Ketoacidosis due to monocarboxylate transporter-1 deficiency

Summary

Ketoacidosis due to monocarboxylate transporter-1 deficiency (MONDO:0014490) is a disease caused by SLC16A1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC16A1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 14

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		9	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	ketoacidosis due to monocarboxylate transporter-1 deficiency
Mondo ID	MONDO:0014490
OMIM	616095
Orphanet	438075
UMLS	C4015186
MedGen	863623
GARD	0017733
Is cancer (heuristic)	no

Also known as: MCT1D · monocarboxylate transporter 1 deficiency

Data availability: 14 ClinVar variants · 6 GenCC gene-disease records.

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 energy metabolism › disorder of fatty acid and ketone body metabolism › ketoacidosis due to monocarboxylate transporter-1 deficiency

Related subtypes (3): disorder of fatty acid oxidation and ketogenesis, disorder of carnitine cycle and carnitine transport, inborn disorder of ketolysis

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

14 retrieved; paginated sample, class counts are floors:

4 likely pathogenic, 3 pathogenic, 2 benign, 2 benign/likely benign, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
158079	NM_003051.4(SLC16A1):c.937C>T (p.Arg313Ter)	SLC16A1	Pathogenic	criteria provided, multiple submitters, no conflicts
158081	NM_003051.4(SLC16A1):c.586C>T (p.Arg196Ter)	SLC16A1	Pathogenic	criteria provided, single submitter
160371	NM_003051.4(SLC16A1):c.747_750del (p.Asn250fs)	SLC16A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
800884	NM_003051.4(SLC16A1):c.1079del (p.Ala360fs)	SLC16A1	Pathogenic	criteria provided, single submitter
2584348	NM_003051.4(SLC16A1):c.41del (p.Pro14fs)	SLC16A1	Likely pathogenic	criteria provided, single submitter
3899393	NM_003051.4(SLC16A1):c.74G>T (p.Gly25Val)	SLC16A1	Likely pathogenic	criteria provided, single submitter
3899396	NM_003051.4(SLC16A1):c.1207C>T (p.Leu403Phe)	SLC16A1	Likely pathogenic	criteria provided, single submitter
4526516	NM_003051.4(SLC16A1):c.1153C>T (p.Gln385Ter)	SLC16A1	Likely pathogenic	criteria provided, single submitter
160369	NM_003051.4(SLC16A1):c.41dup (p.Asp15fs)	SLC16A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3892446	NM_003051.4(SLC16A1):c.98C>G (p.Ser33Cys)	SLC16A1	Uncertain significance	criteria provided, single submitter
130315	NM_003051.4(SLC16A1):c.1470T>A (p.Asp490Glu)	SLC16A1	Benign	criteria provided, multiple submitters, no conflicts
1332975	NM_003051.4(SLC16A1):c.362-21A>C	SLC16A1	Benign	criteria provided, multiple submitters, no conflicts
1570647	NM_003051.4(SLC16A1):c.362-58TATT[8]	SLC16A1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
712920	NM_003051.4(SLC16A1):c.973A>G (p.Ile325Val)	SLC16A1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · 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
SLC16A1	Definitive	Autosomal recessive	ketoacidosis due to monocarboxylate transporter-1 deficiency	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC16A1	Orphanet:165991	Exercise-induced hyperinsulinism
SLC16A1	Orphanet:171690	Metabolic myopathy due to lactate transporter defect
SLC16A1	Orphanet:438075	Ketoacidosis due to monocarboxylate transporter-1 deficiency

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
SLC16A1	HGNC:10922	ENSG00000155380	P53985	Monocarboxylate transporter 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC16A1	Monocarboxylate transporter 1	Bidirectional proton-coupled monocarboxylate transporter.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Transporter	1	77.8×	0.013

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC16A1	Transporter	yes		MCT, MFS, MFS_dom

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
adrenal tissue	1
mucosa of transverse colon	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC16A1	134	ubiquitous	marker	mucosa of transverse colon, ventricular zone, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC16A1	2,296

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC16A1	P53985	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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 SLC16A1 causes symptomatic deficiency in lactate transport (SDLT)	1	5710.0×	0.002	SLC16A1
Proton-coupled monocarboxylate transport	1	1903.3×	0.003	SLC16A1
Basigin interactions	1	439.2×	0.010	SLC16A1
Aspirin ADME	1	317.2×	0.010	SLC16A1
Drug ADME	1	228.4×	0.010	SLC16A1
SLC transporter disorders	1	203.9×	0.010	SLC16A1
R-HSA-425366	1	181.3×	0.010	SLC16A1
Disorders of transmembrane transporters	1	139.3×	0.012	SLC16A1
Cell surface interactions at the vascular wall	1	95.2×	0.015	SLC16A1
SLC-mediated transmembrane transport	1	59.2×	0.022	SLC16A1
Hemostasis	1	36.0×	0.033	SLC16A1
Transport of small molecules	1	25.1×	0.043	SLC16A1
Disease	1	13.1×	0.076	SLC16A1

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
mevalonate transport	1	16852.0×	4e-04	SLC16A1
behavioral response to nutrient	1	16852.0×	4e-04	SLC16A1
pyruvate transmembrane transport	1	5617.3×	7e-04	SLC16A1
plasma membrane lactate transport	1	4213.0×	7e-04	SLC16A1
succinate transmembrane transport	1	4213.0×	7e-04	SLC16A1
carboxylic acid transmembrane transport	1	2808.7×	8e-04	SLC16A1
pyruvate catabolic process	1	2106.5×	9e-04	SLC16A1
monocarboxylic acid transport	1	1532.0×	0.001	SLC16A1
response to food	1	495.6×	0.003	SLC16A1
regulation of insulin secretion	1	391.9×	0.004	SLC16A1
centrosome cycle	1	337.0×	0.004	SLC16A1
transport across blood-brain barrier	1	179.3×	0.007	SLC16A1
glucose homeostasis	1	130.6×	0.008	SLC16A1
lipid metabolic process	1	91.6×	0.011	SLC16A1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC16A1	3	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SYROSINGOPINE	2	SLC16A1
LUTEOLIN	2	SLC16A1
AZD3965	1	SLC16A1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC16A1	52	Binding:49, Functional:3

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

3 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)
SYROSINGOPINE	2	SLC16A1
LUTEOLIN	2	SLC16A1
AZD3965	1	SLC16A1

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	SLC16A1
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.