Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2

Summary

Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2 (MONDO:0030953) is a disease caused by SCUBE3 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: SCUBE3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 21

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2
Mondo ID	MONDO:0030953
OMIM	619184
DOID	DOID:0112358
UMLS	C5543057
MedGen	1782253
Is cancer (heuristic)	no

Also known as: short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies · short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2 · SSFSC2

Data availability: 21 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies › short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2

Related subtypes (1): short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 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

21 retrieved; paginated sample, class counts are floors:

11 uncertain significance, 4 likely pathogenic, 4 pathogenic, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
981655	NM_152753.4(SCUBE3):c.291C>G (p.Cys97Trp)	SCUBE3	Pathogenic	criteria provided, single submitter
981659	NM_152753.4(SCUBE3):c.2239+1G>A	SCUBE3	Pathogenic	criteria provided, single submitter
981660	NM_152753.4(SCUBE3):c.2444T>C (p.Ile815Thr)	SCUBE3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
981662	NM_152753.4(SCUBE3):c.2785C>T (p.Arg929Ter)	SCUBE3	Pathogenic	criteria provided, single submitter
996761	NG_050574.1:g.29310_309865delins27802_27890inv	SCUBE3	Pathogenic	no assertion criteria provided
4845673	NM_152753.4(SCUBE3):c.1981C>T (p.Gln661Ter)	LOC126859661	Likely pathogenic	criteria provided, single submitter
3731373	NM_152753.4(SCUBE3):c.2419G>T (p.Glu807Ter)	SCUBE3	Likely pathogenic	criteria provided, single submitter
3780585	NM_152753.4(SCUBE3):c.1909+1G>A	SCUBE3	Likely pathogenic	criteria provided, single submitter
4292575	NM_152753.4(SCUBE3):c.222C>A (p.Cys74Ter)	SCUBE3	Likely pathogenic	criteria provided, single submitter
981658	NM_152753.4(SCUBE3):c.1717C>T (p.Arg573Ter)	SCUBE3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1679305	NM_152753.4(SCUBE3):c.406T>C (p.Cys136Arg)	SCUBE3	Uncertain significance	criteria provided, single submitter
2352024	NM_152753.4(SCUBE3):c.632C>T (p.Thr211Met)	SCUBE3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2664229	NM_152753.4(SCUBE3):c.799A>C (p.Met267Leu)	SCUBE3	Uncertain significance	criteria provided, single submitter
3065011	NM_152753.4(SCUBE3):c.2795G>A (p.Arg932Gln)	SCUBE3	Uncertain significance	criteria provided, single submitter
3065012	NM_152753.4(SCUBE3):c.1252C>T (p.Arg418Trp)	SCUBE3	Uncertain significance	criteria provided, single submitter
3731287	NM_152753.4(SCUBE3):c.2420A>T (p.Glu807Val)	SCUBE3	Uncertain significance	criteria provided, single submitter
3892368	NM_152753.4(SCUBE3):c.1795C>T (p.Arg599Cys)	SCUBE3	Uncertain significance	criteria provided, single submitter
4086250	NM_152753.4(SCUBE3):c.1349C>T (p.Pro450Leu)	SCUBE3	Uncertain significance	criteria provided, single submitter
4292473	NM_152753.4(SCUBE3):c.223G>A (p.Glu75Lys)	SCUBE3	Uncertain significance	criteria provided, single submitter
4293299	NM_152753.4(SCUBE3):c.1169T>C (p.Leu390Pro)	SCUBE3	Uncertain significance	criteria provided, single submitter
4819017	NM_152753.4(SCUBE3):c.1039T>C (p.Tyr347His)	SCUBE3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 0 · 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
SCUBE3	Strong	Autosomal recessive	short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2	4

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
SCUBE3	HGNC:13655	ENSG00000146197	Q8IX30	Signal peptide, CUB and EGF-like domain-containing protein 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCUBE3	Signal peptide, CUB and EGF-like domain-containing protein 3	Is a positive regulator of the BMP signaling pathway, required for proper chondrogenesis, osteogenesis and skeletal development.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCUBE3	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, CUB_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
cartilage tissue	1
descending thoracic aorta	1
saphenous vein	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCUBE3	175	broad	marker	cartilage tissue, descending thoracic aorta, saphenous vein

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SCUBE3	1,088

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SCUBE3	Q8IX30	77.61

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Degradation of the extracellular matrix	1	117.7×	0.016	SCUBE3
Extracellular matrix organization	1	63.1×	0.016	SCUBE3

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
positive regulation of BMP signaling pathway	1	455.5×	0.007	SCUBE3
positive regulation of osteoblast differentiation	1	224.7×	0.007	SCUBE3
signal transduction	1	16.1×	0.062	SCUBE3

Therapeutics

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
SCUBE3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SCUBE3

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)
SCUBE3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.