Optic nerve disorder

disease

On this page

Also known as cranial nerve II diseasecranial nerve II disease or disorderdisease of cranial nerve IIdisease or disorder of cranial nerve IIdisorder of cranial nerve IIsecond cranial nerve disorder

Summary

Optic nerve disorder (MONDO:0002135) is a disease (an umbrella term covering 8 Mondo subtypes) with 17 cohort genes (5 GWAS associations across 8 studies) and 1 clinical trial. The dominant Reactome pathway is Mitochondrial protein degradation (6 cohort genes).

At a glance

Umbrella term: 8 Mondo subtypes
Cohort genes: 17
GWAS associations: 5
ClinVar variants: 26
Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	optic nerve disorder
Mondo ID	MONDO:0002135
MeSH	D009901
DOID	DOID:1891
NCIT	C79698
SNOMED CT	77157004
UMLS	C3887709
MedGen	854546
Anatomy (UBERON)	UBERON:0000941
Is cancer (heuristic)	no

Also known as: cranial nerve II disease · cranial nerve II disease or disorder · disease of cranial nerve II · disease or disorder of cranial nerve II · disorder of cranial nerve II · optic nerve disorder · second cranial nerve disorder

Data availability: 26 ClinVar variants · 5 GWAS associations (8 studies).

Disease family

An umbrella term covering 8 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › optic nerve disorder

Subtypes (8): optic disk drusen, optic nerve neoplasm, optic atrophy, optic neuritis, anterior ischemic optic neuropathy, low tension glaucoma, extensive peripapillary myelinated nerve fibers, isolated optic nerve aplasia

Genetics & variants

GWAS landscape

5 GWAS associations across 8 studies. Top hits map to 1 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs944801	2e-14	CDKN2B-AS1	G	0.11
rs12615158	1e-13	PNPT1 - EFEMP1	C	0.12
rs6730839	2e-13	PNPT1 - EFEMP1	G	0.11
rs7030641	3e-12	CDKN2B-AS1	C	0.09
chr14:60957171	8e-12		G	0.1

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90475896	Verma A	2024	11,247	429,671	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90477760	Verma A	2024	3,917	114,035	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90480096	Verma A	2024	3,917	114,035	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90477759	Verma A	2024	1,136	57,473	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90079914	Backman JD	2021	511	386,640	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90083900	Backman JD	2021	511	386,640	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90436015	Zhou W	2018	370	401,245	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.
GCST90726860	Kim HI	2026	210	43,816	Exome sequencing and analysis of 44,028 British South Asians enriched for high autozygosity.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	5

MAF distribution

Bucket	Variants
common (>=0.05)	5
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	2
intergenic_variant	2
unknown	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs944801	9	22051671	G>A,C	0.427	intron_variant	CDKN2B-AS1	2e-14	Tier 4: intronic/intergenic
rs12615158	2	55805864	C>G,T	0.238	intergenic_variant	PNPT1 - EFEMP1	1e-13	Tier 4: intronic/intergenic
rs6730839	2	55820972	G>A,C,T	0.178	intergenic_variant	PNPT1 - EFEMP1	2e-13	Tier 4: intronic/intergenic
rs7030641	9	22054041	C>T	0.344	intron_variant	CDKN2B-AS1	3e-12	Tier 4: intronic/intergenic
chr14:60957171				0.45			8e-12	Tier 4: intronic/intergenic

ClinVar germline variants

26 retrieved; paginated sample, class counts are floors:

7 pathogenic, 6 conflicting classifications of pathogenicity, 6 uncertain significance, 5 pathogenic/likely pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1061997	NM_001098.3(ACO2):c.1132C>T (p.Arg378Ter)	ACO2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224983	NM_005548.3(KARS1):c.599C>T (p.Pro200Leu)	KARS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2441821	NM_015909.4(NBAS):c.4255del (p.Ser1419fs)	NBAS	Pathogenic	criteria provided, multiple submitters, no conflicts
3250057	NM_130837.3(OPA1):c.814C>T (p.Gln272Ter)	OPA1	Pathogenic	criteria provided, single submitter
3302321	NM_130837.3(OPA1):c.2676G>A (p.Trp892Ter)	OPA1	Pathogenic	criteria provided, multiple submitters, no conflicts
4539016	NM_130837.3(OPA1):c.1656_1658delinsAAAGCTTTCCCAATGAAAGCTCTTCCCAATGAACAGC (p.Tyr553delinsLysLeuSerGlnTer)	OPA1	Pathogenic	criteria provided, single submitter
4820578	NM_130837.3(OPA1):c.2075del (p.Tyr692fs)	OPA1	Pathogenic	criteria provided, single submitter
496968	NM_130837.3(OPA1):c.610+364G>A	OPA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4820577	NM_130837.3(OPA1):c.681del (p.Leu228fs)	OPA1-AS1	Pathogenic	criteria provided, single submitter
4528900	NM_004181.5(UCHL1):c.360_361dup (p.Thr121fs)	UCHL1	Pathogenic	criteria provided, single submitter
1526050	NM_006005.3(WFS1):c.1433G>A (p.Trp478Ter)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
215376	NM_006005.3(WFS1):c.505G>A (p.Glu169Lys)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
973110	NM_006796.3(AFG3L2):c.1130T>C (p.Phe377Ser)	AFG3L2	Likely pathogenic	criteria provided, single submitter
4688051	NM_015909.4(NBAS):c.6194T>C (p.Leu2065Pro)	NBAS	Likely pathogenic	criteria provided, single submitter
189311	NM_001098.3(ACO2):c.1981G>A (p.Gly661Arg)	ACO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1900	NM_001370658.1(BTD):c.1270G>C (p.Asp424His)	BTD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
562001	NM_005548.3(KARS1):c.787T>G (p.Phe263Val)	KARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1370872	NM_012318.3(LETM1):c.888_889del (p.Arg299fs)	LETM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
42016	NM_003119.4(SPG7):c.1529C>T (p.Ala510Val)	SPG7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1320487	NM_006005.3(WFS1):c.1553T>A (p.Met518Lys)	WFS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
801637	NM_000081.4(LYST):c.949G>A (p.Glu317Lys)	LYST	Uncertain significance	criteria provided, multiple submitters, no conflicts
370051	NC_012920.1(MT-ATP6):m.9166T>C	MT-ATP6	Uncertain significance	criteria provided, single submitter
370050	NC_012920.1(MT-ATP8):m.8418T>C	MT-ATP8	Uncertain significance	reviewed by expert panel
65519	NC_012920.1(MT-ND1):m.3700G>A	MT-ND1	Uncertain significance	reviewed by expert panel
523305	NC_012920.1:m.11443A>C	MT-ND4	Uncertain significance	criteria provided, single submitter
2421395	NM_006005.3(WFS1):c.2057C>A (p.Thr686Asn)	WFS1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 49 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BTD	Orphanet:79241	Biotinidase deficiency
SPG7	Orphanet:35689	Primary lateral sclerosis
SPG7	Orphanet:99013	Spastic paraplegia type 7
ACO2	Orphanet:313850	Infantile cerebellar-retinal degeneration
ACO2	Orphanet:98676	Autosomal recessive isolated optic atrophy
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
UCHL1	Orphanet:2828	Young-onset Parkinson disease
UCHL1	Orphanet:352654	Early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome
WFS1	Orphanet:3463	Wolfram syndrome
WFS1	Orphanet:411590	Wolfram-like syndrome
WFS1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
WFS1	Orphanet:98991	Early-onset nuclear cataract
NBAS	Orphanet:391677	Short stature-optic atrophy-Pelger-Huët anomaly syndrome
NBAS	Orphanet:464724	Fever-associated acute infantile liver failure syndrome
LYST	Orphanet:167	Chédiak-Higashi syndrome
LYST	Orphanet:352723	Attenuated Chédiak-Higashi syndrome
AFG3L2	Orphanet:101109	Spinocerebellar ataxia type 28
AFG3L2	Orphanet:313772	Early-onset spastic ataxia-myoclonic epilepsy-neuropathy syndrome
KARS1	Orphanet:254334	Autosomal recessive intermediate Charcot-Marie-Tooth disease type B
KARS1	Orphanet:3240	Early-onset progressive leukoencephalopathy-central nervous system calcification-deafness-visual impairment syndrome
KARS1	Orphanet:652532	Adult-onset progressive leukoencephalopathy-early-onset deafness
KARS1	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
LETM1	Orphanet:280	Wolf-Hirschhorn syndrome
MT-ATP6	Orphanet:104	Leber hereditary optic neuropathy
MT-ATP6	Orphanet:225154	Familial infantile bilateral striatal necrosis
MT-ATP6	Orphanet:254913	Isolated ATP synthase deficiency
MT-ATP6	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ATP6	Orphanet:320360	MT-ATP6-related mitochondrial spastic paraplegia
MT-ATP6	Orphanet:397750	Periodic paralysis with later-onset distal motor neuropathy
MT-ATP6	Orphanet:644	NARP syndrome
MT-ATP8	Orphanet:254913	Isolated ATP synthase deficiency
MT-ATP8	Orphanet:397750	Periodic paralysis with later-onset distal motor neuropathy
MT-ATP8	Orphanet:480	Kearns-Sayre syndrome
MT-ND1	Orphanet:104	Leber hereditary optic neuropathy
MT-ND1	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND1	Orphanet:2609	Isolated complex I deficiency
MT-ND1	Orphanet:550	MELAS
MT-ND4	Orphanet:104	Leber hereditary optic neuropathy
MT-ND4	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND4	Orphanet:550	MELAS
MT-ND4	Orphanet:90641	Rare mitochondrial non-syndromic sensorineural deafness
MT-ND4	Orphanet:99718	Leber plus disease
OPA1	Orphanet:1215	Autosomal dominant optic atrophy plus syndrome
OPA1	Orphanet:1239	Behr syndrome
OPA1	Orphanet:98673	Autosomal dominant optic atrophy, classic form

Cohort genes → proteins

17 cohort genes, 16 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	17

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BTD	HGNC:1122	ENSG00000169814	P43251	Biotinidase	clinvar
SPG7	HGNC:11237	ENSG00000197912	Q9UQ90	Mitochondrial inner membrane m-AAA protease component paraplegin	clinvar
ACO2	HGNC:118	ENSG00000100412	Q99798	Aconitate hydratase, mitochondrial	clinvar
MED12	HGNC:11957	ENSG00000184634	Q93074	Mediator of RNA polymerase II transcription subunit 12	clinvar
UCHL1	HGNC:12513	ENSG00000154277	P09936	Ubiquitin carboxyl-terminal hydrolase isozyme L1	clinvar
WFS1	HGNC:12762	ENSG00000109501	O76024	Wolframin	clinvar
NBAS	HGNC:15625	ENSG00000151779	A2RRP1	NBAS subunit of NRZ tethering complex	clinvar
LYST	HGNC:1968	ENSG00000143669	Q99698	Lysosomal-trafficking regulator	clinvar
AFG3L2	HGNC:315	ENSG00000141385	Q9Y4W6	Mitochondrial inner membrane m-AAA protease component AFG3L2	clinvar
OPA1-AS1	HGNC:40421	ENSG00000224855		OPA1 antisense RNA 1	clinvar
KARS1	HGNC:6215	ENSG00000065427	Q15046	Lysine–tRNA ligase	clinvar
LETM1	HGNC:6556	ENSG00000168924	O95202	Mitochondrial proton/calcium exchanger protein	clinvar
MT-ATP6	HGNC:7414	ENSG00000198899	P00846	ATP synthase F(0) complex subunit a	clinvar
MT-ATP8	HGNC:7415	ENSG00000228253	P03928	ATP synthase F(0) complex subunit 8	clinvar
MT-ND1	HGNC:7455	ENSG00000198888	P03886	NADH-ubiquinone oxidoreductase chain 1	clinvar
MT-ND4	HGNC:7459	ENSG00000198886	C0HME5	Mitochondrial alternative ND4 protein	clinvar
OPA1	HGNC:8140	ENSG00000198836	O60313	Dynamin-like GTPase OPA1, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BTD	Biotinidase	Catalytic release of biotin from biocytin, the product of biotin-dependent carboxylases degradation.
SPG7	Mitochondrial inner membrane m-AAA protease component paraplegin	Catalytic component of the m-AAA protease, a protease that plays a key role in proteostasis of inner mitochondrial membrane proteins, and which is essential for axonal and neuron development.
ACO2	Aconitate hydratase, mitochondrial	Catalyzes the isomerization of citrate to isocitrate via cis-aconitate.
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.
UCHL1	Ubiquitin carboxyl-terminal hydrolase isozyme L1	Deubiquitinase that plays a role in the regulation of several processes such as maintenance of synaptic function, cardiac function, inflammatory response or osteoclastogenesis.
WFS1	Wolframin	Participates in the regulation of cellular Ca(2+) homeostasis, at least partly, by modulating the filling state of the endoplasmic reticulum Ca(2+) store.
NBAS	NBAS subunit of NRZ tethering complex	Involved in Golgi-to-endoplasmic reticulum (ER) retrograde transport; the function is proposed to depend on its association in the NRZ complex which is believed to play a role in SNARE assembly at the ER.
LYST	Lysosomal-trafficking regulator	Adapter protein that regulates and/or fission of intracellular vesicles such as lysosomes.
AFG3L2	Mitochondrial inner membrane m-AAA protease component AFG3L2	Catalytic component of the m-AAA protease, a protease that plays a key role in proteostasis of inner mitochondrial membrane proteins, and which is essential for axonal and neuron development.
KARS1	Lysine–tRNA ligase	Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA.
LETM1	Mitochondrial proton/calcium exchanger protein	Plays an important role in maintenance of mitochondrial morphology and in mediating either calcium or potassium/proton antiport.
MT-ATP6	ATP synthase F(0) complex subunit a	Subunit a, of the mitochondrial membrane ATP synthase complex (F(1)F(0) ATP synthase or Complex V) that produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of th…
MT-ATP8	ATP synthase F(0) complex subunit 8	Subunit 8, of the mitochondrial membrane ATP synthase complex (F(1)F(0) ATP synthase or Complex V) that produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of th…
MT-ND1	NADH-ubiquinone oxidoreductase chain 1	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.
MT-ND4	Mitochondrial alternative ND4 protein	Regulates mitochondrial respiration by decreasing oxygen consumption.
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.

Protein-family classification

Druggable: 7 · Difficult: 2 · Unknown: 8 · Druggable fraction: 0.41

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	3	6.5×	0.041
Enzyme (other)	4	2.8×	0.095
Scaffold/PPI	2	2.0×	0.344
Other/Unknown	8	0.8×	0.834

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BTD	Enzyme (other)	yes	3.5.1.12	C-N_Hydrolase, Biotinidase-like_euk, C-N_Hydrolase_sf
SPG7	Protease	yes	3.4.24.B18	Peptidase_M41, AAA+_ATPase, ATPase_AAA_core
ACO2	Enzyme (other)	yes	4.2.1.3	AconitaseA/IPMdHydase_ssu_swvl, Acoase/IPM_deHydtase_lsu_aba, Aconitase_mito-like
MED12	Other/Unknown	no		Mediator_Med12, Mediator_Med12_catenin-bd, Mediator_Med12_LCEWAV
UCHL1	Protease	yes	3.4.19.12	Peptidase_C12_UCH, Peptidase_C12_UCH_sf, Papain-like_cys_pep_sf
WFS1	Other/Unknown	no		TPR-like_helical_dom_sf, Wolframin, Wolframin_fam
NBAS	Scaffold/PPI	no		Quino_amine_DH_bsu, Sec39_domain, WD40/YVTN_repeat-like_dom_sf
LYST	Scaffold/PPI	no		BEACH_dom, WD40_rpt, PH-like_dom_sf
AFG3L2	Protease	yes	3.4.24.B18	Peptidase_M41, AAA+_ATPase, ATPase_AAA_core
OPA1-AS1	Other/Unknown	no
KARS1	Enzyme (other)	yes	6.1.1.6	Lys-tRNA-ligase_II, Aa-tRNA-synt_II, NA-bd_OB_tRNA
LETM1	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
MT-ATP6	Other/Unknown	no		ATP_synth_F0_asu, ATP_synth_F0_asu_AS, F0_ATP_A_sf
MT-ATP8	Other/Unknown	no		ATP8_metazoa, ATP8_mammal
MT-ND1	Other/Unknown	no		NADH_UbQ_OxRdtase_su1/FPO, NADH_UbQ_OxRdtase_su1_CS
MT-ND4	Other/Unknown	no		NADH4_N, ND/Mrp_TM, NADH_UbQ_OxRdtase
OPA1	Enzyme (other)	yes	3.6.5.5	Dynamin_GTPase, Dynamin, P-loop_NTPase

Expression context

Cohort genes with no expression data: 0.

16 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)	17
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	3
primordial germ cell in gonad	2
sural nerve	2
apex of heart	2
left ovary	2
right ovary	2
endothelial cell	2
gastrocnemius	2
islet of Langerhans	1
liver	1
right lobe of liver	1
left lobe of thyroid gland	1
heart right ventricle	1
left ventricle myocardium	1
right adrenal gland	1
right adrenal gland cortex	1
lateral nuclear group of thalamus	1
pons	1
right frontal lobe	1
body of uterus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BTD	261	ubiquitous	marker	islet of Langerhans, right lobe of liver, liver
SPG7	302	ubiquitous	marker	primordial germ cell in gonad, sural nerve, left lobe of thyroid gland
ACO2	291	ubiquitous	marker	heart right ventricle, apex of heart, left ventricle myocardium
MED12	281	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left ovary
UCHL1	248	ubiquitous	marker	pons, right frontal lobe, lateral nuclear group of thalamus
WFS1	280	ubiquitous	marker	right ovary, left ovary, body of uterus
NBAS	293	ubiquitous	marker	calcaneal tendon, primordial germ cell in gonad, ventricular zone
LYST	278	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
AFG3L2	288	ubiquitous	marker	Brodmann (1909) area 23, endothelial cell, jejunal mucosa
OPA1-AS1	119		yes	calcaneal tendon, corpus callosum, bone marrow
KARS1	299	ubiquitous	marker	gingival epithelium, parietal pleura, endometrium epithelium
LETM1	268	ubiquitous	marker	mucosa of transverse colon, sural nerve, buccal mucosa cell
MT-ATP6	134	ubiquitous	marker	mucosa of stomach, left uterine tube, descending thoracic aorta
MT-ATP8	134		marker	gastrocnemius, right ovary, right lung
MT-ND1	134	ubiquitous	marker	adipose tissue, gastrocnemius, frontal cortex
MT-ND4	134	ubiquitous	marker	right uterine tube, apex of heart, zone of skin
OPA1	288	ubiquitous	marker	adrenal tissue, calcaneal tendon, endothelial cell

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACO2	4,776
KARS1	4,681
AFG3L2	4,260
UCHL1	4,090
SPG7	3,970
MT-ND1	3,537
WFS1	3,409
MED12	3,322
MT-ATP6	2,869
OPA1	2,630

Intra-cohort edges

A	B	Sources
ACO2	AFG3L2	string_interaction
AFG3L2	SPG7	string_interaction
MT-ATP6	MT-ATP8	string_interaction
MT-ATP6	MT-ND1	string_interaction
MT-ATP8	MT-ND1	string_interaction

Structural data

PDB: 11 · AlphaFold-only: 5 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
UCHL1	P09936	14
KARS1	Q15046	14
OPA1	O60313	11
MT-ATP6	P00846	10
MT-ATP8	P03928	10
MT-ND4	C0HME5	7
MT-ND1	P03886	5
MED12	Q93074	3
AFG3L2	Q9Y4W6	2
LETM1	O95202	2
SPG7	Q9UQ90	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACO2	Q99798	95.44
BTD	P43251	86.77
NBAS	A2RRP1	74.42
WFS1	O76024	73.85
LYST	Q99698

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 68. Enrichment computed across 17 evidence-associated genes (15 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 15 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Mitochondrial protein degradation	6	45.7×	1e-07	SPG7, ACO2, AFG3L2, MT-ATP6, MT-ND1, OPA1
Mitochondrial calcium ion transport	3	108.8×	8e-05	SPG7, AFG3L2, LETM1
Mitochondrial translation termination	4	29.3×	2e-04	MT-ATP6, MT-ATP8, MT-ND1, MT-ND4
Aerobic respiration and respiratory electron transport	4	23.6×	3e-04	ACO2, LETM1, MT-ATP6, MT-ATP8
Metabolism	7	5.4×	0.002	BTD, ACO2, MED12, KARS1, LETM1, MT-ATP6, MT-ATP8
Processing of SMDT1	2	84.6×	0.003	SPG7, AFG3L2
Formation of ATP by chemiosmotic coupling	2	76.1×	0.003	MT-ATP6, MT-ATP8
Respiratory electron transport	3	19.0×	0.004	LETM1, MT-ND1, MT-ND4
Cristae formation	2	46.1×	0.006	MT-ATP6, MT-ATP8
Defective BTD causes biotidinase deficiency	1	761.3×	0.009	BTD
Mitochondrial biogenesis	2	22.4×	0.020	MT-ATP6, MT-ATP8
Complex I biogenesis	2	22.1×	0.020	MT-ND1, MT-ND4
Metabolism of proteins	5	4.1×	0.027	SPG7, ACO2, AFG3L2, KARS1, MT-ATP6
Defects in biotin (Btn) metabolism	1	152.3×	0.032	BTD
Regulation of Apoptosis	1	126.9×	0.036	OPA1
Biotin transport and metabolism	1	69.2×	0.061	BTD
Organelle biogenesis and maintenance	2	8.8×	0.080	MT-ATP6, MT-ATP8
Transport of small molecules	3	5.0×	0.080	SPG7, AFG3L2, LETM1
Defects in vitamin and cofactor metabolism	1	40.1×	0.088	BTD
Maturation of TCA enzymes and regulation of TCA cycle	1	38.1×	0.088	ACO2
Mitochondrial tRNA aminoacylation	1	34.6×	0.092	KARS1
Cytosolic tRNA aminoacylation	1	29.3×	0.099	KARS1
Complex III assembly	1	29.3×	0.099	LETM1
Citric acid cycle (TCA cycle)	1	28.2×	0.099	ACO2
tRNA Aminoacylation	1	19.0×	0.140	KARS1
XBP1(S) activates chaperone genes	1	14.4×	0.167	WFS1
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	14.4×	0.167	MED12
Selenoamino acid metabolism	1	13.1×	0.167	KARS1
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	13.1×	0.167	MED12
Respiratory Syncytial Virus Infection Pathway	1	13.1×	0.167	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 16 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cristae formation	3	197.5×	3e-05	AFG3L2, LETM1, OPA1
proton motive force-driven mitochondrial ATP synthesis	4	65.8×	3e-05	MT-ATP6, MT-ATP8, MT-ND1, MT-ND4
regulation of calcium import into the mitochondrion	2	702.2×	1e-04	SPG7, AFG3L2
mitochondrial protein processing	2	351.1×	5e-04	SPG7, AFG3L2
axonal transport of mitochondrion	2	175.5×	0.002	UCHL1, OPA1
mitochondrial calcium ion homeostasis	2	123.9×	0.002	AFG3L2, LETM1
muscle cell development	2	117.0×	0.002	UCHL1, AFG3L2
inner mitochondrial membrane organization	2	105.3×	0.002	LETM1, OPA1
mitochondrial fusion	2	105.3×	0.002	AFG3L2, OPA1
negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	2	105.3×	0.002	WFS1, OPA1
proton motive force-driven ATP synthesis	2	100.3×	0.002	MT-ATP6, MT-ATP8
mitochondrial respiratory chain complex I assembly	2	51.4×	0.008	MT-ND1, MT-ND4
lysyl-tRNA aminoacylation	1	1053.2×	0.009	KARS1
cellular response to glutathione	1	1053.2×	0.009	AFG3L2
mitochondrial inner membrane fusion	1	1053.2×	0.009	OPA1
mitochondrial electron transport, NADH to ubiquinone	2	44.8×	0.009	MT-ND1, MT-ND4
basophil activation involved in immune response	1	526.6×	0.013	KARS1
mast cell secretory granule organization	1	526.6×	0.013	LYST
mitochondrial outer membrane permeabilization involved in programmed cell death	1	526.6×	0.013	SPG7
negative regulation of ATF6-mediated unfolded protein response	1	526.6×	0.013	WFS1
aerobic respiration	2	31.0×	0.013	MT-ND1, MT-ND4
protein catabolic process	2	29.7×	0.014	UCHL1, AFG3L2
male germ cell proliferation	1	351.1×	0.014	UCHL1
positive regulation of inflammatory response to antigenic stimulus	1	351.1×	0.014	KARS1
axon target recognition	1	351.1×	0.014	UCHL1
diadenosine tetraphosphate biosynthetic process	1	351.1×	0.014	KARS1
axis elongation involved in somitogenesis	1	351.1×	0.014	MED12
membrane tubulation	1	351.1×	0.014	OPA1
calcium export from the mitochondrion	1	351.1×	0.014	LETM1
citrate metabolic process	1	263.3×	0.015	ACO2

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Epoetin Beta	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Methylprednisolone Hemisuccinate.

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 3 · Undrugged: 14

Druggability breadth: 13 of 17 evidence-associated genes (76%) 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
KARS1	IMATINIB
OPA1	MOMELOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
OPA1	2	4
MED12	1	2
KARS1	1	4
BTD	0	0
SPG7	0	0
ACO2	0	0
UCHL1	0	0
WFS1	0	0
NBAS	0	0
LYST	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IMATINIB	4	KARS1
MOMELOTINIB	4	OPA1
TIVANTINIB	3	OPA1
MOLIBRESIB	2	MED12

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 7.

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

Symbol	Assays	Type breakdown
UCHL1	66	Binding:66
KARS1	46	Binding:45, ADMET:1
MED12	6	Binding:6
MT-ND1	5	Binding:5
BTD	3	Binding:3
AFG3L2	3	Binding:3
OPA1	2	Binding:2
WFS1	1	Binding:1
NBAS	1	Binding:1
LETM1	1	Binding:1
MT-ATP6	1	Binding:1
MT-ATP8	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BTD	3.5.1.12	biotinidase
SPG7	3.4.24.B18
ACO2	4.2.1.3	aconitate hydratase
UCHL1	3.4.19.12	ubiquitinyl hydrolase 1
AFG3L2	3.4.24.B18
KARS1	6.1.1.6	lysine-tRNA ligase
OPA1	3.6.5.5	dynamin GTPase

Pharmacogenomics

Cohort genes with a PharmGKB record: 16; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

4 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)
IMATINIB	4	KARS1
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)	2	KARS1, OPA1
B	Phased (≥1) drug, not yet approved	1	MED12
C	Druggable family + PDB, no drug	3	SPG7, UCHL1, AFG3L2
D	Druggable family + AlphaFold only, no drug	2	BTD, ACO2
E	Difficult family or no structure, no drug	9	WFS1, NBAS, LYST, OPA1-AS1, LETM1, MT-ATP6, MT-ATP8, MT-ND1, MT-ND4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BTD	3	—
SPG7	0	—
ACO2	0	—
UCHL1	66	—
WFS1	1	—
NBAS	1	—
LYST	0	—
AFG3L2	3	—
OPA1-AS1	0	—
LETM1	1	—
MT-ATP6	1	—
MT-ATP8	1	—
MT-ND1	5	—
MT-ND4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02382627	Not specified	TERMINATED	Choroidal Thickness in Optic Neuropathy

Cohort genes: BTD, SPG7, ACO2, MED12, UCHL1, WFS1, NBAS, LYST, AFG3L2, OPA1-AS1, KARS1, LETM1, MT-ATP6, MT-ATP8, MT-ND1, MT-ND4, OPA1