Sclerosteosis 2

Summary

Sclerosteosis 2 (MONDO:0013679) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 1,215

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	sclerosteosis 2
Mondo ID	MONDO:0013679
OMIM	614305
DOID	DOID:0060757
UMLS	C3280402
MedGen	482032
GARD	0015786
Is cancer (heuristic)	no

Also known as: LRP4 sclerosteosis · sclerosteosis 2 · sclerosteosis caused by mutation in LRP4 · sclerosteosis type 2 · SOST2

Data availability: 1,215 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone remodeling disease › hyperostosis › sclerosteosis › sclerosteosis 2

Related subtypes (1): sclerosteosis 1

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

600 retrieved; paginated sample, class counts are floors:

299 uncertain significance, 253 likely benign, 24 conflicting classifications of pathogenicity, 9 benign, 7 benign/likely benign, 4 pathogenic, 3 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1180722	NM_002334.4(LRP4):c.3698A>C (p.Glu1233Ala)	LRP4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323250	NM_002334.4(LRP4):c.2830C>T (p.Gln944Ter)	LRP4	Pathogenic	criteria provided, multiple submitters, no conflicts
1393202	NM_002334.4(LRP4):c.2260C>T (p.Arg754Ter)	LRP4	Pathogenic	criteria provided, single submitter
2112258	NM_002334.4(LRP4):c.2498del (p.Thr833fs)	LRP4	Pathogenic	criteria provided, single submitter
2921833	NM_002334.4(LRP4):c.1850del (p.Ala617fs)	LRP4	Pathogenic	criteria provided, single submitter
1179057	NM_002334.4(LRP4):c.1560G>A (p.Trp520Ter)	LRP4	Likely pathogenic	criteria provided, single submitter
1179202	NM_002334.4(LRP4):c.1184-1G>A	LRP4	Likely pathogenic	criteria provided, single submitter
2119457	NM_002334.4(LRP4):c.3699+1G>A	LRP4	Likely pathogenic	criteria provided, single submitter
1032815	NM_002334.4(LRP4):c.4245C>T (p.Asn1415=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1128252	NM_002334.4(LRP4):c.4404T>C (p.Asn1468=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1306610	NM_002334.4(LRP4):c.1654A>T (p.Asn552Tyr)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1460952	NM_002334.4(LRP4):c.2010G>A (p.Thr670=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1500445	NM_002334.4(LRP4):c.1584C>A (p.Thr528=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1512123	NM_002334.4(LRP4):c.1342A>G (p.Ile448Val)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1519697	NM_002334.4(LRP4):c.1633C>T (p.Arg545Trp)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1567023	NM_002334.4(LRP4):c.132C>T (p.Cys44=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1567152	NM_002334.4(LRP4):c.1932C>T (p.Phe644=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1581161	NM_002334.4(LRP4):c.2216-13G>A	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1590124	NM_002334.4(LRP4):c.390T>C (p.Asp130=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
194206	NM_002334.4(LRP4):c.1551T>C (p.Ala517=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1946922	NM_002334.4(LRP4):c.2092+18G>A	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2048965	NM_002334.4(LRP4):c.3292T>A (p.Ser1098Thr)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2062110	NM_002334.4(LRP4):c.5087+13A>G	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2079164	NM_002334.4(LRP4):c.3765A>G (p.Pro1255=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211405	NM_002334.4(LRP4):c.3817C>A (p.Arg1273=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
281776	NM_002334.4(LRP4):c.639C>T (p.Asp213=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
282957	NM_002334.4(LRP4):c.5660C>G (p.Ser1887Cys)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
284378	NM_002334.4(LRP4):c.4317C>T (p.Ala1439=)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
285913	NM_002334.4(LRP4):c.2815-6T>G	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
286738	NM_002334.4(LRP4):c.3620A>G (p.Asn1207Ser)	LRP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 27 · Orphanet: 4 · 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
CORIN	Supportive	Autosomal recessive	sclerosteosis	14
LRP4	Supportive	Autosomal recessive	sclerosteosis	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CORIN	Orphanet:275555	Preeclampsia
LRP4	Orphanet:3152	Sclerosteosis
LRP4	Orphanet:3258	Cenani-Lenz syndrome
LRP4	Orphanet:98913	Postsynaptic congenital myasthenic syndrome

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CORIN	HGNC:19012	ENSG00000145244	Q9Y5Q5	Atrial natriuretic peptide-converting enzyme	gencc,clinvar
LRP4	HGNC:6696	ENSG00000134569	O75096	Low-density lipoprotein receptor-related protein 4	gencc,clinvar
LRP4-AS1	HGNC:44128	ENSG00000247675		LRP4 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CORIN	Atrial natriuretic peptide-converting enzyme	Serine-type endopeptidase involved in atrial natriuretic peptide (NPPA) and brain natriuretic peptide (NPPB) processing.
LRP4	Low-density lipoprotein receptor-related protein 4	Mediates SOST-dependent inhibition of bone formation.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Protease	1	12.2×	0.159
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CORIN	Protease	yes		SRCR, Trypsin_dom, LDrepeatLR_classA_rpt
LRP4	Other/Unknown	no		LDLR_classB_rpt, EGF, EGF-like_Ca-bd_dom
LRP4-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cardiac muscle of right atrium	1
heart right ventricle	1
myocardium	1
dorsal motor nucleus of vagus nerve	1
medial globus pallidus	1
ventricular zone	1
colonic epithelium	1
male germ line stem cell (sensu Vertebrata) in testis	1
skin of leg	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CORIN	176	tissue_specific	marker	cardiac muscle of right atrium, heart right ventricle, myocardium
LRP4	242	ubiquitous	marker	ventricular zone, dorsal motor nucleus of vagus nerve, medial globus pallidus
LRP4-AS1	125	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, colonic epithelium, skin of leg

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CORIN	1,291
LRP4	1,250
LRP4-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LRP4	O75096	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CORIN	Q9Y5Q5	70.20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 3 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
Physiological factors	1	335.9×	0.009	CORIN
ECM proteoglycans	1	75.1×	0.020	LRP4
Extracellular matrix organization	1	31.6×	0.031	LRP4

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 presynaptic membrane organization	1	8426.0×	0.004	LRP4
regulation of systemic arterial blood pressure by atrial natriuretic peptide	1	2808.7×	0.004	CORIN
synaptic assembly at neuromuscular junction	1	2808.7×	0.004	LRP4
regulation of renal sodium excretion	1	2106.5×	0.004	CORIN
postsynaptic membrane assembly	1	1203.7×	0.004	LRP4
amyloid-beta clearance by cellular catabolic process	1	1053.2×	0.004	LRP4
skeletal muscle acetylcholine-gated channel clustering	1	936.2×	0.004	LRP4
positive regulation of skeletal muscle acetylcholine-gated channel clustering	1	936.2×	0.004	LRP4
presynaptic membrane assembly	1	842.6×	0.004	LRP4
generation of neurons	1	766.0×	0.004	LRP4
enzyme-linked receptor protein signaling pathway	1	648.1×	0.004	LRP4
negative regulation of axonogenesis	1	648.1×	0.004	LRP4
peptide hormone processing	1	468.1×	0.005	CORIN
regulation of cardiac conduction	1	421.3×	0.005	CORIN
proximal/distal pattern formation	1	324.1×	0.006	LRP4
positive regulation of Rac protein signal transduction	1	324.1×	0.006	LRP4
negative regulation of ossification	1	312.1×	0.006	LRP4
Rac protein signal transduction	1	280.9×	0.006	LRP4
dendrite morphogenesis	1	216.1×	0.007	LRP4
dorsal/ventral pattern formation	1	210.7×	0.007	LRP4
limb development	1	205.5×	0.007	LRP4
hair follicle development	1	191.5×	0.008	LRP4
regulation of postsynapse assembly	1	172.0×	0.008	LRP4
odontogenesis of dentin-containing tooth	1	150.5×	0.008	LRP4
embryonic digit morphogenesis	1	150.5×	0.008	LRP4
synapse organization	1	140.4×	0.009	LRP4
regulation of blood pressure	1	110.9×	0.011	CORIN
female pregnancy	1	105.3×	0.011	CORIN
kidney development	1	70.2×	0.016	LRP4
negative regulation of canonical Wnt signaling pathway	1	58.9×	0.018	LRP4

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
CORIN	0	0
LRP4	0	0
LRP4-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	0
D	Druggable family + AlphaFold only, no drug	1	CORIN
E	Difficult family or no structure, no drug	2	LRP4, LRP4-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CORIN	0	—
LRP4	0	—
LRP4-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.