Melorheostosis

Summary

Melorheostosis (MONDO:0007970) is a disease with 2 cohort genes and 2 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Europe) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 37
• Phenotypes (HPO): 17
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000	0.09	Europe	Validated

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0000924	Abnormality of the skeletal system	Very frequent (80-99%)
HP:0001004	Lymphedema	Very frequent (80-99%)
HP:0001387	Joint stiffness	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0002652	Skeletal dysplasia	Very frequent (80-99%)
HP:0002653	Bone pain	Very frequent (80-99%)
HP:0002829	Arthralgia	Very frequent (80-99%)
HP:0003202	Skeletal muscle atrophy	Very frequent (80-99%)
HP:0006824	Cranial nerve paralysis	Very frequent (80-99%)
HP:0011001	Increased bone mineral density	Very frequent (80-99%)
HP:0011987	Ectopic ossification in muscle tissue	Very frequent (80-99%)
HP:0100774	Hyperostosis	Very frequent (80-99%)
HP:0100559	Lower limb asymmetry	Frequent (30-79%)
HP:0100560	Upper limb asymmetry	Frequent (30-79%)
HP:0000987	Atypical scarring of skin	Occasional (5-29%)
HP:0001369	Arthritis	Occasional (5-29%)
HP:0100784	Peripheral arteriovenous fistula	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	melorheostosis
Mondo ID	MONDO:0007970
MeSH	D008557
OMIM	155950
Orphanet	2485
DOID	DOID:4253
ICD-11	312433776
NCIT	C84887
SNOMED CT	44697002
UMLS	C3149631
MedGen	460981
GARD	0009474
MedDRA	10050284
NORD	1431
Is cancer (heuristic)	no

Also known as: melorheostosis, isolated, somatic mosaic

Data availability: 37 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › osteopetrosis › melorheostosis

Related subtypes (10): osteomesopyknosis, dysosteosclerosis, pycnodysostosis, anhidrotic ectodermal dysplasia-immunodeficiency-osteopetrosis-lymphedema syndrome, osteopathia striata with cranial sclerosis, infantile osteopetrosis with neuroaxonal dysplasia, osteosclerotic metaphyseal dysplasia, autosomal recessive osteopetrosis, autosomal dominant osteopetrosis, early-onset calcifying leukoencephalopathy-skeletal dysplasia

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

37 retrieved; paginated sample, class counts are floors:

22 uncertain significance, 5 conflicting classifications of pathogenicity, 4 pathogenic, 3 likely benign, 1 pathogenic/likely pathogenic, 1 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
13351	NM_002755.4(MAP2K1):c.389A>G (p.Tyr130Cys)	MAP2K1	Pathogenic	reviewed by expert panel
223140	NM_002755.4(MAP2K1):c.171G>T (p.Lys57Asn)	MAP2K1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
375978	NM_002755.4(MAP2K1):c.167A>C (p.Gln56Pro)	MAP2K1	Pathogenic	criteria provided, multiple submitters, no conflicts
376173	NM_002755.4(MAP2K1):c.169A>G (p.Lys57Glu)	MAP2K1	Pathogenic	no assertion criteria provided
40781	NM_002755.4(MAP2K1):c.199G>A (p.Asp67Asn)	MAP2K1	Pathogenic	reviewed by expert panel
3577599	NM_002755.4(MAP2K1):c.200A>G (p.Asp67Gly)	MAP2K1	Likely pathogenic	criteria provided, single submitter
1138943	NM_002755.4(MAP2K1):c.961-10G>C	MAP2K1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1334255	NM_002755.4(MAP2K1):c.1138G>A (p.Gly380Ser)	MAP2K1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180896	NM_002755.4(MAP2K1):c.277G>A (p.Val93Ile)	MAP2K1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3577604	NM_002755.4(MAP2K1):c.528C>T (p.Gly176=)	MAP2K1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1214837	NM_002755.4(MAP2K1):c.1177G>A (p.Val393Ile)	SNAPC5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1761697	NM_002755.4(MAP2K1):c.801T>A (p.Asp267Glu)	MAP2K1	Uncertain significance	criteria provided, multiple submitters, no conflicts
177942	NM_002755.4(MAP2K1):c.56C>G (p.Ala19Gly)	MAP2K1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1987933	NM_002755.4(MAP2K1):c.1022+6T>G	MAP2K1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2198544	NM_002755.4(MAP2K1):c.1030A>C (p.Lys344Gln)	MAP2K1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2911450	NM_002755.4(MAP2K1):c.516+3G>A	MAP2K1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3577597	NM_002755.4(MAP2K1):c.-7G>A	MAP2K1	Uncertain significance	criteria provided, single submitter
3577598	NM_002755.4(MAP2K1):c.80+5G>A	MAP2K1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3577600	NM_002755.4(MAP2K1):c.427A>C (p.Met143Leu)	MAP2K1	Uncertain significance	criteria provided, single submitter
3577601	NM_002755.4(MAP2K1):c.428T>C (p.Met143Thr)	MAP2K1	Uncertain significance	criteria provided, single submitter
3577602	NM_002755.4(MAP2K1):c.439-19C>G	MAP2K1	Uncertain significance	criteria provided, single submitter
3577603	NM_002755.4(MAP2K1):c.510C>T (p.Ser170=)	MAP2K1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3577606	NM_002755.4(MAP2K1):c.568+2T>C	MAP2K1	Uncertain significance	criteria provided, single submitter
3577607	NM_002755.4(MAP2K1):c.893G>C (p.Ser298Thr)	MAP2K1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3577608	NM_002755.4(MAP2K1):c.1068+5G>A	MAP2K1	Uncertain significance	criteria provided, single submitter
3577609	NM_002755.4(MAP2K1):c.1166A>G (p.His389Arg)	MAP2K1	Uncertain significance	criteria provided, single submitter
3577610	NM_002755.4(MAP2K1):c.*17A>T	MAP2K1	Uncertain significance	criteria provided, multiple submitters, no conflicts
40761	NM_002755.4(MAP2K1):c.1062A>C (p.Gln354His)	MAP2K1	Uncertain significance	criteria provided, multiple submitters, no conflicts
44593	NM_002755.4(MAP2K1):c.875C>G (p.Thr292Ser)	MAP2K1	Uncertain significance	criteria provided, multiple submitters, no conflicts
659397	NM_002755.4(MAP2K1):c.1135A>G (p.Ile379Val)	MAP2K1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MAP2K1	Orphanet:1340	Cardiofaciocutaneous syndrome
MAP2K1	Orphanet:389	Langerhans cell histiocytosis

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
SNAPC5	HGNC:15484	ENSG00000174446	O75971	snRNA-activating protein complex subunit 5	clinvar
MAP2K1	HGNC:6840	ENSG00000169032	Q02750	Dual specificity mitogen-activated protein kinase kinase 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SNAPC5	snRNA-activating protein complex subunit 5	Part of the SNAPc complex required for the transcription of both RNA polymerase II and III small-nuclear RNA genes.
MAP2K1	Dual specificity mitogen-activated protein kinase kinase 1	Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway.

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
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SNAPC5	Other/Unknown	no		SNAPC5
MAP2K1	Kinase	yes	2.7.12.2	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf

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
endothelial cell	1
middle temporal gyrus	1
sperm	1
oocyte	1
orbitofrontal cortex	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SNAPC5	299	ubiquitous	marker	endothelial cell, middle temporal gyrus, sperm
MAP2K1	298	ubiquitous	marker	secondary oocyte, oocyte, orbitofrontal cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MAP2K1	5,944
SNAPC5	438

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MAP2K1	Q02750	94
SNAPC5	O75971	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 68. 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
Signaling by MAP2K mutants	1	1427.5×	0.018	MAP2K1
Negative feedback regulation of MAPK pathway	1	951.7×	0.018	MAP2K1
Prolonged ERK activation events	1	713.8×	0.018	MAP2K1
MAPK3 (ERK1) activation	1	519.1×	0.018	MAP2K1
Frs2-mediated activation	1	475.8×	0.018	MAP2K1
Uptake and function of anthrax toxins	1	475.8×	0.018	MAP2K1
Uptake and actions of bacterial toxins	1	407.9×	0.018	MAP2K1
MAP3K8 (TPL2)-dependent MAPK1/3 activation	1	356.9×	0.018	MAP2K1
RAF-independent MAPK1/3 activation	1	317.2×	0.018	MAP2K1
Signalling to ERKs	1	300.5×	0.018	MAP2K1
Signal transduction by L1	1	259.6×	0.018	MAP2K1
Signaling by RAS mutants	1	211.5×	0.018	MAP2K1
RNA Polymerase III Transcription Initiation From Type 3 Promoter	1	203.9×	0.018	SNAPC5
RAF activation	1	167.9×	0.018	MAP2K1
RNA Polymerase III Transcription Initiation	1	167.9×	0.018	SNAPC5
Bacterial Infection Pathways	1	167.9×	0.018	MAP2K1
RNA Polymerase III Transcription	1	163.1×	0.018	SNAPC5
Signaling by high-kinase activity BRAF mutants	1	158.6×	0.018	MAP2K1
MAP kinase activation	1	154.3×	0.018	MAP2K1
MAP2K and MAPK activation	1	142.8×	0.018	MAP2K1
RNA Polymerase III Abortive And Retractive Initiation	1	139.3×	0.018	SNAPC5
Signaling by RAF1 mutants	1	139.3×	0.018	MAP2K1
Interleukin-1 family signaling	1	135.9×	0.018	MAP2K1
Negative regulation of MAPK pathway	1	132.8×	0.018	MAP2K1
Interleukin-17 signaling	1	126.9×	0.018	MAP2K1
Signaling by moderate kinase activity BRAF mutants	1	126.9×	0.018	MAP2K1
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	126.9×	0.018	MAP2K1
Signaling downstream of RAS mutants	1	126.9×	0.018	MAP2K1
Oncogenic MAPK signaling	1	124.1×	0.018	MAP2K1
Toll Like Receptor 10 (TLR10) Cascade	1	107.7×	0.018	MAP2K1

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 homotypic cell-cell adhesion	1	4213.0×	0.004	MAP2K1
Golgi inheritance	1	4213.0×	0.004	MAP2K1
cerebellar cortex formation	1	2808.7×	0.004	MAP2K1
positive regulation of endodermal cell differentiation	1	2808.7×	0.004	MAP2K1
regulation of Golgi inheritance	1	2106.5×	0.004	MAP2K1
regulation of vascular associated smooth muscle contraction	1	1685.2×	0.004	MAP2K1
epithelial cell proliferation involved in lung morphogenesis	1	1685.2×	0.004	MAP2K1
transcription initiation at RNA polymerase III promoter	1	1203.7×	0.004	SNAPC5
positive regulation of muscle contraction	1	1203.7×	0.004	MAP2K1
regulation of axon regeneration	1	1203.7×	0.004	MAP2K1
trachea formation	1	1203.7×	0.004	MAP2K1
labyrinthine layer development	1	1053.2×	0.004	MAP2K1
negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway	1	1053.2×	0.004	MAP2K1
regulation of early endosome to late endosome transport	1	1053.2×	0.004	MAP2K1
regulation of stress-activated MAPK cascade	1	936.2×	0.004	MAP2K1
snRNA transcription by RNA polymerase III	1	936.2×	0.004	SNAPC5
ERBB2-ERBB3 signaling pathway	1	842.6×	0.004	MAP2K1
snRNA transcription by RNA polymerase II	1	766.0×	0.004	SNAPC5
Bergmann glial cell differentiation	1	766.0×	0.004	MAP2K1
placenta blood vessel development	1	702.2×	0.004	MAP2K1
positive regulation of protein serine/threonine kinase activity	1	648.1×	0.004	MAP2K1
positive regulation of ATP biosynthetic process	1	601.9×	0.004	MAP2K1
Schwann cell development	1	526.6×	0.005	MAP2K1
type B pancreatic cell proliferation	1	443.5×	0.005	MAP2K1
positive regulation of Ras protein signal transduction	1	443.5×	0.005	MAP2K1
vesicle transport along microtubule	1	443.5×	0.005	MAP2K1
regulation of neurotransmitter receptor localization to postsynaptic specialization membrane	1	443.5×	0.005	MAP2K1
face development	1	401.2×	0.005	MAP2K1
melanosome transport	1	383.0×	0.005	MAP2K1
central nervous system neuron differentiation	1	300.9×	0.006	MAP2K1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · 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).

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
MAP2K1	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAP2K1	54	4
SNAPC5	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	MAP2K1
SELUMETINIB	4	MAP2K1
TRAMETINIB	4	MAP2K1
COBIMETINIB	4	MAP2K1
BINIMETINIB	4	MAP2K1
DASATINIB	4	MAP2K1
SORAFENIB	4	MAP2K1
FEDRATINIB	4	MAP2K1
AXITINIB	4	MAP2K1
RUXOLITINIB	4	MAP2K1
NERATINIB	4	MAP2K1
TOFACITINIB	4	MAP2K1
VANDETANIB	4	MAP2K1
BOSUTINIB	4	MAP2K1
GILTERITINIB	4	MAP2K1
NINTEDANIB	4	MAP2K1
SUNITINIB	4	MAP2K1
SARACATINIB	3	MAP2K1
AVUTOMETINIB	3	MAP2K1
LINSITINIB	3	MAP2K1
ORANTINIB	3	MAP2K1
CANERTINIB	3	MAP2K1
DOVITINIB	3	MAP2K1
LESTAURTINIB	3	MAP2K1
CI-1040	2	MAP2K1
MIRDAMETINIB	2	MAP2K1
E-6201	2	MAP2K1
FORETINIB	2	MAP2K1
REFAMETINIB	2	MAP2K1
TAK-733	2	MAP2K1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MAP2K1	1,200	Binding:1150, Functional:47, ADMET:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MAP2K1	2.7.12.2	mitogen-activated protein kinase kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
MAP2K1	1,200

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

30 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)
VEMURAFENIB	4	MAP2K1
SELUMETINIB	4	MAP2K1
TRAMETINIB	4	MAP2K1
COBIMETINIB	4	MAP2K1
BINIMETINIB	4	MAP2K1
DASATINIB	4	MAP2K1
SORAFENIB	4	MAP2K1
FEDRATINIB	4	MAP2K1
AXITINIB	4	MAP2K1
RUXOLITINIB	4	MAP2K1
NERATINIB	4	MAP2K1
TOFACITINIB	4	MAP2K1
VANDETANIB	4	MAP2K1
BOSUTINIB	4	MAP2K1
GILTERITINIB	4	MAP2K1
NINTEDANIB	4	MAP2K1
SUNITINIB	4	MAP2K1
SARACATINIB	3	MAP2K1
AVUTOMETINIB	3	MAP2K1
LINSITINIB	3	MAP2K1
ORANTINIB	3	MAP2K1
CANERTINIB	3	MAP2K1
DOVITINIB	3	MAP2K1
LESTAURTINIB	3	MAP2K1
CI-1040	2	MAP2K1
MIRDAMETINIB	2	MAP2K1
E-6201	2	MAP2K1
FORETINIB	2	MAP2K1
REFAMETINIB	2	MAP2K1
TAK-733	2	MAP2K1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MAP2K1
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	SNAPC5

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)
SNAPC5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07521150	Not specified	NOT_YET_RECRUITING	Physiotherapy and Rehabilitation in Melorheostosis: A Case Report
NCT00076830	Not specified	COMPLETED	Evaluation and Treatment of Patients With Connective Tissue Disease