Combined oxidative phosphorylation deficiency

Summary

Combined oxidative phosphorylation deficiency (MONDO:0000732) is a disease (an umbrella term covering 58 Mondo subtypes) with 6 cohort genes.

At a glance

• Umbrella term: 58 Mondo subtypes
• Cohort genes: 6
• ClinVar variants: 396

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	combined oxidative phosphorylation deficiency
Mondo ID	MONDO:0000732
OMIM	609060
DOID	DOID:0060286
ICD-11	1953023896
UMLS	C4540031
MedGen	1626645
GARD	0012893
Is cancer (heuristic)	no

Data availability: 396 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 58 Mondo subtypes.

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 › combined oxidative phosphorylation deficiency

Related subtypes (47): mitochondrial respiratory chain complex deficiency, myopathy, lactic acidosis, and sideroblastic anemia, optic atrophy 3, autosomal dominant optic atrophy, classic form, 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

Subtypes (58): severe X-linked mitochondrial encephalomyopathy, hepatoencephalopathy due to combined oxidative phosphorylation defect type 1, combined oxidative phosphorylation defect type 2, fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3, combined oxidative phosphorylation defect type 4, hypotonia with lactic acidemia and hyperammonemia, combined oxidative phosphorylation defect type 7, combined oxidative phosphorylation defect type 8, combined oxidative phosphorylation defect type 9, mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency, combined oxidative phosphorylation defect type 11, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome, combined oxidative phosphorylation defect type 13, combined oxidative phosphorylation defect type 14, combined oxidative phosphorylation defect type 15, infantile hypertrophic cardiomyopathy due to MRPL44 deficiency, combined oxidative phosphorylation defect type 17, growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndrome, combined oxidative phosphorylation deficiency 19, combined oxidative phosphorylation defect type 20, combined oxidative phosphorylation defect type 21, mitochondrial proton-transporting ATP synthase complex deficiency, combined oxidative phosphorylation defect type 23, combined oxidative phosphorylation defect type 24, combined oxidative phosphorylation defect type 25, combined oxidative phosphorylation defect type 26, combined oxidative phosphorylation defect type 27, combined oxidative phosphorylation deficiency 28, combined oxidative phosphorylation deficiency 29, combined oxidative phosphorylation defect type 30, lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome, combined oxidative phosphorylation deficiency 40, combined oxidative phosphorylation deficiency 41, combined oxidative phosphorylation deficiency 42, combined oxidative phosphorylation deficiency 43, combined oxidative phosphorylation deficiency 44, combined oxidative phosphorylation deficiency 52, combined oxidative phosphorylation deficiency 53, combined oxidative phosphorylation deficiency 54, combined oxidative phosphorylation deficiency 37, combined oxidative phosphorylation deficiency 38, combined oxidative phosphorylation deficiency 39, combined oxidative phosphorylation deficiency 45, combined oxidative phosphorylation deficiency 46, combined oxidative phosphorylation deficiency 47, combined oxidative phosphorylation deficiency 48, combined oxidative phosphorylation deficiency 51, combined oxidative phosphorylation deficiency 32, combined oxidative phosphorylation deficiency 33, combined oxidative phosphorylation deficiency 34, combined oxidative phosphorylation deficiency 35, combined oxidative phosphorylation deficiency 36, combined oxidative phosphorylation deficiency 55, combined oxidative phosphorylation deficiency 56, combined oxidative phosphorylation deficiency 57, combined oxidative phosphorylation deficiency 58, combined oxidative phosphorylation deficiency 59, combined oxidative phosphorylation deficiency 60

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

396 retrieved; paginated sample, class counts are floors:

178 likely benign, 154 uncertain significance, 24 conflicting classifications of pathogenicity, 19 benign/likely benign, 14 benign, 5 pathogenic/likely pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
162479	NM_004208.4(AIFM1):c.1264C>T (p.Arg422Trp)	AIFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
374094	NM_004208.4(AIFM1):c.1019T>C (p.Met340Thr)	AIFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30598	NM_024996.7(GFM1):c.748C>T (p.Arg250Trp)	GFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
509754	NM_024996.7(GFM1):c.689+908G>A	GFM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
162480	NM_004208.4(AIFM1):c.1265G>A (p.Arg422Gln)	RAB33A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2933356	NM_004208.4(AIFM1):c.1195G>A (p.Gly399Ser)	AIFM1	Likely pathogenic	criteria provided, single submitter
162481	NM_004208.4(AIFM1):c.1424C>T (p.Pro475Leu)	RAB33A	Likely pathogenic	criteria provided, single submitter
1204071	NM_004208.4(AIFM1):c.8G>A (p.Arg3Gln)	AIFM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1357142	NM_004208.4(AIFM1):c.1663G>A (p.Val555Ile)	AIFM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
162477	NM_004208.4(AIFM1):c.1030C>T (p.Leu344Phe)	AIFM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1954172	NM_004208.4(AIFM1):c.174T>A (p.Gly58=)	AIFM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2136048	NM_004208.4(AIFM1):c.1020G>T (p.Met340Ile)	AIFM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214081	NM_004208.4(AIFM1):c.1642C>T (p.Pro548Ser)	AIFM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2426260	NC_000023.10:g.(?128674417)(129299630_?)del	AIFM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
243069	NM_004208.4(AIFM1):c.1388G>T (p.Arg463Ile)	AIFM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2934504	NM_004208.4(AIFM1):c.258G>T (p.Lys86Asn)	AIFM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
373913	NM_004208.4(AIFM1):c.1646C>T (p.Ala549Val)	AIFM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
411665	NM_004208.4(AIFM1):c.1643C>T (p.Pro548Leu)	AIFM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
518002	NM_004208.4(AIFM1):c.1036G>A (p.Glu346Lys)	AIFM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
547098	NM_004208.4(AIFM1):c.556A>G (p.Asn186Asp)	AIFM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
594797	NM_004208.4(AIFM1):c.952G>A (p.Ala318Thr)	AIFM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
640384	NM_004208.4(AIFM1):c.1075+4G>C	AIFM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
655000	NM_004208.4(AIFM1):c.893G>A (p.Arg298Gln)	AIFM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
660192	NM_004208.4(AIFM1):c.141A>C (p.Glu47Asp)	AIFM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
836326	NM_004208.4(AIFM1):c.724A>G (p.Met242Val)	AIFM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
857026	NM_004208.4(AIFM1):c.340G>A (p.Ala114Thr)	AIFM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
958283	NM_004208.4(AIFM1):c.1045A>G (p.Ser349Gly)	AIFM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
982823	NM_004208.4(AIFM1):c.506C>T (p.Pro169Leu)	AIFM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
445310	NM_004208.4(AIFM1):c.170C>G (p.Ser57Cys)	RAB33A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
641733	NM_004208.4(AIFM1):c.1006G>A (p.Glu336Lys)	RAB33A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 5 · 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
OXA1L	Moderate	Autosomal recessive	combined oxidative phosphorylation deficiency
TOMM70	Limited	Autosomal recessive	combined oxidative phosphorylation deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GFM1	Orphanet:137681	Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1
AIFM1	Orphanet:101078	X-linked Charcot-Marie-Tooth disease type 4
AIFM1	Orphanet:139583	X-linked hereditary sensory and autonomic neuropathy with deafness
AIFM1	Orphanet:238329	Severe X-linked mitochondrial encephalomyopathy
AIFM1	Orphanet:83629	Leukoencephalopathy-spondyloepimetaphyseal dysplasia syndrome

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TOMM70	HGNC:11985	ENSG00000154174	O94826	Mitochondrial import receptor subunit TOM70	gencc
OXA1L	HGNC:8526	ENSG00000155463	Q15070	Mitochondrial inner membrane protein OXA1L	gencc
GFM1	HGNC:13780	ENSG00000168827	Q96RP9	Elongation factor G, mitochondrial	clinvar
TAMM41	HGNC:25187	ENSG00000144559	Q96BW9	Phosphatidate cytidylyltransferase, mitochondrial	clinvar
AIFM1	HGNC:8768	ENSG00000156709	O95831	Apoptosis-inducing factor 1, mitochondrial	clinvar
RAB33A	HGNC:9773	ENSG00000134594	Q14088	Ras-related protein Rab-33A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TOMM70	Mitochondrial import receptor subunit TOM70	Acts as a receptor of the preprotein translocase complex of the outer mitochondrial membrane (TOM complex).
OXA1L	Mitochondrial inner membrane protein OXA1L	Mitochondrial membrane insertase that mediates the cotranslational insertion of integral membrane proteins into the mitochondrial inner membrane.
GFM1	Elongation factor G, mitochondrial	Mitochondrial GTPase that catalyzes the GTP-dependent ribosomal translocation step during translation elongation.
TAMM41	Phosphatidate cytidylyltransferase, mitochondrial	Catalyzes the conversion of phosphatidic acid (PA) to CDP-diacylglycerol (CDP-DAG), an essential intermediate in the synthesis of phosphatidylglycerol, cardiolipin and phosphatidylinositol.
AIFM1	Apoptosis-inducing factor 1, mitochondrial	Functions both as NADH oxidoreductase and as regulator of apoptosis.
RAB33A	Ras-related protein Rab-33A	The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 5 · Druggable fraction: 0.17

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
Other/Unknown	5	1.5×	0.348
Enzyme (other)	1	2.0×	0.407

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TOMM70	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt
OXA1L	Other/Unknown	no		YidC/ALB3/OXA1/COX18, YidC/Oxa/ALB_C
GFM1	Other/Unknown	no		EFG_V-like, T_Tr_GTP-bd_dom, EFTu-like_2
TAMM41	Other/Unknown	no		Tam41
AIFM1	Enzyme (other)	yes	7.1.1.2	FAD/NAD-linked_Rdtase_dimer_sf, FAD/NAD-binding_dom, AIF_C
RAB33A	Other/Unknown	no		Small_GTPase, Small_GTP-bd, P-loop_NTPase

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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endothelial cell	2
Brodmann (1909) area 23	1
gluteal muscle	1
body of pancreas	1
diaphragm	1
hindlimb stylopod muscle	1
adrenal tissue	1
biceps brachii	1
granulocyte	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
adult mammalian kidney	1
apex of heart	1
heart left ventricle	1
C1 segment of cervical spinal cord	1
cortical plate	1
prefrontal cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TOMM70	299	ubiquitous	marker	endothelial cell, gluteal muscle, Brodmann (1909) area 23
OXA1L	290	ubiquitous	marker	hindlimb stylopod muscle, body of pancreas, diaphragm
GFM1	271	ubiquitous	marker	endothelial cell, biceps brachii, adrenal tissue
TAMM41	136	ubiquitous	yes	primordial germ cell in gonad, granulocyte, male germ line stem cell (sensu Vertebrata) in testis
AIFM1	273	ubiquitous	marker	apex of heart, adult mammalian kidney, heart left ventricle
RAB33A	207	ubiquitous	yes	cortical plate, C1 segment of cervical spinal cord, prefrontal cortex

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GFM1	5,789
AIFM1	4,780
OXA1L	2,947
TOMM70	2,629
RAB33A	1,603
TAMM41	869

Intra-cohort edges

A	B	Sources
OXA1L	TOMM70	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AIFM1	O95831	26
OXA1L	Q15070	17
GFM1	Q96RP9	5
TOMM70	O94826	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RAB33A	Q14088	81.85
TAMM41	Q96BW9	73.42

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 6 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Mitochondrial translation elongation	2	63.4×	0.005	GFM1, OXA1L
PINK1-PRKN Mediated Mitophagy	1	89.2×	0.039	TOMM70
SARS-CoV-1 activates/modulates innate immune responses	1	68.0×	0.039	TOMM70
TBC/RABGAPs	1	64.9×	0.039	RAB33A
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1	63.4×	0.039	TOMM70
RAB geranylgeranylation	1	43.3×	0.039	RAB33A
Mitochondrial protein import	1	42.0×	0.039	TOMM70
Complex I biogenesis	1	41.4×	0.039	OXA1L
Mitochondrial translation initiation	1	31.7×	0.042	OXA1L
Mitochondrial ribosome-associated quality control	1	30.7×	0.042	OXA1L
Mitochondrial translation termination	1	27.4×	0.042	OXA1L
SARS-CoV-2 activates/modulates innate and adaptive immune responses	1	22.3×	0.048	TOMM70
Ub-specific processing proteases	1	13.3×	0.073	TOMM70

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein import into mitochondrial intermembrane space	1	936.2×	0.009	AIFM1
response to thyroxine	1	936.2×	0.009	TOMM70
protein import into the intermembrane space via the disulfide relay system	1	936.2×	0.009	AIFM1
mitochondrial translational elongation	1	702.2×	0.009	GFM1
mitochondrial protein quality control	1	702.2×	0.009	OXA1L
cardiolipin biosynthetic process	1	561.7×	0.009	TAMM41
protein insertion into mitochondrial inner membrane from matrix	1	561.7×	0.009	OXA1L
mitochondrial respiratory chain complex assembly	1	468.1×	0.009	AIFM1
negative regulation of oxidoreductase activity	1	468.1×	0.009	OXA1L
positive regulation of necroptotic process	1	468.1×	0.009	AIFM1
cellular response to aldosterone	1	401.2×	0.010	AIFM1
mitochondrial proton-transporting ATP synthase complex assembly	1	351.1×	0.010	OXA1L
negative regulation of ATP-dependent activity	1	280.9×	0.011	OXA1L
response to L-glutamate	1	280.9×	0.011	AIFM1
negative regulation of cell growth involved in cardiac muscle cell development	1	234.1×	0.011	TOMM70
CDP-diacylglycerol biosynthetic process	1	216.1×	0.011	TAMM41
protein insertion into mitochondrial inner membrane	1	216.1×	0.011	TOMM70
protein insertion into mitochondrial outer membrane	1	216.1×	0.011	TOMM70
Rab protein signal transduction	1	165.2×	0.014	RAB33A
cellular response to nitric oxide	1	156.0×	0.014	AIFM1
antigen processing and presentation	1	117.0×	0.017	RAB33A
protein import into mitochondrial matrix	1	117.0×	0.017	TOMM70
protein tetramerization	1	104.0×	0.018	OXA1L
obsolete protein targeting to mitochondrion	1	96.8×	0.019	TOMM70
positive regulation of defense response to virus by host	1	87.8×	0.019	TOMM70
obsolete positive regulation of protein targeting to mitochondrion	1	82.6×	0.019	TOMM70
activation of innate immune response	1	80.2×	0.019	TOMM70
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	1	80.2×	0.019	AIFM1
mitochondrial respiratory chain complex I assembly	1	68.5×	0.021	OXA1L
cellular response to estradiol stimulus	1	68.5×	0.021	AIFM1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 6

Druggability breadth: 4 of 6 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TOMM70	0	0
OXA1L	0	0
GFM1	0	0
TAMM41	0	0
AIFM1	0	0
RAB33A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TOMM70	2	Binding:2
AIFM1	2	Binding:2
OXA1L	1	Binding:1
GFM1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AIFM1	7.1.1.2	NADH:ubiquinone reductase (H+-translocating)

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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	1	AIFM1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	TOMM70, OXA1L, GFM1, TAMM41, RAB33A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TOMM70	2	—
OXA1L	1	—
GFM1	1	—
TAMM41	0	—
AIFM1	2	—
RAB33A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.