orofaciodigital syndrome III

Summary

orofaciodigital syndrome III (MONDO:0009793) is a disease with 4 cohort genes.

At a glance

• Cohort genes: 4
• ClinVar variants: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	orofaciodigital syndrome III
Mondo ID	MONDO:0009793
MeSH	C557817
OMIM	258850
Orphanet	2752
DOID	DOID:0060373
SNOMED CT	239030004
UMLS	C0406726
MedGen	96069
GARD	0010518
Is cancer (heuristic)	no

Also known as: OFD syndrome 3 · OFD3 · oral facial digital syndrome 3 · oral facial digital syndrome type 3 · oral-facial-digital syndrome type 3 · orofaciodigital syndrome 3 · orofaciodigital syndrome III · orofaciodigital syndrome type III · Sugarman syndrome

Data availability: 4 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › orofaciodigital syndrome › orofaciodigital syndrome III

Related subtypes (18): orofaciodigital syndrome X, orofaciodigital syndrome V, orofaciodigital syndrome type II, orofaciodigital syndrome IV, orofaciodigital syndrome IX, orofaciodigital syndrome type 6, orofaciodigital syndrome VIII, orofaciodigital syndrome VII, orofaciodigital syndrome XI, orofaciodigital syndrome type 14, orofaciodigital syndrome XV, orofaciodigital syndrome type 12, orofaciodigital syndrome 16, orofaciodigital syndrome 17, orofaciodigital syndrome 18, orofaciodigital syndrome 19, orofaciodigital syndrome 20, orofaciodigital syndrome 21

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

4 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
266104	NM_003611.3(OFD1):c.1246del (p.Gln416fs)	OFD1	Pathogenic	criteria provided, single submitter
266103	NM_014714.4(IFT140):c.3943GCCAAG[2] (p.1315AK[2])	IFT140	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
871667	NM_001077418.3(TMEM231):c.373C>G (p.Pro125Ala)	TMEM231	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
266080	NM_001408.3(CELSR2):c.8235_8246dup (p.Glu2749_Glu2752dup)	CELSR2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 13 · 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
TMEM231	Supportive	Autosomal recessive	orofaciodigital syndrome III	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TMEM231	Orphanet:2318	Joubert syndrome with oculorenal defect
TMEM231	Orphanet:2754	Orofaciodigital syndrome type 6
TMEM231	Orphanet:564	Meckel syndrome
OFD1	Orphanet:244	Primary ciliary dyskinesia
OFD1	Orphanet:2750	Orofaciodigital syndrome type 1
OFD1	Orphanet:2754	Orofaciodigital syndrome type 6
OFD1	Orphanet:475	Isolated Joubert syndrome
OFD1	Orphanet:791	Retinitis pigmentosa
IFT140	Orphanet:140969	Saldino-Mainzer syndrome
IFT140	Orphanet:474	Jeune syndrome
IFT140	Orphanet:65	Leber congenital amaurosis
IFT140	Orphanet:730	Autosomal dominant polycystic kidney disease
IFT140	Orphanet:791	Retinitis pigmentosa

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TMEM231	HGNC:37234	ENSG00000205084	Q9H6L2	Transmembrane protein 231	gencc,clinvar
OFD1	HGNC:2567	ENSG00000046651	O75665	Centriole and centriolar satellite protein OFD1	clinvar
IFT140	HGNC:29077	ENSG00000187535	Q96RY7	Intraflagellar transport protein 140 homolog	clinvar
CELSR2	HGNC:3231	ENSG00000143126	Q9HCU4	Cadherin EGF LAG seven-pass G-type receptor 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TMEM231	Transmembrane protein 231	Transmembrane component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes.
OFD1	Centriole and centriolar satellite protein OFD1	Component of the centrioles controlling mother and daughter centrioles length.
IFT140	Intraflagellar transport protein 140 homolog	Component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs).
CELSR2	Cadherin EGF LAG seven-pass G-type receptor 2	Receptor that may have an important role in cell/cell signaling during nervous system formation.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

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
GPCR	1	6.0×	0.318
Scaffold/PPI	1	4.3×	0.318
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TMEM231	Other/Unknown	no		TMEM231
OFD1	Other/Unknown	no		LisH, OFD1
IFT140	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf
CELSR2	GPCR	yes		EGF-type_Asp/Asn_hydroxyl_site, GPS, EGF

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bronchial epithelial cell	2
bronchus	1
epithelium of bronchus	1
cervix squamous epithelium	1
sperm	1
left lobe of thyroid gland	1
right lobe of thyroid gland	1
right uterine tube	1
ganglionic eminence	1
right frontal lobe	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TMEM231	257	ubiquitous	marker	bronchial epithelial cell, epithelium of bronchus, bronchus
OFD1	288	ubiquitous	marker	sperm, bronchial epithelial cell, cervix squamous epithelium
IFT140	214	ubiquitous	marker	right uterine tube, right lobe of thyroid gland, left lobe of thyroid gland
CELSR2	248	ubiquitous	marker	ganglionic eminence, ventricular zone, right frontal lobe

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
OFD1	2,878
IFT140	1,602
CELSR2	1,539
TMEM231	858

Structural data

PDB: 1 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IFT140	Q96RY7	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TMEM231	Q9H6L2	88.65
OFD1	O75665	68.41
CELSR2	Q9HCU4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 4 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
Hedgehog ‘off’ state	2	178.4×	3e-04	OFD1, IFT140
Intraflagellar transport	1	100.2×	0.018	IFT140
Loss of Nlp from mitotic centrosomes	1	79.3×	0.018	OFD1
Loss of proteins required for interphase microtubule organization from the centrosome	1	79.3×	0.018	OFD1
AURKA Activation by TPX2	1	76.1×	0.018	OFD1
Recruitment of mitotic centrosome proteins and complexes	1	68.0×	0.018	OFD1
Regulation of PLK1 Activity at G2/M Transition	1	63.4×	0.018	OFD1
Recruitment of NuMA to mitotic centrosomes	1	58.3×	0.018	OFD1
Anchoring of the basal body to the plasma membrane	1	56.5×	0.018	OFD1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cilium assembly	4	73.6×	1e-06	TMEM231, OFD1, IFT140, CELSR2
embryonic digit morphogenesis	2	150.5×	0.001	TMEM231, IFT140
regulation of protein localization	2	102.8×	0.002	TMEM231, CELSR2
obsolete negative regulation of fibroblast growth factor receptor signaling pathway involved in neural plate anterior/posterior pattern formation	1	2106.5×	0.005	OFD1
neural plate anterior/posterior regionalization	1	1404.3×	0.005	CELSR2
cerebrospinal fluid secretion	1	1053.2×	0.006	CELSR2
neural tube patterning	1	702.2×	0.008	IFT140
embryonic body morphogenesis	1	526.6×	0.009	OFD1
motor neuron migration	1	421.3×	0.009	CELSR2
neuroepithelial cell differentiation	1	383.0×	0.009	TMEM231
epithelial cilium movement involved in determination of left/right asymmetry	1	324.1×	0.009	OFD1
regulation of cell-cell adhesion	1	300.9×	0.009	CELSR2
embryonic camera-type eye development	1	300.9×	0.009	IFT140
vasculature development	1	280.9×	0.009	TMEM231
intraciliary retrograde transport	1	280.9×	0.009	IFT140
photoreceptor cell outer segment organization	1	263.3×	0.009	IFT140
ventricular system development	1	210.7×	0.011	CELSR2
embryonic brain development	1	200.6×	0.011	IFT140
regulation of smoothened signaling pathway	1	156.0×	0.012	IFT140
regulation of cilium assembly	1	150.5×	0.012	IFT140
embryonic cranial skeleton morphogenesis	1	145.3×	0.012	IFT140
axoneme assembly	1	135.9×	0.013	OFD1
Wnt signaling pathway, planar cell polarity pathway	1	113.9×	0.014	CELSR2
dendrite morphogenesis	1	108.0×	0.014	CELSR2
cell-cell adhesion mediated by cadherin	1	102.8×	0.014	CELSR2
protein localization to cilium	1	100.3×	0.014	IFT140
cilium movement	1	98.0×	0.014	CELSR2
camera-type eye development	1	89.6×	0.015	TMEM231
non-motile cilium assembly	1	72.6×	0.018	IFT140
determination of left/right symmetry	1	63.8×	0.020	IFT140

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 4 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
TMEM231	0	0
OFD1	0	0
IFT140	0	0
CELSR2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	CELSR2
E	Difficult family or no structure, no drug	3	TMEM231, OFD1, IFT140

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TMEM231	0	—
OFD1	0	—
IFT140	0	—
CELSR2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.