Hartnup disease

Summary

Hartnup disease (MONDO:0009324) is a disease caused by SLC6A19 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC6A19 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 205
• Phenotypes (HPO): 30

Clinical features

Epidemiology

Prevalence records

5 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	4.2	Worldwide	Validated
Point prevalence	1-9 / 100 000	4	United Kingdom	Validated
Prevalence at birth	1-9 / 100 000	3.3	Australia	Validated
Prevalence at birth	1-9 / 100 000	3.85	United States	Validated
Prevalence at birth	1-9 / 100 000	1.9	Specific population	Validated

Signs & symptoms

Clinical features (HPO)

30 HPO clinical features (Orphanet curated; top 30 by frequency):

HPO ID	Term	Frequency
HP:0000712	Emotional lability	Very frequent (80-99%)
HP:0000738	Hallucinations	Very frequent (80-99%)
HP:0000739	Anxiety	Very frequent (80-99%)
HP:0000992	Cutaneous photosensitivity	Very frequent (80-99%)
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001347	Hyperreflexia	Very frequent (80-99%)
HP:0002076	Migraine	Very frequent (80-99%)
HP:0002353	EEG abnormality	Very frequent (80-99%)
HP:0008353	Neutral hyperaminoaciduria	Very frequent (80-99%)
HP:0012086	Abnormal urinary color	Very frequent (80-99%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000504	Abnormality of vision	Frequent (30-79%)
HP:0000613	Photophobia	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000988	Skin rash	Frequent (30-79%)
HP:0001337	Tremor	Frequent (30-79%)
HP:0002024	Malabsorption	Frequent (30-79%)
HP:6000130	Elevated urinary indican level	Frequent (30-79%)
HP:0000206	Glossitis	Occasional (5-29%)
HP:0000230	Gingivitis	Occasional (5-29%)
HP:0000709	Psychosis	Occasional (5-29%)
HP:0001053	Hypopigmented skin patches	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0002383	Infectious encephalitis	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0007400	Irregular hyperpigmentation	Occasional (5-29%)
HP:0008066	Abnormal blistering of the skin	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Hartnup disease
Mondo ID	MONDO:0009324
MeSH	D006250
OMIM	234500
Orphanet	2116
DOID	DOID:1060
NCIT	C84748
SNOMED CT	80902009
UMLS	C0018609
MedGen	6723
GARD	0006569
MedDRA	10019165
NORD	1217
Is cancer (heuristic)	no

Also known as: aminoaciduria, Hartnup type · Hartnup disease · Hartnup disorder · HND

Data availability: 205 ClinVar variants · 5 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn disorder of amino acid transport › Hartnup disease

Related subtypes (18): blue diaper syndrome, ocular cystinosis, juvenile nephropathic cystinosis, cystinuria, hyperdibasic aminoaciduria type 1, lysinuric protein intolerance, dicarboxylic aminoaciduria, histidinuria due to a renal tubular defect, iminoglycinuria, oculocerebrorenal syndrome, hypotonia-cystinuria syndrome, foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome, episodic ataxia type 6, progressive essential tremor-speech impairment-facial dysmorphism-intellectual disability-abnormal behavior syndrome, disorder of neutral amino acid transport, autosomal recessive cerebellar ataxia - pyramidal signs - nystagmus - oculomotor apraxia syndrome, nephropathic infantile cystinosis, undetermined early-onset epileptic encephalopathy

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

205 retrieved; paginated sample, class counts are floors:

120 uncertain significance, 21 likely pathogenic, 21 likely benign, 16 conflicting classifications of pathogenicity, 10 benign/likely benign, 8 benign, 5 pathogenic, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2018	NM_001003841.3(SLC6A19):c.884_885del (p.Val295fs)	SLC6A19	Pathogenic	no assertion criteria provided
2019	NM_001003841.3(SLC6A19):c.517G>A (p.Asp173Asn)	SLC6A19	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2020	NM_001003841.3(SLC6A19):c.718C>T (p.Arg240Ter)	SLC6A19	Pathogenic	criteria provided, multiple submitters, no conflicts
2203603	NM_001003841.3(SLC6A19):c.850G>A (p.Gly284Arg)	SLC6A19	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2203604	NM_001003841.3(SLC6A19):c.1501G>A (p.Glu501Lys)	SLC6A19	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3339144	NM_001003841.3(SLC6A19):c.1173+2T>C	SLC6A19	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
449553	NM_001003841.3(SLC6A19):c.1173+2T>G	SLC6A19	Pathogenic	criteria provided, multiple submitters, no conflicts
916044	NM_001003841.3(SLC6A19):c.1787_1788insG (p.Ile597fs)	SLC6A19	Pathogenic	no assertion criteria provided
917714	NM_001003841.3(SLC6A19):c.532C>T (p.Arg178Ter)	SLC6A19	Pathogenic	criteria provided, multiple submitters, no conflicts
1174952	NM_001003841.3(SLC6A19):c.774+1G>A	SLC6A19	Likely pathogenic	criteria provided, single submitter
1482366	NM_001003841.3(SLC6A19):c.277G>A (p.Gly93Arg)	SLC6A19	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705051	NM_001003841.3(SLC6A19):c.1550A>G (p.Asp517Gly)	SLC6A19	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2430279	NM_001003841.3(SLC6A19):c.170G>A (p.Arg57His)	SLC6A19	Likely pathogenic	criteria provided, single submitter
2431061	NM_001003841.3(SLC6A19):c.311G>A (p.Trp104Ter)	SLC6A19	Likely pathogenic	criteria provided, single submitter
2500902	NM_001003841.3(SLC6A19):c.1169C>G (p.Ser390Ter)	SLC6A19	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3591604	NM_001003841.3(SLC6A19):c.522C>A (p.Tyr174Ter)	SLC6A19	Likely pathogenic	criteria provided, single submitter
3591607	NM_001003841.3(SLC6A19):c.609_610insA (p.Ala204fs)	SLC6A19	Likely pathogenic	criteria provided, single submitter
3591621	NM_001003841.3(SLC6A19):c.774+1G>C	SLC6A19	Likely pathogenic	criteria provided, single submitter
3591624	NM_001003841.3(SLC6A19):c.834dup (p.Phe279fs)	SLC6A19	Likely pathogenic	criteria provided, single submitter
3591635	NM_001003841.3(SLC6A19):c.1125C>A (p.Tyr375Ter)	SLC6A19	Likely pathogenic	criteria provided, single submitter
3591636	NM_001003841.3(SLC6A19):c.1125C>G (p.Tyr375Ter)	SLC6A19	Likely pathogenic	criteria provided, single submitter
3591649	NM_001003841.3(SLC6A19):c.1358G>A (p.Trp453Ter)	SLC6A19	Likely pathogenic	criteria provided, single submitter
3591653	NM_001003841.3(SLC6A19):c.1435C>T (p.Gln479Ter)	SLC6A19	Likely pathogenic	criteria provided, single submitter
3591660	NM_001003841.3(SLC6A19):c.1589G>A (p.Trp530Ter)	SLC6A19	Likely pathogenic	criteria provided, single submitter
3591662	NM_001003841.3(SLC6A19):c.1601G>A (p.Trp534Ter)	SLC6A19	Likely pathogenic	criteria provided, single submitter
3591663	NM_001003841.3(SLC6A19):c.1602G>A (p.Trp534Ter)	SLC6A19	Likely pathogenic	criteria provided, single submitter
3591671	NM_001003841.3(SLC6A19):c.1702G>T (p.Glu568Ter)	SLC6A19	Likely pathogenic	criteria provided, single submitter
3591672	NM_001003841.3(SLC6A19):c.1736C>T (p.Pro579Leu)	SLC6A19	Likely pathogenic	criteria provided, single submitter
3902540	NM_001003841.3(SLC6A19):c.1016+1G>A	SLC6A19	Likely pathogenic	criteria provided, single submitter
4845789	NM_001003841.3(SLC6A19):c.1141C>T (p.Gln381Ter)	SLC6A19	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · 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
SLC6A19	Definitive	Autosomal recessive	Hartnup disease	5
CLTRN	Supportive	Autosomal recessive	Hartnup disease

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC6A19	Orphanet:2116	Hartnup disease
SLC6A19	Orphanet:42062	Iminoglycinuria
CLTRN	Orphanet:2116	Hartnup disease

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
SLC6A19	HGNC:27960	ENSG00000174358	Q695T7	Sodium-dependent neutral amino acid transporter B(0)AT1	gencc,clinvar
CLTRN	HGNC:29437	ENSG00000147003	Q9HBJ8	Collectrin	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC6A19	Sodium-dependent neutral amino acid transporter B(0)AT1	Transporter that mediates resorption of neutral amino acids across the apical membrane of renal and intestinal epithelial cells.
CLTRN	Collectrin	Plays an important role in amino acid transport by acting as binding partner of amino acid transporters SLC6A18 and SLC6A19, regulating their trafficking on the cell surface and their amino acid transporter activity.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC6A19	Other/Unknown	no		Na/ntran_symport, Neutral_aa_SLC6, SNS_sf
CLTRN	Other/Unknown	no		Collectrin_dom, Collectrin

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
kidney epithelium	2
ileal mucosa	1
jejunal mucosa	1
adult mammalian kidney	1
pigmented layer of retina	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC6A19	67	tissue_specific	marker	ileal mucosa, kidney epithelium, jejunal mucosa
CLTRN	172	broad	marker	kidney epithelium, adult mammalian kidney, pigmented layer of retina

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC6A19	975
CLTRN	733

Intra-cohort edges

A	B	Sources
CLTRN	SLC6A19	intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC6A19	Q695T7	21

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CLTRN	Q9HBJ8	77.38

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. 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
Defective transport of neurotransmitters by SLC6A19 causes Hartnup disorder (HND)	1	5710.0×	0.001	SLC6A19
Defective transport of amino acids by SLC6A19 causes Hartnup disorder (HND)	1	5710.0×	0.001	SLC6A19
Insulin processing	1	228.4×	0.015	CLTRN
SLC-mediated transport of neurotransmitters	1	203.9×	0.015	SLC6A19
Amino acid transport across the plasma membrane	1	150.3×	0.016	SLC6A19
SLC transporter disorders	1	102.0×	0.019	SLC6A19
R-HSA-425366	1	90.6×	0.019	SLC6A19
Disorders of transmembrane transporters	1	69.6×	0.020	SLC6A19
R-HSA-425393	1	64.9×	0.020	SLC6A19
SLC-mediated transmembrane transport	1	29.6×	0.040	SLC6A19
Transport of small molecules	1	12.6×	0.085	SLC6A19
Disease	1	6.5×	0.147	SLC6A19

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
positive regulation of amino acid transport	1	4213.0×	0.001	CLTRN
positive regulation of L-proline import across plasma membrane	1	4213.0×	0.001	CLTRN
viral life cycle	1	2106.5×	0.002	SLC6A19
SNARE complex assembly	1	702.2×	0.003	CLTRN
insulin secretion involved in cellular response to glucose stimulus	1	648.1×	0.003	CLTRN
calcium-ion regulated exocytosis	1	495.6×	0.003	CLTRN
neutral amino acid transport	1	443.5×	0.003	SLC6A19
amino acid transport	1	156.0×	0.008	SLC6A19
response to nutrient	1	147.8×	0.008	SLC6A19
sodium ion transmembrane transport	1	101.5×	0.010	SLC6A19

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC6A19	1	2
CLTRN	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CINROMIDE	2	SLC6A19

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC6A19	4	Functional:3, Binding:1

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

1 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)
CINROMIDE	2	SLC6A19

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	1	SLC6A19
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CLTRN

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)
CLTRN	0	SLC6A19

Clinical trials & evidence

Clinical trials

Clinical trials: 0.