c.954C>G (p.Ser318Arg)	SLC46A1	Pathogenic	no assertion criteria provided
855	NM_080669.6(SLC46A1):c.337C>T (p.Arg113Cys)	SLC46A1	Pathogenic	no assertion criteria provided
3233965	NM_080669.6(SLC46A1):c.3G>A (p.Met1Ile)	LOC130060550	Likely pathogenic	criteria provided, single submitter
21743	NM_080669.6(SLC46A1):c.1274C>G (p.Pro425Arg)	SARM1	Likely pathogenic	criteria provided, single submitter
3255576	NM_080669.6(SLC46A1):c.1173_1174del (p.Ser393fs)	SARM1	Likely pathogenic	criteria provided, single submitter
3391327	NM_080669.6(SLC46A1):c.138T>A (p.Tyr46Ter)	SLC46A1	Likely pathogenic	criteria provided, single submitter
193480	NM_080669.6(SLC46A1):c.22C>T (p.Pro8Ser)	LOC130060550	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1489802	NM_080669.6(SLC46A1):c.1214C>T (p.Thr405Met)	SARM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
65749	NM_080669.6(SLC46A1):c.1127G>A (p.Arg376Gln)	SARM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193481	NM_080669.6(SLC46A1):c.158C>T (p.Ala53Val)	SLC46A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2173040	NM_080669.6(SLC46A1):c.340C>T (p.Arg114Cys)	SLC46A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
252777	NM_080669.6(SLC46A1):c.623A>T (p.Tyr208Phe)	SLC46A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
30923	NM_080669.6(SLC46A1):c.1004C>A (p.Ala335Asp)	SLC46A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
322409	NM_080669.6(SLC46A1):c.512T>A (p.Val171Asp)	SLC46A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
322410	NM_080669.6(SLC46A1):c.462C>T (p.Leu154=)	SLC46A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
713611	NM_080669.6(SLC46A1):c.972C>T (p.Leu324=)	SLC46A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
890432	NM_080669.6(SLC46A1):c.849G>A (p.Gly283=)	SLC46A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
891002	NM_080669.6(SLC46A1):c.501C>G (p.Ser167=)	SLC46A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
892226	NM_080669.6(SLC46A1):c.189G>T (p.Arg63Ser)	SLC46A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
892227	NM_080669.6(SLC46A1):c.85G>A (p.Val29Ile)	SLC46A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
SLC46A1	Definitive	Autosomal recessive	hereditary folate malabsorption	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC46A1	Orphanet:90045	Hereditary folate malabsorption

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC46A1	HGNC:30521	ENSG00000076351	Q96NT5	Proton-coupled folate transporter	gencc,clinvar
SARM1	HGNC:17074	ENSG00000004139	Q6SZW1	NAD(+) hydrolase SARM1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC46A1	Proton-coupled folate transporter	Proton-coupled folate symporter that mediates folate absorption using an H(+) gradient as a driving force.
SARM1	NAD(+) hydrolase SARM1	NAD(+) hydrolase, which plays a key role in axonal degeneration following injury by regulating NAD(+) metabolism.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	38.9×	0.051
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC46A1	Transporter	yes		Sugar_transporter_CS, MFS, MFS_dom
SARM1	Other/Unknown	no		TIR_dom, SAM, ARM-like

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
duodenum	1
jejunal mucosa	1
oviduct epithelium	1
body of pancreas	1
cortical plate	1
islet of Langerhans	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC46A1	198	ubiquitous	marker	jejunal mucosa, duodenum, oviduct epithelium
SARM1	206	ubiquitous	marker	body of pancreas, cortical plate, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SARM1	1,013
SLC46A1	826

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SARM1	Q6SZW1	55

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC46A1	Q96NT5	82.94

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TRAF6-mediated induction of TAK1 complex within TLR4 complex	1	356.9×	0.008	SARM1
Metabolism of folate and pterines	1	317.2×	0.008	SLC46A1
Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)	1	300.5×	0.008	SARM1
IKK complex recruitment mediated by RIP1	1	248.3×	0.008	SARM1
Iron uptake and transport	1	173.0×	0.009	SLC46A1
Heme signaling	1	107.7×	0.011	SLC46A1
Toll Like Receptor 3 (TLR3) Cascade	1	96.8×	0.011	SARM1
MyD88-independent TLR4 cascade	1	92.1×	0.011	SARM1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of MyD88-independent toll-like receptor signaling pathway	1	8426.0×	0.002	SARM1
intestinal folate absorption	1	4213.0×	0.002	SLC46A1
folate transmembrane transport	1	2106.5×	0.002	SLC46A1
folate import across plasma membrane	1	2106.5×	0.002	SLC46A1
NAD+ catabolic process	1	1685.2×	0.002	SARM1
heme metabolic process	1	1685.2×	0.002	SLC46A1
folic acid transport	1	1404.3×	0.002	SLC46A1
tetrahydrofolate biosynthetic process	1	1404.3×	0.002	SLC46A1
regulation of synapse pruning	1	1053.2×	0.003	SARM1
modification of postsynaptic structure	1	936.2×	0.003	SARM1
protein localization to mitochondrion	1	648.1×	0.003	SARM1
nervous system process	1	601.9×	0.003	SARM1
folic acid metabolic process	1	561.7×	0.003	SLC46A1
regulation of dendrite morphogenesis	1	366.4×	0.005	SARM1
regulation of neuron apoptotic process	1	351.1×	0.005	SARM1
response to axon injury	1	255.3×	0.006	SARM1
proton transmembrane transport	1	156.0×	0.009	SLC46A1
response to glucose	1	127.7×	0.010	SARM1
intracellular iron ion homeostasis	1	122.1×	0.010	SLC46A1
transmembrane transport	1	84.3×	0.014	SLC46A1
nervous system development	1	23.0×	0.049	SARM1
innate immune response	1	16.8×	0.064	SARM1
cell differentiation	1	14.6×	0.070	SARM1
signal transduction	1	8.0×	0.121	SARM1

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SLC46A1	PRALATREXATE
SARM1	NIACINAMIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SARM1	7	4
SLC46A1	4	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PRALATREXATE	4	SLC46A1
RALTITREXED	4	SLC46A1
PEMETREXED	4	SLC46A1
METHOTREXATE	4	SLC46A1
NIACINAMIDE	4	SARM1
PHENAZOPYRIDINE HYDROCHLORIDE	4	SARM1
DEXLANSOPRAZOLE	4	SARM1
RABEPRAZOLE	4	SARM1
NITROFURAZONE	4	SARM1
TENATOPRAZOLE	2	SARM1
BERBERINE CHLORIDE	1	SARM1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC46A1	45	Binding:45
SARM1	25	Binding:25

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

11 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.

Compound	Max phase	Cohort target (bioactivity)
PRALATREXATE	4	SLC46A1
RALTITREXED	4	SLC46A1
PEMETREXED	4	SLC46A1
METHOTREXATE	4	SLC46A1
NIACINAMIDE	4	SARM1
PHENAZOPYRIDINE HYDROCHLORIDE	4	SARM1
DEXLANSOPRAZOLE	4	SARM1
RABEPRAZOLE	4	SARM1
NITROFURAZONE	4	SARM1
TENATOPRAZOLE	2	SARM1
BERBERINE CHLORIDE	1	SARM1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	SLC46A1, SARM1
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.