Autosomal dominant optic atrophy, classic form

Summary

Autosomal dominant optic atrophy, classic form (MONDO:0008134) is a disease caused by OPA1 (GenCC Definitive), with 4 cohort genes and 3 clinical trials.

At a glance

• Prevalence: 1-5 / 10 000 (Denmark) [Orphanet-validated]
• Causal gene: OPA1 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 221
• Phenotypes (HPO): 44
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	10	Denmark	Validated
Point prevalence	1-9 / 100 000	2.86	United Kingdom	Validated
Point prevalence	6-9 / 10 000	83.33	Specific population	Validated
Point prevalence	1-9 / 100 000	2	Worldwide	Not yet validated

Signs & symptoms

Clinical features (HPO)

44 HPO clinical features (Orphanet curated; top 44 by frequency):

HPO ID	Term	Frequency
HP:0000505	Visual impairment	Very frequent (80-99%)
HP:0000648	Optic atrophy	Very frequent (80-99%)
HP:0000407	Sensorineural hearing impairment	Frequent (30-79%)
HP:0000551	Color vision defect	Frequent (30-79%)
HP:0000602	Ophthalmoplegia	Frequent (30-79%)
HP:0007141	Sensorimotor neuropathy	Frequent (30-79%)
HP:0012511	Temporal optic disc pallor	Frequent (30-79%)
HP:0025514	Morning glory anomaly	Frequent (30-79%)
HP:0030515	Moderately reduced visual acuity	Frequent (30-79%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0000603	Central scotoma	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001288	Gait disturbance	Occasional (5-29%)
HP:0003198	Myopathy	Occasional (5-29%)
HP:0000135	Hypogonadism	Very rare (<1-4%)
HP:0000518	Cataract	Very rare (<1-4%)
HP:0000639	Nystagmus	Very rare (<1-4%)
HP:0000726	Dementia	Very rare (<1-4%)
HP:0000738	Hallucinations	Very rare (<1-4%)
HP:0000819	Diabetes mellitus	Very rare (<1-4%)
HP:0000821	Hypothyroidism	Very rare (<1-4%)
HP:0001250	Seizure	Very rare (<1-4%)
HP:0001257	Spasticity	Very rare (<1-4%)
HP:0001258	Spastic paraplegia	Very rare (<1-4%)
HP:0001263	Global developmental delay	Very rare (<1-4%)
HP:0001269	Hemiparesis	Very rare (<1-4%)
HP:0001272	Cerebellar atrophy	Very rare (<1-4%)
HP:0001284	Areflexia	Very rare (<1-4%)
HP:0001761	Pes cavus	Very rare (<1-4%)
HP:0001972	Macrocytic anemia	Very rare (<1-4%)
HP:0002015	Dysphagia	Very rare (<1-4%)
HP:0002076	Migraine	Very rare (<1-4%)
HP:0002135	Basal ganglia calcification	Very rare (<1-4%)
HP:0002518	Abnormal periventricular white matter morphology	Very rare (<1-4%)
HP:0003202	Skeletal muscle atrophy	Very rare (<1-4%)
HP:0003326	Myalgia	Very rare (<1-4%)
HP:0003691	Scapular winging	Very rare (<1-4%)
HP:0007366	Atrophy/Degeneration affecting the brainstem	Very rare (<1-4%)
HP:0007371	Corpus callosum atrophy	Very rare (<1-4%)
HP:0009921	Duane anomaly	Very rare (<1-4%)
HP:0011968	Feeding difficulties	Very rare (<1-4%)
HP:0012378	Fatigue	Very rare (<1-4%)
HP:0030319	Weakness of facial musculature	Very rare (<1-4%)
HP:0100543	Cognitive impairment	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant optic atrophy, classic form
Mondo ID	MONDO:0008134
OMIM	165500
Orphanet	98673
DOID	DOID:0111441
SNOMED CT	717336005
UMLS	C0338508
MedGen	137902
GARD	0009890
Is cancer (heuristic)	no

Also known as: autosomal dominant optic atrophy, Kjer type · Kjer optic atrophy · OAK · OPA1 · optic atrophy 1 · optic atrophy type 1

Data availability: 221 ClinVar variants · 3 GenCC gene-disease records · 8 cell lines.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › autosomal dominant optic atrophy, classic form

Related subtypes (47): mitochondrial respiratory chain complex deficiency, combined oxidative phosphorylation deficiency, myopathy, lactic acidosis, and sideroblastic anemia, optic atrophy 3, Leigh syndrome, mitochondrial non-syndromic sensorineural hearing loss, maternally-inherited diabetes and deafness, chronic diarrhea with villous atrophy, Kearns-Sayre syndrome, Leber hereditary optic neuropathy, NARP syndrome, deafness, aminoglycoside-induced, hereditary spastic paraplegia 7, spinocerebellar ataxia type 28, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, spastic ataxia 3, pontocerebellar hypoplasia type 6, autosomal recessive optic atrophy, OPA7 type, acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins, congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome, spastic ataxia 4, hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome, hereditary spastic paraplegia 55, cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome, Charcot-Marie-Tooth disease recessive intermediate D, autosomal dominant mitochondrial myopathy with exercise intolerance, Charcot-Marie-Tooth disease type 4K, hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome, hereditary spastic paraplegia 77, fatal infantile encephalocardiomyopathy, FASTKD2-related infantile mitochondrial encephalomyopathy, autosomal dominant optic atrophy and peripheral neuropathy, ataxia neuropathy spectrum, maternally-inherited mitochondrial dystonia, Perrault syndrome, hypertrophic cardiomyopathy and renal tubular disease due to mitochondrial DNA mutation, adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy, mitochondrial DNA maintenance syndrome, coenzyme Q10 deficiency, mitochondrial DNA depletion syndrome, periodic paralysis with later-onset distal motor neuropathy, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, Zellweger-like syndrome without peroxisomal anomalies, maternally-inherited progressive external ophthalmoplegia, Leber plus disease, encephalopathy due to mitochondrial and peroxisomal fission defect, severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency

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

221 retrieved; paginated sample, class counts are floors:

66 uncertain significance, 36 pathogenic, 33 benign, 32 conflicting classifications of pathogenicity, 22 likely pathogenic, 16 pathogenic/likely pathogenic, 10 benign/likely benign, 4 not provided, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1709100	NM_130837.3(OPA1):c.1852C>T (p.Gln618Ter)	LOC126806913	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3233374	NM_130837.3(OPA1):c.1870+1G>C	LOC126806913	Pathogenic	criteria provided, single submitter
1213866	NM_130837.3(OPA1):c.2293A>T (p.Lys765Ter)	OPA1	Pathogenic	criteria provided, single submitter
1526127	NM_130837.3(OPA1):c.357del (p.Phe119fs)	OPA1	Pathogenic	criteria provided, single submitter
1675202	NM_130837.3(OPA1):c.2686del (p.Tyr896fs)	OPA1	Pathogenic	criteria provided, single submitter
1679213	NM_130837.3(OPA1):c.1377+1G>T	OPA1	Pathogenic	criteria provided, single submitter
1691850	NM_130837.3(OPA1):c.2051C>G (p.Ser684Ter)	OPA1	Pathogenic/Likely pathogenic	criteria provided, single submitter
1708159	NM_130837.3(OPA1):c.1606_1608+10delinsCAGTCCACAAATCT	OPA1	Pathogenic	criteria provided, single submitter
1709891	NM_130837.3(OPA1):c.70dup (p.Ile24fs)	OPA1	Pathogenic	criteria provided, single submitter
1710214	NM_130837.3(OPA1):c.2750dup (p.Tyr917Ter)	OPA1	Pathogenic	no assertion criteria provided
195896	NM_130837.3(OPA1):c.2734C>T (p.Arg912Ter)	OPA1	Pathogenic	criteria provided, multiple submitters, no conflicts
198219	NM_130837.3(OPA1):c.800_801del (p.Lys267fs)	OPA1	Pathogenic	criteria provided, multiple submitters, no conflicts
216979	NM_130837.3(OPA1):c.2296C>T (p.Arg766Ter)	OPA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2203476	NM_130837.3(OPA1):c.1038TGT[1] (p.Val349del)	OPA1	Pathogenic	criteria provided, multiple submitters, no conflicts
2203477	NM_130837.3(OPA1):c.1099C>T (p.Arg367Ter)	OPA1	Pathogenic	criteria provided, multiple submitters, no conflicts
2571197	NM_130837.3(OPA1):c.2869G>T (p.Glu957Ter)	OPA1	Pathogenic	criteria provided, multiple submitters, no conflicts
2627600	NM_130837.3(OPA1):c.2778+1G>A	OPA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2687786	NM_130837.3(OPA1):c.2605del (p.Glu868_Ile869insTer)	OPA1	Pathogenic	criteria provided, single submitter
280006	NM_130837.3(OPA1):c.1681+1G>T	OPA1	Pathogenic	criteria provided, multiple submitters, no conflicts
30461	NM_130837.3(OPA1):c.1800C>G (p.Ser600Arg)	OPA1	Pathogenic	criteria provided, multiple submitters, no conflicts
3236000	NM_130837.3(OPA1):c.2714dup (p.Asn906fs)	OPA1	Pathogenic	criteria provided, single submitter
3250086	NM_130837.3(OPA1):c.1149+1_1149+5del	OPA1	Pathogenic/Likely pathogenic	no assertion criteria provided
3250149	NM_130837.3(OPA1):c.2012+4_2012+7del	OPA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3250177	NM_130837.3(OPA1):c.1478A>G (p.Asp493Gly)	OPA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
431939	NM_130837.3(OPA1):c.1035+5G>A	OPA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
431941	NM_130837.3(OPA1):c.2362C>T (p.Arg788Ter)	OPA1	Pathogenic	criteria provided, multiple submitters, no conflicts
447898	NM_130837.3(OPA1):c.2406del (p.Phe802fs)	OPA1	Pathogenic	criteria provided, multiple submitters, no conflicts
447904	NM_130837.3(OPA1):c.868C>T (p.Arg290Ter)	OPA1	Pathogenic	criteria provided, multiple submitters, no conflicts
4819126	NM_130837.3(OPA1):c.33-280_180del	OPA1	Pathogenic	criteria provided, single submitter
500848	NM_130837.3(OPA1):c.1389dup (p.Gly464fs)	OPA1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 42 · Orphanet: 11 · 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
MED12	Definitive	Autosomal dominant	autosomal dominant optic atrophy, classic form	21
OPA1	Definitive	Autosomal dominant	autosomal dominant optic atrophy, classic form	11
DNM1L	Strong	Autosomal dominant	optic atrophy 5	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MED12	Orphanet:1415	Hardikar syndrome
MED12	Orphanet:293707	Blepharophimosis-intellectual disability syndrome, MKB type
MED12	Orphanet:776	Lujan-Fryns syndrome
MED12	Orphanet:777	X-linked non-syndromic intellectual disability
MED12	Orphanet:93932	FG syndrome type 1
OPA1	Orphanet:1215	Autosomal dominant optic atrophy plus syndrome
OPA1	Orphanet:1239	Behr syndrome
OPA1	Orphanet:98673	Autosomal dominant optic atrophy, classic form
DNM1L	Orphanet:330050	DNM1L-related encephalopathy due to mitochondrial and peroxisomal fission defect
DNM1L	Orphanet:98673	Autosomal dominant optic atrophy, classic form
ATP13A3	Orphanet:275777	Heritable pulmonary arterial hypertension

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
MED12	HGNC:11957	ENSG00000184634	Q93074	Mediator of RNA polymerase II transcription subunit 12	gencc,clinvar
OPA1	HGNC:8140	ENSG00000198836	O60313	Dynamin-like GTPase OPA1, mitochondrial	gencc,clinvar
DNM1L	HGNC:2973	ENSG00000087470	O00429	Dynamin-1-like protein	gencc
ATP13A3	HGNC:24113	ENSG00000133657	Q9H7F0	Polyamine-transporting ATPase 13A3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MED12	Mediator of RNA polymerase II transcription subunit 12	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
OPA1	Dynamin-like GTPase OPA1, mitochondrial	Dynamin-related GTPase that is essential for normal mitochondrial morphology by mediating fusion of the mitochondrial inner membranes, regulating cristae morphology and maintaining respiratory chain function.
DNM1L	Dynamin-1-like protein	Functions in mitochondrial and peroxisomal division.
ATP13A3	Polyamine-transporting ATPase 13A3	ATP-driven pump involved in endocytosis-dependent polyamine transport.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	2	6.0×	0.112
Transcription factor	1	2.1×	0.605
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MED12	Other/Unknown	no		Mediator_Med12, Mediator_Med12_catenin-bd, Mediator_Med12_LCEWAV
OPA1	Enzyme (other)	yes	3.6.5.5	Dynamin_GTPase, Dynamin, P-loop_NTPase
DNM1L	Enzyme (other)	yes	3.6.5.5	Dynamin_stalk, Dynamin_GTPase, GED
ATP13A3	Transcription factor	no		P_typ_ATPase, ATPase_P-typ_cation-transptr_N, P-type_TPase_V

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
left ovary	1
right adrenal gland	1
right adrenal gland cortex	1
adrenal tissue	1
calcaneal tendon	1
endothelial cell	1
lateral nuclear group of thalamus	1
sperm	1
substantia nigra pars compacta	1
amniotic fluid	1
decidua	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MED12	281	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left ovary
OPA1	288	ubiquitous	marker	adrenal tissue, calcaneal tendon, endothelial cell
DNM1L	295	ubiquitous	marker	lateral nuclear group of thalamus, substantia nigra pars compacta, sperm
ATP13A3	291	ubiquitous	marker	decidua, secondary oocyte, amniotic fluid

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNM1L	4,801
MED12	3,322
OPA1	2,630
ATP13A3	1,870

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
OPA1	O60313	11
DNM1L	O00429	11
MED12	Q93074	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATP13A3	Q9H7F0	77.96

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. Enrichment computed across 4 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
Regulation of Apoptosis	1	634.4×	0.036	OPA1
Apoptotic execution phase	1	158.6×	0.053	DNM1L
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	71.8×	0.053	MED12
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	65.6×	0.053	MED12
Respiratory Syncytial Virus Infection Pathway	1	65.6×	0.053	MED12
RSV-host interactions	1	52.1×	0.053	MED12
Adipogenesis	1	52.1×	0.053	MED12
Epigenetic regulation by WDR5-containing histone modifying complexes	1	51.4×	0.053	MED12
Regulation of lipid metabolism by PPARalpha	1	47.0×	0.053	MED12
Transcriptional regulation of white adipocyte differentiation	1	43.3×	0.053	MED12
Mitochondrial protein degradation	1	38.1×	0.054	OPA1
PPARA activates gene expression	1	31.5×	0.060	MED12
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	27.6×	0.063	MED12
Epigenetic regulation of gene expression	1	23.8×	0.068	MED12
Metabolism of lipids	1	10.5×	0.136	MED12
Viral Infection Pathways	1	10.3×	0.136	MED12
Infectious disease	1	8.3×	0.157	MED12
RNA Polymerase II Transcription	1	7.5×	0.163	MED12
Gene expression (Transcription)	1	6.0×	0.192	MED12
Generic Transcription Pathway	1	5.0×	0.212	MED12
Developmental Biology	1	4.8×	0.212	MED12
Disease	1	4.4×	0.222	MED12
Metabolism	1	3.9×	0.237	MED12

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
peroxisome fission	2	766.0×	1e-04	OPA1, DNM1L
mitochondrial fission	2	526.6×	1e-04	OPA1, DNM1L
protein complex oligomerization	2	337.0×	2e-04	OPA1, DNM1L
neural tube closure	2	93.6×	0.002	MED12, OPA1
mitochondrial inner membrane fusion	1	4213.0×	0.002	OPA1
mitochondrion organization	2	75.9×	0.002	OPA1, DNM1L
mitochondrial membrane fission	1	2106.5×	0.003	DNM1L
regulation of ATP metabolic process	1	2106.5×	0.003	DNM1L
axis elongation involved in somitogenesis	1	1404.3×	0.003	MED12
membrane tubulation	1	1404.3×	0.003	OPA1
regulation of peroxisome organization	1	1404.3×	0.003	DNM1L
polyamine transmembrane transport	1	1053.2×	0.004	ATP13A3
mitocytosis	1	702.2×	0.006	DNM1L
intracellular distribution of mitochondria	1	601.9×	0.006	DNM1L
positive regulation of T-helper 17 cell lineage commitment	1	526.6×	0.007	OPA1
embryonic neurocranium morphogenesis	1	468.1×	0.007	MED12
axonal transport of mitochondrion	1	351.1×	0.008	OPA1
mitochondrial fragmentation involved in apoptotic process	1	351.1×	0.008	DNM1L
protein localization to mitochondrion	1	324.1×	0.009	DNM1L
regulation of mitophagy	1	300.9×	0.009	DNM1L
GTP metabolic process	1	280.9×	0.009	OPA1
Schwann cell development	1	263.3×	0.009	MED12
cristae formation	1	263.3×	0.009	OPA1
inner mitochondrial membrane organization	1	210.7×	0.009	OPA1
mitochondrial fusion	1	210.7×	0.009	OPA1
negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	1	210.7×	0.009	OPA1
negative regulation of release of cytochrome c from mitochondria	1	200.6×	0.009	OPA1
embryonic brain development	1	200.6×	0.009	MED12
heart contraction	1	191.5×	0.009	DNM1L
positive regulation of mitochondrial fission	1	191.5×	0.009	DNM1L

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 2

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
OPA1	MOMELOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
OPA1	2	4
MED12	1	2
DNM1L	0	0
ATP13A3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOMELOTINIB	4	OPA1
TIVANTINIB	3	OPA1
MOLIBRESIB	2	MED12

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MED12	6	Binding:6
DNM1L	4	Binding:4
OPA1	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
OPA1	3.6.5.5	dynamin GTPase
DNM1L	3.6.5.5	dynamin GTPase

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

3 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.

Compound	Max phase	Cohort target (bioactivity)
MOMELOTINIB	4	OPA1
TIVANTINIB	3	OPA1
MOLIBRESIB	2	MED12

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	OPA1
B	Phased (≥1) drug, not yet approved	1	MED12
C	Druggable family + PDB, no drug	1	DNM1L
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ATP13A3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DNM1L	4	—
ATP13A3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	1
PHASE1	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06970106	PHASE1/PHASE2	RECRUITING	Safety of Single and Repeat Dose of PYC-001 Eye Injections in People With Autosomal Dominant Optic Atrophy (Myrtle)
NCT06461286	PHASE1	ACTIVE_NOT_RECRUITING	SAD of IVT PYC-001 in OPA1 Mutation-Associated Autosomal Dominant Optic Atrophy (Sundew)
NCT06140329	Not specified	TERMINATED	Natural History of Autosomal Dominant Optic Atrophy (ADOA), Caused by OPA1 Mutation