YME1L1

Summary

YME1L1 (YME1 like 1 ATPase, HGNC:12843) is a protein-coding gene on chromosome 10p12.1, encoding ATP-dependent zinc metalloprotease YME1L1 (Q96TA2). ATP-dependent metalloprotease that catalyzes the degradation of folded and unfolded proteins with a suitable degron sequence in the mitochondrial intermembrane region. It is a selective cancer dependency (DepMap: 25.6% of cell lines).

The protein encoded by this gene is the human ortholog of yeast mitochondrial AAA metalloprotease, Yme1p. It is localized in the mitochondria and can functionally complement a yme1 disruptant yeast strain. It is proposed that this gene plays a role in mitochondrial protein metabolism and could be involved in mitochondrial pathologies. Three transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 10730 — RefSeq curated summary.

At a glance

• Gene–disease (curated): optic atrophy 11 (Moderate, GenCC) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 309 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 48
• Cancer dependency (DepMap): dependent in 25.6% of screened cell lines
• MANE Select transcript: NM_014263

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12843
Approved symbol	YME1L1
Name	YME1 like 1 ATPase
Location	10p12.1
Locus type	gene with protein product
Status	Approved
Aliases	YME1L
Ensembl gene	ENSG00000136758
Ensembl biotype	protein_coding
OMIM	607472
Entrez	10730

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 21 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000326799, ENST00000376016, ENST00000396296, ENST00000427324, ENST00000463270, ENST00000477432, ENST00000491542, ENST00000891814, ENST00000891815, ENST00000891816, ENST00000891817, ENST00000891818, ENST00000891819, ENST00000891820, ENST00000891821, ENST00000927723, ENST00000927724, ENST00000969514, ENST00000969515, ENST00000969516, ENST00000969517, ENST00000969518

RefSeq mRNA: 3 — MANE Select: NM_014263 NM_001253866, NM_014263, NM_139312

CCDS: CCDS58072, CCDS7151, CCDS7152

Canonical transcript exons

ENST00000376016 — 19 exons

Exon	Start	End
ENSE00001098492	27142387	27142485
ENSE00001098495	27136276	27136385
ENSE00003390188	27148906	27149040
ENSE00003438742	27145428	27145590
ENSE00003501683	27134831	27134981
ENSE00003548345	27134039	27134122
ENSE00003788271	27131859	27131941
ENSE00003899576	27110111	27112120
ENSE00003901327	27154178	27154384
ENSE00004034749	27122841	27122973
ENSE00004034750	27121386	27121448
ENSE00004034751	27116060	27116133
ENSE00004034753	27114521	27114607
ENSE00004034755	27119294	27119449
ENSE00004034756	27120435	27120547
ENSE00004034757	27117576	27117727
ENSE00004034758	27126696	27126786
ENSE00004034759	27116219	27116345
ENSE00004034760	27123547	27123699

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.36.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 60.6347 / max 320.5754, expressed in 1825 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
108748	47.3139	1823
108747	8.9130	1751
108751	1.7156	776
108750	1.3314	462
108752	1.2142	919
108749	0.1465	59

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
germinal epithelium of ovary	UBERON:0001304	99.36	gold quality
tibia	UBERON:0000979	99.27	gold quality
parietal pleura	UBERON:0002400	99.10	gold quality
visceral pleura	UBERON:0002401	99.01	gold quality
pleura	UBERON:0000977	98.96	gold quality
esophagus squamous epithelium	UBERON:0006920	98.95	gold quality
squamous epithelium	UBERON:0006914	98.61	gold quality
amniotic fluid	UBERON:0000173	98.59	gold quality
corpus epididymis	UBERON:0004359	98.57	gold quality
gingival epithelium	UBERON:0001949	98.54	gold quality
choroid plexus epithelium	UBERON:0003911	98.51	gold quality
gingiva	UBERON:0001828	98.29	gold quality
epithelium of esophagus	UBERON:0001976	98.28	gold quality
cauda epididymis	UBERON:0004360	98.27	gold quality
caput epididymis	UBERON:0004358	98.15	gold quality
pigmented layer of retina	UBERON:0001782	98.14	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.13	gold quality
epithelium of nasopharynx	UBERON:0001951	98.09	gold quality
superficial temporal artery	UBERON:0001614	98.07	gold quality
oral cavity	UBERON:0000167	98.05	gold quality
tongue squamous epithelium	UBERON:0006919	98.00	gold quality
parotid gland	UBERON:0001831	97.97	gold quality
cartilage tissue	UBERON:0002418	97.95	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.95	gold quality
biceps brachii	UBERON:0001507	97.91	gold quality
calcaneal tendon	UBERON:0003701	97.83	gold quality
nephron tubule	UBERON:0001231	97.79	gold quality
penis	UBERON:0000989	97.78	gold quality
colonic mucosa	UBERON:0000317	97.74	gold quality
heart right ventricle	UBERON:0002080	97.73	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.89
E-MTAB-7606	no	571.39
E-MTAB-4850	no	481.07

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, GLI3

miRNA regulators (miRDB)

114 targeting YME1L1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 25.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 12)

• Results reveal a crucial role for YME1L in the maintenance of mitochondrial inner-membrane proteostasis and in the proteolytic regulation of respiratory chain biogenesis. (PMID:22262461)
• YME1L degradation reduces mitochondrial proteolytic capacity during oxidative stress.Loss of YME1L compromises the regulation of mitochondrial inner membrane proteostasis. (PMID:25433032)
• differential stress-induced degradation of YME1L and OMA1 as a mechanism for sensitively adapting mitochondrial inner membrane protease activity and function in response to distinct types of cellular insults. (PMID:26923599)
• These results identify mutations in YME1L1 as a cause of a mitochondriopathy with optic nerve atrophy highlighting the importance of YME1L1 for mitochondrial functionality in humans. (PMID:27495975)
• Data show that engineered YME1L protease discriminates between degradation signals by amino acid composition, implying the use of sequence-specific signals in mitochondrial proteostasis. (PMID:27786171)
• YME1L1 was identified as the first NUMT (nuclear mtDNA) suppressor gene in human and demonstrate that inactivation of YME1L1 induces migration of mtDNA to the nuclear genome. (PMID:28356157)
• in the absence of ROMO1, mitochondria lose the inner membrane YME1L protease, which participates in OPA1 processing and ROMO1 turnover. While ROMO1 is dispensable for general protein import along the presequence pathway, we show that it participates in the dynamics of TIM21 during respiratory chain biogenesis and is specifically required for import of YME1L. (PMID:30598479)
• identify the mTORC1-LIPIN1-YME1L axis as a post-translational regulator of mitochondrial proteostasis at the interface between metabolism and mitochondrial dynamics (PMID:31695197)
• Regulation of mitochondrial plasticity by the i-AAA protease YME1L. (PMID:32087062)
• Examination of the Role of Mg(2+) in the Mechanism of Nucleotide Binding to the Monomeric YME1L AAA+ Domain. (PMID:33155794)
• The mitochondrial protein YME1 Like 1 is important for non-small cell lung cancer cell growth. (PMID:37063426)
• Targeting the mitochondrial protein YME1L to inhibit osteosarcoma cell growth in vitro and in vivo. (PMID:38769124)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	yme1l1a	ENSDARG00000075192
danio_rerio	yme1l1b	ENSDARG00000104401
mus_musculus	Yme1l1	ENSMUSG00000026775
rattus_norvegicus	Yme1l1	ENSRNOG00000055012
drosophila_melanogaster	YME1L	FBGN0034792
caenorhabditis_elegans		WBGENE00010842

Paralogs (2): AFG3L2 (ENSG00000141385), SPG7 (ENSG00000197912)

Protein

Protein identifiers

ATP-dependent zinc metalloprotease YME1L1 — Q96TA2 (reviewed: Q96TA2)

Alternative names: ATP-dependent metalloprotease FtsH1, Meg-4, Presenilin-associated metalloprotease, YME1-like protein 1

All UniProt accessions (5): Q96TA2, Q5T8D1, Q5T8D2, Q6PJ89, R4GNA5

UniProt curated annotations — full annotation on UniProt →

Function. ATP-dependent metalloprotease that catalyzes the degradation of folded and unfolded proteins with a suitable degron sequence in the mitochondrial intermembrane region. Plays an important role in regulating mitochondrial morphology and function by cleaving OPA1 at position S2, giving rise to a form of OPA1 that promotes maintenance of normal mitochondrial structure and mitochondrial protein metabolism. Ensures cell proliferation, maintains normal cristae morphology and complex I respiration activity, promotes antiapoptotic activity and protects mitochondria from the accumulation of oxidatively damaged membrane proteins. Required to control the accumulation of nonassembled respiratory chain subunits (NDUFB6, OX4 and ND1). Involved in the mitochondrial adaptation in response to various signals, such as stress or developmental cues, by mediating degradation of mitochondrial proteins to rewire the mitochondrial proteome. Catalyzes degradation of mitochondrial proteins, such as translocases, lipid transfer proteins and metabolic enzymes in response to nutrient starvation in order to limit mitochondrial biogenesis: mechanistically, YME1L is activated by decreased phosphatidylethanolamine levels caused by LPIN1 activity in response to mTORC1 inhibition. Acts as a regulator of adult neural stem cell self-renewal by promoting mitochondrial proteome rewiring, preserving neural stem and progenitor cells self-renewal. Required for normal, constitutive degradation of PRELID1. Catalyzes the degradation of OMA1 in response to membrane depolarization. Mediates degradation of TIMM17A downstream of the integrated stress response (ISR). Catalyzes degradation of MICU1 when MICU1 is not assembled via an interchain disulfide.

Subunit / interactions. Homohexamer; may also form heterohexamers. Exists in several complexes of 600-1100 kDa. Interacts with AFG1L.

Subcellular location. Mitochondrion inner membrane. Mitochondrion.

Tissue specificity. High expression in cardiac and skeletal muscle mitochondria.

Post-translational modifications. Proteolytically processed by mitochondrial processing peptidase (MPP) to generate the mature form. Degraded in an OMA1-dependent manner in response to oxidative stress.

Disease relevance. Optic atrophy 11 (OPA11) [MIM:617302] An autosomal recessive disease characterized by progressive visual loss in association with optic atrophy. Atrophy of the optic disk indicates a deficiency in the number of nerve fibers which arise in the retina and converge to form the optic disk, optic nerve, optic chiasm and optic tracts. OPA11 patients also manifest delayed psychomotor development, intellectual disability, ataxia, and leukoencephalopathy on brain imaging. The disease may be caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 zinc ion per subunit.

Miscellaneous. Mutagenesis of Glu-543 to Gln does not complement excessive accumulation of subunits (NDUFB6, COX4,ND1) due to YME1 deletion mutant. Probably has no ATPase activity.

Similarity. In the N-terminal section; belongs to the AAA ATPase family. In the C-terminal section; belongs to the peptidase M41 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q96TA2-1	1	yes
Q96TA2-2	2
Q96TA2-3	3

RefSeq proteins (3): NP_001240795, NP_055078, NP_647473 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000642	Peptidase_M41	Domain
IPR003593	AAA+_ATPase	Domain
IPR003959	ATPase_AAA_core	Domain
IPR003960	ATPase_AAA_CS	Conserved_site
IPR005936	FtsH	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR037219	Peptidase_M41-like	Homologous_superfamily
IPR041569	AAA_lid_3	Domain

Pfam: PF00004, PF01434, PF17862

Enzyme classification (BRENDA):

• EC 3.4.24.B18 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (20 total): binding site 9, topological domain 2, splice variant 2, mutagenesis site 2, chain 1, sequence variant 1, sequence conflict 1, transmembrane region 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96TA2-F1	70.79	0.42

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 600

Ligand- & substrate-binding residues (9): 387; 599; 603; 677; 341; 383; 384; 385; 386

Mutagenesis-validated functional residues (2):

Position	Phenotype
439	loss of atpase and protease activity. loss of prelid1 degradation. cannot restore oma1 degradation in yme1l-depleted cel
600	loss of protease activity. cannot restore oma1 degradation in yme1l-depleted cells.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-8949664	Processing of SMDT1
R-HSA-9837999	Mitochondrial protein degradation
R-HSA-9840373	Cellular response to mitochondrial stress

MSigDB gene sets: 296 (showing top): MULLIGHAN_NPM1_SIGNATURE_3_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOMF_METALLOPEPTIDASE_ACTIVITY, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, CREBP1_Q2, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GTGCCTT_MIR506, GOBP_STEM_CELL_DIVISION, GOBP_REGULATION_OF_MITOCHONDRION_ORGANIZATION, MORF_SKP1A, GOBP_PROTEIN_MATURATION, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, GOBP_REGULATION_OF_CELL_DIVISION, GOCC_MITOCHONDRIAL_ENVELOPE

GO Biological Process (12): protein quality control for misfolded or incompletely synthesized proteins (GO:0006515), mitochondrion organization (GO:0007005), cell population proliferation (GO:0008283), cellular response to starvation (GO:0009267), positive regulation of mitochondrial fusion (GO:0010636), protein hexamerization (GO:0034214), mitochondrial protein processing (GO:0034982), mitochondrial protein catabolic process (GO:0035694), negative regulation of apoptotic process (GO:0043066), neuronal stem cell population maintenance (GO:0097150), regulation of stem cell division (GO:2000035), proteolysis (GO:0006508)

GO Molecular Function (10): ATP-dependent peptidase activity (GO:0004176), metalloendopeptidase activity (GO:0004222), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), protein binding (GO:0005515), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), membrane (GO:0016020), nuclear body (GO:0016604)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Mitochondrial calcium ion transport	1
Metabolism of proteins	1
Cellular responses to stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein catabolic process	2
mitochondrion	2
peptidase activity	2
ATP-dependent activity	2
organelle organization	1
cellular process	1
cellular response to nutrient levels	1
cellular response to stress	1
response to starvation	1
mitochondrial fusion	1
regulation of mitochondrial fusion	1
positive regulation of organelle organization	1
positive regulation of developmental process	1
protein complex oligomerization	1
protein processing	1
mitochondrion organization	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
stem cell population maintenance	1
stem cell division	1
regulation of cell division	1
protein metabolic process	1
endopeptidase activity	1
metallopeptidase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

3866 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
YME1L1	OMA1	Q96E52	916
YME1L1	CLPX	O76031	905
YME1L1	PARL	Q9H300	903
YME1L1	A0A1W2PP11	A0A1W2PP11	898
YME1L1	CLPP	Q16740	854
YME1L1	CLPB	Q9H078	769
YME1L1	LONP1	P36776	740
YME1L1	HSPD1	P10809	735
YME1L1	TIMM17A	Q99595	703
YME1L1	HSPE1	P61604	702
YME1L1	MFN2	O95140	693
YME1L1	MFN1	Q8IWA4	693
YME1L1	PHB1	P35232	689
YME1L1	GRPEL1	Q9HAV7	687
YME1L1	FIS1	Q9Y3D6	680

IntAct

166 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
PKN3	ARHGAP10	psi-mi:“MI:0914”(association)	0.680
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
TIMMDC1	NDUFS8	psi-mi:“MI:0914”(association)	0.530
APOOL	MTX2	psi-mi:“MI:0914”(association)	0.530
SMARCB1	VWA8	psi-mi:“MI:0914”(association)	0.530
ODAD4	GNPAT	psi-mi:“MI:0914”(association)	0.530
SLC39A4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
PBXIP1	KCNN4	psi-mi:“MI:0914”(association)	0.530
TUBA1A	TUBAL3	psi-mi:“MI:0914”(association)	0.420
HTRA2	HAX1	psi-mi:“MI:2364”(proximity)	0.420
YME1L1		psi-mi:“MI:0915”(physical association)	0.370
YME1L1	MYOG	psi-mi:“MI:0915”(physical association)	0.370
YME1L1	BCL11A	psi-mi:“MI:0915”(physical association)	0.370
NDUFA11	NDUFS8	psi-mi:“MI:0914”(association)	0.350
NDUFA13	SLC22A20P	psi-mi:“MI:0914”(association)	0.350
Kif2c	MRPS12	psi-mi:“MI:0914”(association)	0.350
Tnpo1	CCHCR1	psi-mi:“MI:0914”(association)	0.350
Ncaph	ATP5MF-PTCD1	psi-mi:“MI:0914”(association)	0.350
Ppp4c	NAP1L1	psi-mi:“MI:0914”(association)	0.350
Shcbp1	DERL1	psi-mi:“MI:0914”(association)	0.350
Ubr5	SFI1	psi-mi:“MI:0914”(association)	0.350
Ercc6l	RPL17	psi-mi:“MI:0914”(association)	0.350
TBC1D9	SRSF2	psi-mi:“MI:0914”(association)	0.350

BioGRID (242): YME1L1 (Affinity Capture-RNA), ATP5A1 (Co-fractionation), YME1L1 (Co-fractionation), YME1L1 (Co-fractionation), YME1L1 (Affinity Capture-MS), YME1L1 (Synthetic Growth Defect), YME1L1 (Affinity Capture-MS), YME1L1 (Affinity Capture-MS), YME1L1 (Affinity Capture-MS), YME1L1 (Affinity Capture-MS), YME1L1 (Affinity Capture-MS), YME1L1 (Affinity Capture-MS), YME1L1 (Affinity Capture-MS), YME1L1 (Affinity Capture-MS), YME1L1 (Affinity Capture-MS)

ESM2 similar proteins: A0A061I403, A7SVT1, A8X181, B0B8S7, B0B970, B0BAF6, B0W429, B3MK83, B3N5J3, B4F6I5, B4GJC1, B4I1V5, B4JBN5, B4KFW6, B4LQT7, B4MUQ2, B4P0E1, B4Q4M7, B7F7B9, D8WUA4, F3YDF1, G7LCC3, O59824, O84707, O88967, P0DPS8, P32795, P39143, P45876, P46508, Q17A75, Q23544, Q29JP8, Q36795, Q3KKZ3, Q3KM61, Q55575, Q6AY47, Q6E0V2, Q6MDI5

Diamond homologs: A0L4S0, A0LN68, A0PXM8, A1AT11, A1URA3, A2ZVG7, A6TWP7, A8F7F7, A9BJK3, A9EXK6, B0B970, B0K5A3, B1GZK7, B2A3Q4, B2UE66, B3DV46, B3DY14, B4SCV5, B4U7U4, B7J0N5, B8D065, B8G4Q6, B8H444, B8J992, B9KXV3, B9L3S8, B9MPK5, C1F8X6, C5CES8, C6V4R9, C7M0M0, C7N1I1, C8WEG0, D0LWB8, D0MGU8, D1BLD0, D1C1U7, D1C8C0, D1CDT8, D3EZK2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
YME1L1	“up-regulates activity”	OPA1	cleavage

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 183 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Respiratory electron transport	8	6.9×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrion organization	8	8.4×	3e-03
protein phosphorylation	11	5.2×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

309 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	133
Likely benign	95
Benign	54

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
374984	NM_014263.4(YME1L1):c.445C>T (p.Arg149Trp)	Pathogenic
3362877	NM_014263.4(YME1L1):c.1999C>G (p.Leu667Val)	Likely pathogenic

SpliceAI

2504 predictions. Top by Δscore:

Variant	Effect	Δscore
10:27112116:GAGTC:G	acceptor_gain	1.0000
10:27112118:GTC:G	acceptor_gain	1.0000
10:27112118:GTCC:G	acceptor_loss	1.0000
10:27112119:TC:T	acceptor_gain	1.0000
10:27112119:TCCTG:T	acceptor_loss	1.0000
10:27112120:CC:C	acceptor_gain	1.0000
10:27112120:CCTG:C	acceptor_loss	1.0000
10:27112121:C:CC	acceptor_gain	1.0000
10:27112121:CTGAA:C	acceptor_loss	1.0000
10:27112122:T:A	acceptor_loss	1.0000
10:27114516:ATTAC:A	donor_gain	1.0000
10:27114519:AC:A	donor_gain	1.0000
10:27114520:CC:C	donor_gain	1.0000
10:27114608:C:CC	acceptor_gain	1.0000
10:27116054:TATTA:T	donor_loss	1.0000
10:27116056:TTAC:T	donor_loss	1.0000
10:27116057:TACCT:T	donor_loss	1.0000
10:27116058:ACCT:A	donor_loss	1.0000
10:27116059:CCTTT:C	donor_gain	1.0000
10:27116129:AGCAC:A	acceptor_gain	1.0000
10:27116130:GCAC:G	acceptor_gain	1.0000
10:27116131:CAC:C	acceptor_gain	1.0000
10:27116131:CACC:C	acceptor_gain	1.0000
10:27116132:AC:A	acceptor_gain	1.0000
10:27116133:CC:C	acceptor_gain	1.0000
10:27116134:C:CC	acceptor_gain	1.0000
10:27116134:C:T	acceptor_gain	1.0000
10:27116135:T:A	acceptor_loss	1.0000
10:27116139:A:AC	acceptor_gain	1.0000
10:27116139:A:C	acceptor_gain	1.0000

AlphaMissense

4696 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:27112062:A:G	L746P	1.000
10:27114525:A:G	L725P	1.000
10:27116073:C:T	G693E	1.000
10:27116085:A:T	V689D	1.000
10:27116097:G:T	A685E	1.000
10:27116098:C:G	A685P	1.000
10:27116121:T:A	D677V	1.000
10:27116121:T:C	D677G	1.000
10:27116121:T:G	D677A	1.000
10:27116130:G:T	A674D	1.000
10:27116253:C:A	E661D	1.000
10:27116253:C:G	E661D	1.000
10:27116258:C:G	A660P	1.000
10:27116269:C:T	G656E	1.000
10:27116270:C:G	G656R	1.000
10:27116270:C:T	G656R	1.000
10:27116296:A:G	L647P	1.000
10:27117580:C:T	G629E	1.000
10:27117581:C:G	G629R	1.000
10:27117581:C:T	G629R	1.000
10:27117595:C:G	R624P	1.000
10:27117655:G:T	A604D	1.000
10:27117656:C:G	A604P	1.000
10:27117661:C:T	G602D	1.000
10:27117670:T:G	H599P	1.000
10:27117671:G:C	H599D	1.000
10:27117676:G:T	A597E	1.000
10:27119338:A:T	V565D	1.000
10:27119363:C:G	A557P	1.000
10:27119372:C:G	A554P	1.000

dbSNP variants (sampled 300 via entrez): RS1000085929 (10:27143595 G>A), RS1000113887 (10:27125855 T>C), RS1000184104 (10:27143404 T>C), RS1000184528 (10:27127446 A>G), RS1000200052 (10:27137923 T>C), RS1000316782 (10:27117492 C>T), RS1000357280 (10:27149116 T>C), RS1000364745 (10:27130814 T>C), RS1000452101 (10:27149298 T>C), RS1000471775 (10:27123952 G>A,C), RS1000610016 (10:27117192 T>C), RS1000689389 (10:27147791 G>A,T), RS1000810049 (10:27125724 T>C,G), RS1000825039 (10:27148073 C>G), RS1000927616 (10:27149346 A>G)

Disease associations

OMIM: gene MIM:607472 | disease phenotypes: MIM:617302, MIM:250950

GenCC curated gene-disease

Disease	Classification	Inheritance
optic atrophy 11	Moderate	Autosomal recessive
autosomal recessive optic atrophy	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
optic atrophy 11	Limited	AR
mitochondrial disease	Limited	AR

Mondo (6): optic atrophy 11 (MONDO:0015011), long QT syndrome (MONDO:0002442), inherited retinal dystrophy (MONDO:0019118), 3-methylglutaconic aciduria (MONDO:0017359), microcephaly (MONDO:0001149), (MONDO:0014753)

Orphanet (2): OBSOLETE: Inherited retinal disorder (Orphanet:71862), 3-methylglutaconic aciduria (Orphanet:289902)

HPO phenotypes

48 total (30 of 48 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000365	Hearing impairment
HP:0000400	Macrotia
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000540	Hypermetropia
HP:0000545	Myopia
HP:0000609	Optic nerve hypoplasia
HP:0000646	Amblyopia
HP:0000648	Optic atrophy
HP:0000752	Hyperactivity
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001310	Dysmetria
HP:0001321	Cerebellar hypoplasia
HP:0001344	Absent speech
HP:0001349	Facial diplegia
HP:0001744	Splenomegaly
HP:0001776	Bilateral talipes equinovarus
HP:0002019	Constipation
HP:0002119	Ventriculomegaly
HP:0002151	Increased circulating lactate concentration
HP:0002188	Delayed CNS myelination
HP:0002305	Athetosis

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST008810_19	Smoking initiation (ever regular vs never regular)	2.000000e-08
GCST012207_9	Shigella-associated diarrhea	3.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005670	smoking initiation

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D058499	Retinal Dystrophies	C11.768.585.658
C579867	3-Methylglutaconic Aciduria (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	5
bisphenol A	affects expression, decreases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
arsenite	affects binding, decreases reaction, increases degradation	1
sodium arsenite	increases expression	1
K 7174	increases expression	1
abrine	decreases expression	1
jinfukang	decreases expression	1
picoxystrobin	increases expression	1
NSC 689534	increases expression, affects binding	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Acetaminophen	decreases expression	1
Copper	affects binding, increases expression	1
Cycloheximide	increases degradation, decreases reaction	1
Formaldehyde	increases expression	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Tunicamycin	increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	1
Aflatoxin B1	decreases methylation	1
Copper Sulfate	increases expression	1
Lactic Acid	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D9VX	Ubigene HEK293 YME1L1 KO	Transformed cell line	Female

Clinical trials (associated diseases)

122 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT00316459	PHASE1	COMPLETED	Study Evaluating the Effects of Multiple Oral Doses of ERB-041 on Cardiac Repolarization in Healthy Subjects
NCT01849003	PHASE1	COMPLETED	Study of the Effect of GS-6615 in Subjects With LQT-3
NCT02365532	PHASE1	COMPLETED	Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Adults
NCT02412098	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Hepatic Function
NCT02441829	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Renal Function
NCT05759962	PHASE1	COMPLETED	Phase 1 Study of LQT-1213 in Healthy Adults
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT06455826	PHASE1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)
NCT05906732	PHASE1/PHASE2	TERMINATED	Study of LQT-1213 on QTc-induced Prolongation in Healthy Adult Subjects (Part1) and on Congenital Long QT in Patients Diagnosed With Type 2 or 3 Long QT Syndrome (Part 2).
NCT00005176	Not specified	COMPLETED	Long QT Syndrome-Population Genetics and Cardiac Studies
NCT00005250	Not specified	COMPLETED	Linkage Study of Long QT Syndrome In An Amish Kindred
NCT00005367	Not specified	COMPLETED	Epidemiology of Long QTand Asian Sudden Death in Sleep
NCT00221832	Not specified	UNKNOWN	Molecular Genetic Screening and Identification of Congenital Arrhythmogenic Diseases
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT00335036	Not specified	TERMINATED	Pediatric Lead Extractability and Survival Evaluation (PLEASE)
NCT00399412	Not specified	COMPLETED	ECG Signal Collection From Long QT Syndrome, Wide QRS Complexes, Heart Failure, and Cardiac Resynchronization Patients
NCT00488254	Not specified	COMPLETED	The Long QT Syndrome in Pregnancy
NCT00588965	Not specified	COMPLETED	Effect of Beta-blocker Therapy on QTc Response in Exercise and Recovery in Normal Subjects
NCT01705925	Not specified	COMPLETED	Multicenter Evaluation of Children and Young Adults With Genotype Positive Long QT Syndrome
NCT01903564	Not specified	COMPLETED	Fetal and Neonatal Magnetophysiology
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02413450	Not specified	ENROLLING_BY_INVITATION	Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias
NCT02425189	Not specified	COMPLETED	The Canadian National Long QT Syndrome Registry
NCT02439645	Not specified	TERMINATED	A Registry to Determine the Clinical and Genetic Risk Factors for Torsade De Pointes
NCT02439658	Not specified	UNKNOWN	Genetics of QT Prolongation With Antiarrhythmics
NCT02549664	Not specified	COMPLETED	Exercise in Genetic Cardiovascular Conditions
NCT02581241	Not specified	COMPLETED	Abnormal QT-Response to the Sudden Tachycardia Provoked by Standing in Individuals With Drug-induced Long QT Syndrome