Mevalonate kinase deficiency

Summary

Mevalonate kinase deficiency (MONDO:0017708) is a disease with 1 cohort gene and 4 clinical trials. Top therapeutic interventions include canakinumab and geranylgeraniol.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 8
• Clinical trials: 4

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		300	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	mevalonate kinase deficiency
Mondo ID	MONDO:0017708
MeSH	D054078
Orphanet	309025
ICD-11	772056052
UMLS	C0342731
MedGen	87453
GARD	0021315
MedDRA	10072221
NORD	1260
Is cancer (heuristic)	no

Data availability: 8 ClinVar variants · 2 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic dyslipidemia › mevalonate kinase deficiency

Related subtypes (28): familial apolipoprotein C-II deficiency, sitosterolemia, cerebrotendinous xanthomatosis, rhizomelic chondrodysplasia punctata type 1, apparent mineralocorticoid excess, GM1 gangliosidosis type 1, familial lipoprotein lipase deficiency, sea-blue histiocyte syndrome, Sjogren-Larsson syndrome, Smith-Lemli-Opitz syndrome, CHIME syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, Barth syndrome, CHILD syndrome, neuronal ceroid lipofuscinosis 8 northern epilepsy variant, Krabbe disease due to saposin A deficiency, lipoprotein glomerulopathy, hereditary spastic paraplegia 39, PHARC syndrome, congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome, hyperlipoproteinemia, type 1D, intellectual disability, autosomal recessive 53, hyperphosphatasia-intellectual disability syndrome, fatty acid hydroxylase-associated neurodegeneration, nephrotic syndrome 14, autosomal recessive complex spastic paraplegia due to kennedy pathway dysfunction, peroxisome biogenesis disorder due to PEX5 defect in the PEX7-binding domain, lysosomal acid lipase deficiency

Subtypes (2): hyperimmunoglobulinemia D with periodic fever, mevalonic aciduria

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

8 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
39727	NM_000431.4(MVK):c.417dup (p.Gly140fs)	MVK	Pathogenic	criteria provided, multiple submitters, no conflicts
4081743	NM_000431.4(MVK):c.622dup (p.Ser208fs)	MVK	Pathogenic	criteria provided, single submitter
97569	NM_000431.4(MVK):c.1139A>G (p.His380Arg)	MVK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
97601	NM_000431.4(MVK):c.608T>C (p.Val203Ala)	MVK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2441609	NM_000431.4(MVK):c.1039+1G>C	MVK	Likely pathogenic	criteria provided, multiple submitters, no conflicts
97637	NM_000431.4(MVK):c.925G>A (p.Gly309Ser)	MVK	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3754414	NM_000431.4(MVK):c.748G>T (p.Val250Phe)	MVK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3572948	NM_000431.4(MVK):c.82G>T (p.Ala28Ser)	MVK	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MVK	Orphanet:29	Mevalonic aciduria
MVK	Orphanet:343	Hyperimmunoglobulinemia D with periodic fever
MVK	Orphanet:735	Porokeratosis of Mibelli
MVK	Orphanet:79152	Disseminated superficial actinic porokeratosis

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
MVK	HGNC:7530	ENSG00000110921	Q03426	Mevalonate kinase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MVK	Mevalonate kinase	Catalyzes the phosphorylation of mevalonate to mevalonate 5-phosphate, a key step in isoprenoid and cholesterol biosynthesis.

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MVK	Kinase	yes	2.7.1.36	GHMP_knse_ATP-bd_CS, GHMP_kinase_N_dom, Mev_gal_kin

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
lower esophagus mucosa	1
metanephros cortex	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MVK	271	ubiquitous	marker	lower esophagus mucosa, right lobe of liver, metanephros cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MVK	3,424

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MVK	Q03426	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Cholesterol biosynthesis	1	1142.0×	0.005	MVK
Lanosterol biosynthesis	1	761.3×	0.005	MVK
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1	317.2×	0.007	MVK
Activation of gene expression by SREBF (SREBP)	1	259.6×	0.007	MVK
Metabolism of steroids	1	137.6×	0.010	MVK
Metabolism of lipids	1	31.6×	0.037	MVK
Metabolism	1	11.6×	0.086	MVK

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
isopentenyl diphosphate biosynthetic process, mevalonate pathway	1	5617.3×	7e-04	MVK
isoprenoid biosynthetic process	1	1685.2×	0.001	MVK
cholesterol biosynthetic process	1	421.3×	0.003	MVK
negative regulation of inflammatory response	1	137.0×	0.007	MVK

Therapeutics

Drugs indicated for this disease

1 approved. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Canakinumab	Approved (phase 4)

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
MVK	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MVK	2.7.1.36	mevalonate kinase

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	1	MVK
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
MVK	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01303380	PHASE2	COMPLETED	Canakinumab in Patients With Active Hyper-IgD Syndrome
NCT06497829	Not specified	RECRUITING	Geranylgeraniol Supplementation in Patients With Mevalonate Kinase Deficiency
NCT00260299	Not specified	TERMINATED	Dietary Cholesterol and Defects in Cholesterol Synthesis in Mevalonate Kinase Deficiency
NCT01568736	Not specified	WITHDRAWN	B7 Coreceptor Molecules in Hyper IgD Syndrome Form of Mevalonate Kinase Deficiency

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CANAKINUMAB	4	1
GERANYLGERANIOL	0	1