Optic atrophy 12

Summary

Optic atrophy 12 (MONDO:0033549) is a disease caused by AFG3L2 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: AFG3L2 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 27

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	optic atrophy 12
Mondo ID	MONDO:0033549
OMIM	618977
DOID	DOID:0080840
UMLS	C5436534
MedGen	1720703
GARD	0016399
Is cancer (heuristic)	no

Also known as: OPA12

Data availability: 27 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › optic nerve disorder › optic atrophy › primary optic atrophy › hereditary optic atrophy › optic atrophy 12

Related subtypes (14): optic atrophy 13 with retinal and foveal abnormalities, optic atrophy 6, optic atrophy 2, Leber hereditary optic neuropathy, optic atrophy 4, autosomal recessive optic atrophy, OPA7 type, optic atrophy 11, osteogenesis imperfecta-retinopathy-seizures-intellectual disability syndrome, autosomal dominant optic atrophy, optic atrophy 10 with or without ataxia, intellectual disability, and seizures, optic atrophy 14, optic atrophy 15, optic atrophy 16, ACO2-related optic atrophy with or without extraocular features

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

27 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 5 benign, 5 conflicting classifications of pathogenicity, 5 likely pathogenic, 3 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1676883	NM_006796.3(AFG3L2):c.1378G>A (p.Asp460Asn)	AFG3L2	Pathogenic	criteria provided, single submitter
30423	NM_006796.3(AFG3L2):c.1996A>G (p.Met666Val)	AFG3L2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
565275	NM_006796.3(AFG3L2):c.1402C>T (p.Arg468Cys)	AFG3L2	Pathogenic	criteria provided, single submitter
973106	NM_006796.3(AFG3L2):c.1541C>T (p.Pro514Leu)	AFG3L2	Pathogenic	no assertion criteria provided
2583175	NM_006796.3(AFG3L2):c.1270C>T (p.Gln424Ter)	AFG3L2	Likely pathogenic	criteria provided, single submitter
973105	NM_006796.3(AFG3L2):c.1220A>G (p.Asp407Gly)	AFG3L2	Likely pathogenic	criteria provided, single submitter
976488	NM_006796.3(AFG3L2):c.1010G>A (p.Gly337Glu)	AFG3L2	Likely pathogenic	criteria provided, single submitter
4849505	NM_015076.5:c.128+28397_204+4425del	CDK19	Likely pathogenic	criteria provided, single submitter
3779244	NM_001135924.3(VWDE):c.4759-36_4759-35del	VWDE	Likely pathogenic	criteria provided, single submitter
214062	NM_006796.3(AFG3L2):c.2167G>A (p.Val723Met)	AFG3L2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2161341	NM_006796.3(AFG3L2):c.2312C>T (p.Ser771Leu)	AFG3L2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2664732	NM_006796.3(AFG3L2):c.1714G>A (p.Ala572Thr)	AFG3L2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
385335	NM_006796.3(AFG3L2):c.1064C>T (p.Thr355Met)	AFG3L2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
546814	NM_006796.3(AFG3L2):c.1385C>T (p.Ala462Val)	AFG3L2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1256165	NM_006796.3(AFG3L2):c.2314C>A (p.Leu772Ile)	AFG3L2	Uncertain significance	criteria provided, multiple submitters, no conflicts
214049	NM_006796.3(AFG3L2):c.463G>A (p.Gly155Ser)	AFG3L2	Uncertain significance	criteria provided, multiple submitters, no conflicts
214054	NM_006796.3(AFG3L2):c.1762G>A (p.Ala588Thr)	AFG3L2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2444141	NM_006796.3(AFG3L2):c.1013C>A (p.Ala338Glu)	AFG3L2	Uncertain significance	criteria provided, single submitter
3393353	NM_006796.3(AFG3L2):c.965A>G (p.Glu322Gly)	AFG3L2	Uncertain significance	criteria provided, single submitter
3779239	NM_006796.3(AFG3L2):c.1097A>G (p.Asn366Ser)	AFG3L2	Uncertain significance	criteria provided, single submitter
4076977	NM_006796.3(AFG3L2):c.1663+1G>A	AFG3L2	Uncertain significance	criteria provided, single submitter
931039	NM_006796.3(AFG3L2):c.2030T>C (p.Leu677Pro)	AFG3L2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1188960	NM_006796.3(AFG3L2):c.753-55T>C	AFG3L2	Benign	criteria provided, multiple submitters, no conflicts
128286	NM_006796.3(AFG3L2):c.1389G>A (p.Leu463=)	AFG3L2	Benign	criteria provided, multiple submitters, no conflicts
128287	NM_006796.3(AFG3L2):c.1650A>G (p.Glu550=)	AFG3L2	Benign	criteria provided, multiple submitters, no conflicts
136312	NM_006796.3(AFG3L2):c.752+6C>T	AFG3L2	Benign	criteria provided, multiple submitters, no conflicts
326101	NM_006796.3(AFG3L2):c.*28G>C	AFG3L2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 3 · 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
AFG3L2	Strong	Autosomal dominant	optic atrophy 12	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AFG3L2	Orphanet:101109	Spinocerebellar ataxia type 28
AFG3L2	Orphanet:313772	Early-onset spastic ataxia-myoclonic epilepsy-neuropathy syndrome
CDK19	Orphanet:442835	Non-specific early-onset epileptic encephalopathy

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
AFG3L2	HGNC:315	ENSG00000141385	Q9Y4W6	Mitochondrial inner membrane m-AAA protease component AFG3L2	gencc,clinvar
CDK19	HGNC:19338	ENSG00000155111	Q9BWU1	Cyclin-dependent kinase 19	clinvar
VWDE	HGNC:21897	ENSG00000146530	Q8N2E2	von Willebrand factor D and EGF domain-containing protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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×	0.157
Kinase	1	9.2×	0.157
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AFG3L2	Protease	yes	3.4.24.B18	Peptidase_M41, AAA+_ATPase, ATPase_AAA_core
CDK19	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
VWDE	Other/Unknown	no		EGF, VWF_type-D, Dev_Signal_Modulators

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
endothelial cell	2
Brodmann (1909) area 23	1
jejunal mucosa	1
corpus callosum	1
medial globus pallidus	1
male germ line stem cell (sensu Vertebrata) in testis	1
pituitary gland	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AFG3L2	288	ubiquitous	marker	Brodmann (1909) area 23, endothelial cell, jejunal mucosa
CDK19	282	ubiquitous	marker	endothelial cell, medial globus pallidus, corpus callosum
VWDE	159	broad	marker	pituitary gland, right uterine tube, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AFG3L2	4,260
CDK19	1,516
VWDE	1,133

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AFG3L2	Q9Y4W6	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CDK19	Q9BWU1	77.97
VWDE	Q8N2E2	71.33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 3 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
Processing of SMDT1	1	317.2×	0.031	AFG3L2
Mitochondrial calcium ion transport	1	271.9×	0.031	AFG3L2
Respiratory Syncytial Virus Infection Pathway	1	98.5×	0.037	CDK19
RSV-host interactions	1	78.2×	0.037	CDK19
Adipogenesis	1	78.2×	0.037	CDK19
Regulation of lipid metabolism by PPARalpha	1	70.5×	0.037	CDK19
Transcriptional regulation of white adipocyte differentiation	1	64.9×	0.037	CDK19
Mitochondrial protein degradation	1	57.1×	0.037	AFG3L2
PPARA activates gene expression	1	47.2×	0.040	CDK19
Metabolism of lipids	1	15.8×	0.099	CDK19
Viral Infection Pathways	1	15.4×	0.099	CDK19
Transport of small molecules	1	12.6×	0.103	AFG3L2
Infectious disease	1	12.4×	0.103	CDK19
Developmental Biology	1	7.2×	0.162	CDK19
Disease	1	6.5×	0.165	CDK19
Metabolism of proteins	1	6.2×	0.165	AFG3L2
Metabolism	1	5.8×	0.165	CDK19

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cellular response to glutathione	1	8426.0×	0.003	AFG3L2
regulation of calcium import into the mitochondrion	1	2808.7×	0.004	AFG3L2
mitochondrial protein quality control	1	2106.5×	0.004	AFG3L2
mitochondrial protein processing	1	1404.3×	0.004	AFG3L2
righting reflex	1	936.2×	0.004	AFG3L2
calcium import into the mitochondrion	1	601.9×	0.004	AFG3L2
membrane protein proteolysis	1	526.6×	0.004	AFG3L2
cristae formation	1	526.6×	0.004	AFG3L2
mitochondrial calcium ion homeostasis	1	495.6×	0.004	AFG3L2
nerve development	1	468.1×	0.004	AFG3L2
muscle cell development	1	468.1×	0.004	AFG3L2
mitochondrial fusion	1	421.3×	0.005	AFG3L2
protein autoprocessing	1	324.1×	0.005	AFG3L2
regulation of multicellular organism growth	1	324.1×	0.005	AFG3L2
neuromuscular junction development	1	263.3×	0.006	AFG3L2
myelination	1	125.8×	0.011	AFG3L2
protein catabolic process	1	118.7×	0.011	AFG3L2
protein processing	1	85.1×	0.014	AFG3L2
protein maturation	1	81.8×	0.014	AFG3L2
axonogenesis	1	80.2×	0.014	AFG3L2
cellular response to lipopolysaccharide	1	49.0×	0.022	CDK19
positive regulation of apoptotic process	1	28.4×	0.037	CDK19
proteolysis	1	17.1×	0.058	AFG3L2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
CDK19	SORAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CDK19	21	4
AFG3L2	0	0
VWDE	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SORAFENIB	4	CDK19
QUIZARTINIB	4	CDK19
MIDOSTAURIN	4	CDK19
IMATINIB	4	CDK19
VATALANIB	3	CDK19
LINIFANIB	3	CDK19
ALVOCIDIB	3	CDK19
INDIRUBIN	2	CDK19
ISTISOCICLIB	2	CDK19
DORAMAPIMOD	2	CDK19
FORETINIB	2	CDK19
AT-7519	2	CDK19
CP-724714	2	CDK19
RAF-265	2	CDK19
TOZASERTIB	2	CDK19
SENEXIN B	1	CDK19
SEL-120 FREE BASE	1	CDK19
BMS-387032	1	CDK19
SEL-120	1	CDK19
SNS-314	1	CDK19
AST-487	1	CDK19

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CDK19	210	Binding:209, Functional:1
AFG3L2	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AFG3L2	3.4.24.B18

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CDK19	210

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

21 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)
SORAFENIB	4	CDK19
QUIZARTINIB	4	CDK19
MIDOSTAURIN	4	CDK19
IMATINIB	4	CDK19
VATALANIB	3	CDK19
LINIFANIB	3	CDK19
ALVOCIDIB	3	CDK19
INDIRUBIN	2	CDK19
ISTISOCICLIB	2	CDK19
DORAMAPIMOD	2	CDK19
FORETINIB	2	CDK19
AT-7519	2	CDK19
CP-724714	2	CDK19
RAF-265	2	CDK19
TOZASERTIB	2	CDK19
SENEXIN B	1	CDK19
SEL-120 FREE BASE	1	CDK19
BMS-387032	1	CDK19
SEL-120	1	CDK19
SNS-314	1	CDK19
AST-487	1	CDK19

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CDK19
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	AFG3L2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	VWDE

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)
AFG3L2	3	—
VWDE	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.