COACH syndrome 1

Summary

COACH syndrome 1 (MONDO:0800103) is a disease caused by TMEM67 (GenCC Definitive), with 3 cohort genes. The dominant Reactome pathway is Anchoring of the basal body to the plasma membrane (3 cohort genes).

At a glance

• Causal gene: TMEM67 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 260

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	COACH syndrome 1
Mondo ID	MONDO:0800103
OMIM	216360
UMLS	C5435651
MedGen	1769861
GARD	0015153
Is cancer (heuristic)	no

Also known as: cerebellar vermis hypo/aplasia, oligophrenia, congenital ataxia, ocular coloboma, and hepatic fibrosis

Data availability: 260 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive cerebellar ataxia › autosomal recessive congenital cerebellar ataxia › Joubert syndrome and related disorders › COACH syndrome › COACH syndrome 1

Related subtypes (2): COACH syndrome 2, COACH syndrome 3

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

260 retrieved; paginated sample, class counts are floors:

119 uncertain significance, 44 conflicting classifications of pathogenicity, 35 pathogenic/likely pathogenic, 19 likely pathogenic, 17 likely benign, 16 pathogenic, 8 benign/likely benign, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
210609	NM_001378615.1(CC2D2A):c.2683C>T (p.Gln895Ter)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217602	NM_001378615.1(CC2D2A):c.3055C>T (p.Arg1019Ter)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217607	NM_001378615.1(CC2D2A):c.4667A>T (p.Asp1556Val)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217618	NM_001378615.1(CC2D2A):c.1558C>T (p.Arg520Ter)	CC2D2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
522909	NM_001378615.1(CC2D2A):c.4483G>T (p.Glu1495Ter)	CC2D2A	Pathogenic	criteria provided, single submitter
56309	NM_001378615.1(CC2D2A):c.3774dup (p.Glu1259Ter)	CC2D2A	Pathogenic	criteria provided, multiple submitters, no conflicts
1074	NM_015272.5(RPGRIP1L):c.2614C>T (p.Gln872Ter)	RPGRIP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076	NM_015272.5(RPGRIP1L):c.2050C>T (p.Gln684Ter)	RPGRIP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
848273	NM_015272.5(RPGRIP1L):c.3558_3559dup (p.Pro1187fs)	RPGRIP1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072098	NM_153704.6(TMEM67):c.1975C>T (p.Arg659Ter)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074275	NM_153704.6(TMEM67):c.1338_1350del (p.Ala447fs)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
126306	NM_153704.6(TMEM67):c.748G>A (p.Gly250Arg)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1371	NM_153704.6(TMEM67):c.1538A>G (p.Tyr513Cys)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1375	NM_153704.6(TMEM67):c.1961-2A>C	TMEM67	Pathogenic	criteria provided, single submitter
1376	NM_153704.6(TMEM67):c.622A>T (p.Arg208Ter)	TMEM67	Pathogenic	criteria provided, multiple submitters, no conflicts
1378	NM_153704.6(TMEM67):c.2498T>C (p.Ile833Thr)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1379	NM_153704.6(TMEM67):c.2556+1G>T	TMEM67	Pathogenic	criteria provided, single submitter
1380	NM_153704.6(TMEM67):c.312+5G>A	TMEM67	Pathogenic	criteria provided, multiple submitters, no conflicts
1381	NM_153704.6(TMEM67):c.1769T>C (p.Phe590Ser)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1383	NM_153704.6(TMEM67):c.1843T>C (p.Cys615Arg)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1387	NM_153704.6(TMEM67):c.755T>C (p.Met252Thr)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1411457	NM_153704.6(TMEM67):c.1387C>T (p.Arg463Ter)	TMEM67	Pathogenic	criteria provided, multiple submitters, no conflicts
1454299	NM_153704.6(TMEM67):c.1927C>T (p.Arg643Ter)	TMEM67	Pathogenic	criteria provided, multiple submitters, no conflicts
1691287	NM_153704.6(TMEM67):c.479_480del (p.Phe160fs)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
191259	NM_153704.6(TMEM67):c.1413-2A>G	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
216826	NM_153704.6(TMEM67):c.725A>G (p.Asn242Ser)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217710	NM_153704.6(TMEM67):c.769A>G (p.Met257Val)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217712	NM_153704.6(TMEM67):c.300C>A (p.Cys100Ter)	TMEM67	Pathogenic	criteria provided, multiple submitters, no conflicts
217717	NM_153704.6(TMEM67):c.2290C>T (p.Arg764Ter)	TMEM67	Pathogenic	criteria provided, multiple submitters, no conflicts
217724	NM_153704.6(TMEM67):c.1351C>T (p.Arg451Ter)	TMEM67	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 12 · 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
TMEM67	Definitive	Autosomal recessive	COACH syndrome 1	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TMEM67	Orphanet:140976	RHYNS syndrome
TMEM67	Orphanet:1454	Joubert syndrome with hepatic defect
TMEM67	Orphanet:475	Isolated Joubert syndrome
TMEM67	Orphanet:564	Meckel syndrome
TMEM67	Orphanet:84081	Senior-Boichis syndrome
RPGRIP1L	Orphanet:1454	Joubert syndrome with hepatic defect
RPGRIP1L	Orphanet:220497	Joubert syndrome with renal defect
RPGRIP1L	Orphanet:564	Meckel syndrome
CC2D2A	Orphanet:1454	Joubert syndrome with hepatic defect
CC2D2A	Orphanet:2318	Joubert syndrome with oculorenal defect
CC2D2A	Orphanet:564	Meckel syndrome
CC2D2A	Orphanet:791	Retinitis pigmentosa

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TMEM67	HGNC:28396	ENSG00000164953	Q5HYA8	Meckelin	gencc,clinvar
RPGRIP1L	HGNC:29168	ENSG00000103494	Q68CZ1	Protein fantom	clinvar
CC2D2A	HGNC:29253	ENSG00000048342	Q9P2K1	Coiled-coil and C2 domain-containing protein 2A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TMEM67	Meckelin	Required for ciliary structure and function.
RPGRIP1L	Protein fantom	Negatively regulates signaling through the G-protein coupled thromboxane A2 receptor (TBXA2R).
CC2D2A	Coiled-coil and C2 domain-containing protein 2A	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.

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)
TMEM67	Other/Unknown	no		Growth_fac_rcpt_cys_sf, Meckelin
RPGRIP1L	Other/Unknown	no		C2_dom, C2-C2_1, RPGRIP1_fam
CC2D2A	Protease	yes		C2_dom, CC2D2AN-C2, C2_domain_sf

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
right uterine tube	2
bronchial epithelial cell	2
buccal mucosa cell	1
calcaneal tendon	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
bronchus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TMEM67	203	ubiquitous	marker	buccal mucosa cell, right uterine tube, calcaneal tendon
RPGRIP1L	207	ubiquitous	marker	bronchial epithelial cell, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
CC2D2A	247	ubiquitous	marker	right uterine tube, bronchial epithelial cell, bronchus

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RPGRIP1L	2,027
TMEM67	1,194
CC2D2A	899

Intra-cohort edges

A	B	Sources
CC2D2A	RPGRIP1L	string_interaction
CC2D2A	TMEM67	string_interaction
RPGRIP1L	TMEM67	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TMEM67	Q5HYA8	1
RPGRIP1L	Q68CZ1	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CC2D2A	Q9P2K1	69.46

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Anchoring of the basal body to the plasma membrane	3	113.1×	3e-06	TMEM67, RPGRIP1L, CC2D2A
Cilium Assembly	2	72.5×	5e-04	TMEM67, CC2D2A
Organelle biogenesis and maintenance	2	44.0×	9e-04	TMEM67, CC2D2A
Hedgehog ‘off’ state	1	59.5×	0.017	RPGRIP1L

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
non-motile cilium assembly	2	193.7×	7e-04	RPGRIP1L, CC2D2A
determination of left/right symmetry	2	170.2×	7e-04	RPGRIP1L, CC2D2A
kidney development	2	93.6×	0.002	RPGRIP1L, CC2D2A
cilium assembly	2	49.1×	0.004	TMEM67, CC2D2A
negative regulation of centrosome duplication	1	1123.5×	0.005	TMEM67
neural tube patterning	1	936.2×	0.005	RPGRIP1L
nose development	1	802.5×	0.005	RPGRIP1L
protein localization to ciliary transition zone	1	802.5×	0.005	CC2D2A
pericardium development	1	624.1×	0.006	RPGRIP1L
retinal rod cell development	1	561.7×	0.006	RPGRIP1L
lateral ventricle development	1	432.1×	0.007	RPGRIP1L
negative regulation of G protein-coupled receptor signaling pathway	1	401.2×	0.007	RPGRIP1L
establishment of planar polarity	1	351.1×	0.007	RPGRIP1L
corpus callosum development	1	280.9×	0.008	RPGRIP1L
embryonic brain development	1	267.5×	0.008	CC2D2A
olfactory bulb development	1	255.3×	0.008	RPGRIP1L
regulation of smoothened signaling pathway	1	208.1×	0.008	RPGRIP1L
embryonic hindlimb morphogenesis	1	193.7×	0.008	RPGRIP1L
non-canonical Wnt signaling pathway	1	193.7×	0.008	TMEM67
motile cilium assembly	1	193.7×	0.008	CC2D2A
axoneme assembly	1	181.2×	0.008	CC2D2A
embryonic forelimb morphogenesis	1	165.2×	0.009	RPGRIP1L
cochlea development	1	156.0×	0.009	RPGRIP1L
establishment or maintenance of cell polarity	1	133.8×	0.010	RPGRIP1L
cerebellum development	1	119.5×	0.010	RPGRIP1L
camera-type eye development	1	119.5×	0.010	CC2D2A
liver development	1	73.9×	0.016	RPGRIP1L
neural tube closure	1	62.4×	0.018	CC2D2A
smoothened signaling pathway	1	60.4×	0.018	CC2D2A
ERAD pathway	1	60.4×	0.018	TMEM67

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
TMEM67	0	0
RPGRIP1L	0	0
CC2D2A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	CC2D2A
E	Difficult family or no structure, no drug	2	TMEM67, RPGRIP1L

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)
TMEM67	0	—
RPGRIP1L	0	—
CC2D2A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.