Smith-McCort dysplasia 2

Summary

Smith-McCort dysplasia 2 (MONDO:0014087) is a disease caused by RAB33B (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: RAB33B (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 79

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Smith-McCort dysplasia 2
Mondo ID	MONDO:0014087
OMIM	615222
DOID	DOID:0081271
UMLS	C3714896
MedGen	811489
GARD	0015921
Is cancer (heuristic)	no

Also known as: RAB33B Smith-McCort dysplasia · Smc2 · Smith-McCort dysplasia 2 · Smith-McCort dysplasia caused by mutation in RAB33B · Smith-McCort dysplasia type 2

Data availability: 79 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 development disease › osteochondrodysplasia › spondyloepiphyseal dysplasia › Smith-McCort dysplasia › Smith-McCort dysplasia 2

Related subtypes (1): Smith-McCort dysplasia 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

79 retrieved; paginated sample, class counts are floors:

44 uncertain significance, 11 likely benign, 8 pathogenic, 7 conflicting classifications of pathogenicity, 6 benign, 1 benign/likely benign, 1 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
425560	NM_031296.3(RAB33B):c.211C>T (p.Arg71Ter)	LOC129993110	Pathogenic	criteria provided, single submitter
599277	NM_031296.3(RAB33B):c.186del (p.Glu63fs)	LOC129993110	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048093	NM_031296.3(RAB33B):c.400C>T (p.Gln134Ter)	RAB33B	Pathogenic	criteria provided, multiple submitters, no conflicts
1098420	NM_031296.3(RAB33B):c.253C>T (p.Gln85Ter)	RAB33B	Pathogenic	no assertion criteria provided
1098421	NM_031296.3(RAB33B):c.144C>A (p.Cys48Ter)	RAB33B	Pathogenic	no assertion criteria provided
1098422	NM_031296.3(RAB33B):c.280C>T (p.Arg94Ter)	RAB33B	Pathogenic	criteria provided, single submitter
425562	NM_031296.3(RAB33B):c.48_55del (p.Gly17fs)	RAB33B	Pathogenic	no assertion criteria provided
425563	NM_031296.3(RAB33B):c.490C>T (p.Gln164Ter)	RAB33B	Pathogenic	no assertion criteria provided
50231	NM_031296.3(RAB33B):c.444T>A (p.Asn148Lys)	RAB33B	Pathogenic	no assertion criteria provided
50230	NM_031296.3(RAB33B):c.136A>C (p.Lys46Gln)	RAB33B	Likely pathogenic	criteria provided, single submitter
901355	NM_031296.3(RAB33B):c.201G>A (p.Gly67=)	LOC129993110	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347562	NM_031296.3(RAB33B):c.135C>G (p.Gly45=)	RAB33B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347564	NM_031296.3(RAB33B):c.336C>T (p.Phe112=)	RAB33B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347566	NM_031296.3(RAB33B):c.432T>C (p.Ile144=)	RAB33B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
425561	NM_031296.3(RAB33B):c.365T>C (p.Phe122Ser)	RAB33B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
901955	NM_031296.3(RAB33B):c.530C>T (p.Thr177Met)	RAB33B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
902856	NM_031296.3(RAB33B):c.678G>A (p.Thr226=)	RAB33B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
347559	NM_031296.3(RAB33B):c.-48C>T	LOC129993109	Uncertain significance	criteria provided, single submitter
1384265	NM_031296.3(RAB33B):c.193A>G (p.Thr65Ala)	LOC129993110	Uncertain significance	criteria provided, multiple submitters, no conflicts
1679887	NM_031296.3(RAB33B):c.690A>C (p.Ter230Tyr)	RAB33B	Uncertain significance	criteria provided, single submitter
2687888	NM_031296.3(RAB33B):c.133G>A (p.Gly45Ser)	RAB33B	Uncertain significance	criteria provided, single submitter
3064853	NM_031296.3(RAB33B):c.118G>T (p.Gly40Cys)	RAB33B	Uncertain significance	criteria provided, single submitter
347561	NM_031296.3(RAB33B):c.128A>G (p.Asn43Ser)	RAB33B	Uncertain significance	criteria provided, multiple submitters, no conflicts
347563	NM_031296.3(RAB33B):c.249+10T>C	RAB33B	Uncertain significance	criteria provided, single submitter
347565	NM_031296.3(RAB33B):c.417T>G (p.Asn139Lys)	RAB33B	Uncertain significance	criteria provided, multiple submitters, no conflicts
347567	NM_031296.3(RAB33B):c.553A>G (p.Asn185Asp)	RAB33B	Uncertain significance	criteria provided, multiple submitters, no conflicts
347569	NM_031296.3(RAB33B):c.*118T>G	RAB33B	Uncertain significance	criteria provided, single submitter
347570	NM_031296.3(RAB33B):c.*219A>G	RAB33B	Uncertain significance	criteria provided, single submitter
347572	NM_031296.3(RAB33B):c.*494A>C	RAB33B	Uncertain significance	criteria provided, single submitter
347576	NM_031296.3(RAB33B):c.*632A>G	RAB33B	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · 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
RAB33B	Strong	Autosomal recessive	Smith-McCort dysplasia 2	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RAB33B	Orphanet:178355	Smith-McCort dysplasia

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
RAB33B	HGNC:16075	ENSG00000172007	Q9H082	Ras-related protein Rab-33B	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RAB33B	Ras-related protein Rab-33B	The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes.

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)
RAB33B	Other/Unknown	no		Small_GTPase, Small_GTP-bd, P-loop_NTPase

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
calcaneal tendon	1
saphenous vein	1
vein	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RAB33B	282	ubiquitous	marker	calcaneal tendon, saphenous vein, vein

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RAB33B	1,936

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RAB33B	Q9H082	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Intra-Golgi traffic	1	259.6×	0.006	RAB33B
TBC/RABGAPs	1	259.6×	0.006	RAB33B
RAB geranylgeranylation	1	173.0×	0.006	RAB33B

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
negative regulation of constitutive secretory pathway	1	16852.0×	7e-04	RAB33B
regulation of retrograde vesicle-mediated transport, Golgi to ER	1	8426.0×	7e-04	RAB33B
regulation of Golgi organization	1	1123.5×	0.002	RAB33B
Rab protein signal transduction	1	991.3×	0.002	RAB33B
protein localization to phagophore assembly site	1	991.3×	0.002	RAB33B
protein localization to Golgi apparatus	1	802.5×	0.002	RAB33B
regulation of exocytosis	1	702.2×	0.002	RAB33B
intra-Golgi vesicle-mediated transport	1	526.6×	0.002	RAB33B
skeletal system morphogenesis	1	495.6×	0.002	RAB33B
autophagosome assembly	1	224.7×	0.005	RAB33B
protein transport	1	43.9×	0.023	RAB33B

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
RAB33B	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	RAB33B

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)
RAB33B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.