MARCHF6

Summary

MARCHF6 (membrane associated ring-CH-type finger 6, HGNC:30550) is a protein-coding gene on chromosome 5p15.2, encoding E3 ubiquitin-protein ligase MARCHF6 (O60337). Endoplasmic reticulum membrane-associated E3 ubiquitin ligase that plays a critical role in mitigating endoplasmic reticulum stress, the regulation of cholesterol and lipid homeostasis, and ferroptosis.

This gene encodes a member of a family of membrane-associated E3 ubiquitin ligases containing RING-CH-type zinc finger motifs. Ubiquitination of type II deiodinase by the encoded protein is an important regulatory step in thyroid hormone signalling. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 10299 — RefSeq curated summary.

At a glance

• Gene–disease (curated): benign adult familial myoclonic epilepsy (Supportive, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 138 total — 2 pathogenic
• Phenotypes (HPO): 20
• MANE Select transcript: NM_005885

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30550
Approved symbol	MARCHF6
Name	membrane associated ring-CH-type finger 6
Location	5p15.2
Locus type	gene with protein product
Status	Approved
Aliases	TEB4, MARCH-VI, RNF176
Ensembl gene	ENSG00000145495
Ensembl biotype	protein_coding
OMIM	613297
Entrez	10299

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 14 protein_coding, 5 retained_intron, 4 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000274140, ENST00000449913, ENST00000502795, ENST00000503788, ENST00000505253, ENST00000506131, ENST00000507863, ENST00000510792, ENST00000510872, ENST00000511802, ENST00000512449, ENST00000514312, ENST00000514961, ENST00000606497, ENST00000863549, ENST00000863550, ENST00000863551, ENST00000863552, ENST00000863553, ENST00000863554, ENST00000930189, ENST00000956723, ENST00000956724, ENST00000956725

RefSeq mRNA: 3 — MANE Select: NM_005885 NM_001270660, NM_001270661, NM_005885

CCDS: CCDS34135, CCDS59487, CCDS59488

Canonical transcript exons

ENST00000274140 — 26 exons

Exon	Start	End
ENSE00000970763	10400784	10400842
ENSE00000970784	10433594	10440388
ENSE00002032992	10353695	10353917
ENSE00003459075	10394753	10394785
ENSE00003467128	10411333	10411537
ENSE00003478162	10397293	10397344
ENSE00003508368	10377798	10377894
ENSE00003509177	10402059	10402139
ENSE00003516115	10405558	10405677
ENSE00003524739	10403407	10403541
ENSE00003529597	10402533	10402607
ENSE00003533544	10390332	10390500
ENSE00003538091	10414433	10414502
ENSE00003548887	10386994	10387066
ENSE00003554924	10426390	10426522
ENSE00003580178	10391542	10391731
ENSE00003580675	10407102	10407202
ENSE00003581150	10381800	10381943
ENSE00003581666	10417270	10417404
ENSE00003582403	10415488	10415669
ENSE00003584958	10394082	10394143
ENSE00003617480	10402384	10402452
ENSE00003657608	10429893	10430028
ENSE00003671789	10410139	10410276
ENSE00003686190	10378759	10378832
ENSE00003693606	10423735	10423824

Expression profiles

Bgee: expression breadth ubiquitous, 302 present calls, max score 99.37.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 111.8203 / max 1023.6016, expressed in 1825 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
55695	104.5691	1825
55696	6.4445	1545
55705	0.6240	219
55704	0.1827	57

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	99.37	gold quality
endothelial cell	CL:0000115	99.35	gold quality
gluteal muscle	UBERON:0002000	98.82	gold quality
CA1 field of hippocampus	UBERON:0003881	98.77	gold quality
middle temporal gyrus	UBERON:0002771	98.76	gold quality
cerebellar vermis	UBERON:0004720	98.72	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	98.71	gold quality
cortical plate	UBERON:0005343	98.70	gold quality
corpus callosum	UBERON:0002336	98.60	gold quality
pons	UBERON:0000988	98.59	gold quality
postcentral gyrus	UBERON:0002581	98.58	gold quality
inferior olivary complex	UBERON:0002127	98.52	gold quality
triceps brachii	UBERON:0001509	98.47	gold quality
ganglionic eminence	UBERON:0004023	98.47	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.47	gold quality
parietal lobe	UBERON:0001872	98.46	gold quality
caput epididymis	UBERON:0004358	98.46	gold quality
mucosa of paranasal sinus	UBERON:0005030	98.45	gold quality
germinal epithelium of ovary	UBERON:0001304	98.43	gold quality
entorhinal cortex	UBERON:0002728	98.42	gold quality
superior frontal gyrus	UBERON:0002661	98.36	gold quality
ventricular zone	UBERON:0003053	98.33	gold quality
cauda epididymis	UBERON:0004360	98.30	gold quality
tibia	UBERON:0000979	98.29	gold quality
medulla oblongata	UBERON:0001896	98.29	gold quality
superior vestibular nucleus	UBERON:0007227	98.28	gold quality
biceps brachii	UBERON:0001507	98.24	gold quality
renal medulla	UBERON:0000362	98.23	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.21	gold quality
parietal pleura	UBERON:0002400	98.20	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-130473	yes	5713.94
E-CURD-114	yes	6.86
E-GEOD-81608	no	15.86
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

360 targeting MARCHF6, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-3662	99.99	73.82	5684

Literature-anchored findings (GeneRIF, showing 17)

• analysis of yeast endoplasmic reticulum-localized ubiquitin ligase Doa10 and comparison with its human ortholog TEB4 (PMID:16373356)
• TEB4 interacts with and mediates loss of type 2 iodothyronine deiodinase (D2)activity, indicating that D2 ubiquitination and degradation can be tissue specific, depending on WSB-1 and TEB4 expression levels. (PMID:19651899)
• MARCH6 and squalene monooxygenase (SM) physically interact, and consistent with MARCH6 acting as an E3 ligase, its overexpression reduces SM abundance in a RING-dependent manner. (PMID:24449766)
• Data suggest that unsaturated fatty acids (oleate; oleoyl-CoA) stabilize SM/SQLE (squalene monooxygenase; catalyzes 1st oxygenation step in cholesterol synthesis) most likely via inhibition of poly-ubiquitination by MARCH6. (PMID:24840124)
• Loss of MARCH6 increases expression of SREBP-regulated genes involved in cholesterol biosynthesis and lipoprotein uptake. (PMID:26527619)
• Data suggest that human MARCH6 and Saccharomyces cerevisiae Doa10 ubiquitin ligases are functionally similar. (PMID:27068744)
• TRC8 and MARCH6 depletion altered the turnover of the tail-anchored protein heme oxygenase-1. (PMID:29519897)
• mutant NPC1 degradation is regulated by selective endoplasmic reticulum autophagy and MARCH6-dependent endoplasmic-reticulum-associated degradation (PMID:30202070)
• cholesterol reduced the levels of at least three known MARCH6 substrates, indicating that cholesterol-mediated MARCH6 stabilization increases its activity. (PMID:30545937)
• UBE2J2 as an important partner of MARCH6 for regulated degradation of the rate-limiting enzymes HMGCR and SQLE in cholesterol biosynthesis. (PMID:30658189)
• MARCH6 and AR expression are strongly correlated in primary prostate cancer tissues. This correlation is unrelated to androgen receptor signalling. MARCH6 and AR share common regulation by the transcription factor Sp1. (PMID:31422115)
• TTTTA/TTTCA repeat expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3. (PMID:31664039)
• the E3 ubiquitin ligase membrane-associated ring-CH-type finger 6 (MARCH6), known to control earlier rate-limiting steps in cholesterol synthesis, also control levels of LDM and the terminal cholesterol synthesis enzyme, 24-dehydrocholesterol reductase. (PMID:31904814)
• The MARCH6-SQLE Axis Controls Endothelial Cholesterol Homeostasis and Angiogenic Sprouting. (PMID:32755570)
• The E3 ubiquitin ligase MARCHF6 as a metabolic integrator in cholesterol synthesis and beyond. (PMID:33049405)
• MARCH6 promotes hepatocellular carcinoma development through up-regulation of ATF2. (PMID:34273954)
• MARCH6 promotes Papillary Thyroid Cancer development by destabilizing DHX9. (PMID:34512155)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	marchf6	ENSDARG00000076066
mus_musculus	Marchf6	ENSMUSG00000039100
rattus_norvegicus	Marchf6	ENSRNOG00000011066
drosophila_melanogaster	CG1317	FBGN0035333
caenorhabditis_elegans	marc-6	WBGENE00018847

Protein

Protein identifiers

E3 ubiquitin-protein ligase MARCHF6 — O60337 (reviewed: O60337)

Alternative names: Doa10 homolog, Membrane-associated RING finger protein 6, Membrane-associated RING-CH protein VI, Protein TEB-4, RING finger protein 176, RING-type E3 ubiquitin transferase MARCHF6

All UniProt accessions (3): O60337, A0A0B4J206, D6RHY7

UniProt curated annotations — full annotation on UniProt →

Function. Endoplasmic reticulum membrane-associated E3 ubiquitin ligase that plays a critical role in mitigating endoplasmic reticulum stress, the regulation of cholesterol and lipid homeostasis, and ferroptosis. Acts as a pivotal component of both the Ac/N-degron pathway (targeting the N-terminal acetyl group of substrates) and the ER-associated protein degradation-cytosol (ERAD-C) pathway (targeting misfolded substrates). For instance, mediates the degradation of Ac/N-degron-bearing proteins such as the G-protein regulator RGS2 and the lipid droplet protein PLIN2. Suppresses endoplasmic reticulum stress and ferroptosis through cytosolic POMC degradation. Prevents ferroptosis by acting as a NADPH sensor during lipid peroxidation through its C-terminal regulatory region. Facilitates also the degradation of selected endoplasmic reticulum proteins by associating with signal peptide peptidase for the turnover of endogenous tail-anchored proteins. Promotes ubiquitination of DIO2, leading to its degradation. By ubiquitinating and thereby modulating the stability of many proteins of the cholesterol pathway including SQLE, CYP51A1, CYP11A1 and HMGCR, acts as a crucial post-translational regulator of cholesterol synthesis.

Subunit / interactions. Interacts with DIO2. Interacts with SQLE.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Present in brain (at protein level).

Post-translational modifications. Auto-ubiquitinated, which results in proteasomal degradation. Deubiquitinated by USP19; protecting MARCHF6 from p97-mediated proteasomal degradation.

Disease relevance. Epilepsy, familial adult myoclonic, 3 (FAME3) [MIM:613608] A form of familial myoclonic epilepsy, a neurologic disorder characterized by cortical hand tremors, myoclonic jerks and occasional generalized or focal seizures with a non-progressive or very slowly progressive disease course. Usually, myoclonic tremor is the presenting symptom, characterized by tremulous finger movements and myoclonic jerks of the limbs increased by action and posture. In a minority of patients, seizures are the presenting symptom. Some patients exhibit mild cognitive impairment. FAME3 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The RING-CH-type zinc finger domain is required for E3 ligase activity.

Pathway. Protein modification; protein ubiquitination.

Isoforms (3)

UniProt ID	Names	Canonical?
O60337-4	1	yes
O60337-5	2
O60337-6	3

RefSeq proteins (3): NP_001257589, NP_001257590, NP_005876* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011016	Znf_RING-CH	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR056521	MARCHF6-like_C	Domain

Pfam: PF12906, PF23113

Enzyme classification (BRENDA):

• EC 2.3.2.27 — RING-type E3 ubiquitin transferase (BRENDA: 28 organisms, 138 substrates, 10 inhibitors, 1 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
[UBE2W]-S-UBIQUITINYL-L-CYSTEINE	0.3014	1

UniProt features (55 total): topological domain 15, transmembrane region 14, binding site 8, sequence conflict 6, mutagenesis site 4, splice variant 2, chain 1, zinc finger region 1, region of interest 1, compositionally biased region 1, modified residue 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60337-F1	78.23	0.33

Functional residue map

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

Ligand- & substrate-binding residues (8): 9; 12; 26; 28; 36; 39; 52; 55

Post-translational modifications (1): 1

Mutagenesis-validated functional residues (4):

Position	Phenotype
9	abolished auto-ubiquitination. loss of ubiquitin ligase activity.
571	complete loss of ac/n-degron recognition.
885	does not restore the degradation of plin2 in marchf6-knockout cells.
888	does not restore the degradation of plin2 in marchf6-knockout cells.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-901032	ER Quality Control Compartment (ERQC)
R-HSA-392499	Metabolism of proteins
R-HSA-446203	Asparagine N-linked glycosylation
R-HSA-532668	N-glycan trimming in the ER and Calnexin/Calreticulin cycle
R-HSA-597592	Post-translational protein modification
R-HSA-901042	Calnexin/calreticulin cycle

MSigDB gene sets: 381 (showing top): AGGAAGC_MIR5163P, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, LFA1_Q6, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, CGGAARNGGCNG_UNKNOWN, MORF_ATRX, GCM_ZNF198, GOBP_NEGATIVE_REGULATION_OF_STEROID_METABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, MODULE_182, MITSIADES_RESPONSE_TO_APLIDIN_DN, GOBP_NEGATIVE_REGULATION_OF_ALCOHOL_BIOSYNTHETIC_PROCESS, CREBP1_Q2

GO Biological Process (8): proteasomal protein catabolic process (GO:0010498), protein ubiquitination (GO:0016567), ERAD pathway (GO:0036503), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), negative regulation of cholesterol biosynthetic process (GO:0045541), protein K48-linked ubiquitination (GO:0070936), endoplasmic reticulum mannose trimming (GO:1904380), cholesterol biosynthetic process (GO:0006695)

GO Molecular Function (9): ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), enzyme binding (GO:0019899), ubiquitin conjugating enzyme binding (GO:0031624), ubiquitin protein ligase activity (GO:0061630), ubiquitin-specific protease binding (GO:1990381), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (5): ER ubiquitin ligase complex (GO:0000835), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), endoplasmic reticulum quality control compartment (GO:0044322)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Calnexin/calreticulin cycle	1
Post-translational protein modification	1
Asparagine N-linked glycosylation	1
Metabolism of proteins	1
N-glycan trimming in the ER and Calnexin/Calreticulin cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
proteasomal protein catabolic process	2
endoplasmic reticulum	2
cellular anatomical structure	2
protein catabolic process	1
protein modification by small protein conjugation	1
response to endoplasmic reticulum stress	1
response to chemical	1
ubiquitin-dependent protein catabolic process	1
cholesterol biosynthetic process	1
regulation of cholesterol biosynthetic process	1
negative regulation of cholesterol metabolic process	1
negative regulation of sterol biosynthetic process	1
negative regulation of alcohol biosynthetic process	1
protein polyubiquitination	1
protein alpha-1,2-demannosylation	1
endoplasmic reticulum quality control compartment	1
cholesterol metabolic process	1
sterol biosynthetic process	1
secondary alcohol biosynthetic process	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
protein binding	1
ubiquitin-like protein conjugating enzyme binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
protease binding	1
binding	1
catalytic activity	1
cation binding	1
cytoplasmic ubiquitin ligase complex	1
endoplasmic reticulum membrane	1
membrane protein complex	1
endoplasmic reticulum protein-containing complex	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1

Protein interactions and networks

STRING

1453 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MARCHF6	UBE2G2	P56554	994
MARCHF6	SYVN1	Q86TM6	908
MARCHF6	AMFR	P26442	906
MARCHF6	NPLOC4	Q8TAT6	847
MARCHF6	DERL1	Q9BUN8	833
MARCHF6	RNF5	Q99942	812
MARCHF6	UBE2J2	Q8N2K1	807
MARCHF6	UBR1	Q8IWV7	805
MARCHF6	UFD1	Q92890	793
MARCHF6	SEL1L	Q9UBV2	780
MARCHF6	VCP	P55072	774
MARCHF6	RNF139	Q8WU17	756
MARCHF6	UBE2J1	Q9Y385	742
MARCHF6	SQLE	Q14534	729
MARCHF6	OS9	Q13438	718

IntAct

44 interactions, top by confidence:

A	B	Type	Score
KIF22	KPNA4	psi-mi:“MI:0914”(association)	0.730
ADGRE2	MARCHF6	psi-mi:“MI:0915”(physical association)	0.560
MARCHF6	ADGRE2	psi-mi:“MI:0915”(physical association)	0.560
GPR21	TMEM120B	psi-mi:“MI:0914”(association)	0.530
RGS2	MARCHF6	psi-mi:“MI:0915”(physical association)	0.520
MARCHF6	RGS2	psi-mi:“MI:0915”(physical association)	0.520
SQLE	MARCHF6	psi-mi:“MI:0915”(physical association)	0.400
MARCHF6	ENPEP	psi-mi:“MI:0915”(physical association)	0.400
MARCHF6	BUD31	psi-mi:“MI:0915”(physical association)	0.370
MARCHF6		psi-mi:“MI:0915”(physical association)	0.370
Anapc13	ANAPC15	psi-mi:“MI:0914”(association)	0.350
Cdc26		psi-mi:“MI:0914”(association)	0.350
Cenph	CENPX	psi-mi:“MI:0914”(association)	0.350
TXNDC15	ORC4	psi-mi:“MI:0914”(association)	0.350
SLC17A2	PSMD11	psi-mi:“MI:0914”(association)	0.350
HTR3A	GPAA1	psi-mi:“MI:0914”(association)	0.350
GLRA2	MARCHF6	psi-mi:“MI:0914”(association)	0.350
ZDHHC7	MARCHF6	psi-mi:“MI:0914”(association)	0.350
CCDC47	ESYT2	psi-mi:“MI:0914”(association)	0.350
GPR88	POTEF	psi-mi:“MI:0914”(association)	0.350
SPSB4	CCDC85C	psi-mi:“MI:0914”(association)	0.350
TXNDC15	GET1	psi-mi:“MI:0914”(association)	0.350
MARCHF4	C2CD2L	psi-mi:“MI:0914”(association)	0.350
CMTM2	GAPDHS	psi-mi:“MI:0914”(association)	0.350
GLRB	GAPDHS	psi-mi:“MI:0914”(association)	0.350
MS4A15	ABCD4	psi-mi:“MI:0914”(association)	0.350
OR10H1	NRP1	psi-mi:“MI:0914”(association)	0.350

BioGRID (112): SQLE (Affinity Capture-Western), UBE2D2 (Reconstituted Complex), MARCH6 (Biochemical Activity), MARCH6 (Affinity Capture-MS), MARCH6 (Affinity Capture-MS), MARCH6 (Affinity Capture-MS), MARCH6 (Affinity Capture-MS), MARCH6 (Affinity Capture-MS), MARCH6 (Affinity Capture-MS), MARCH6 (Affinity Capture-MS), MARCH6 (Synthetic Lethality), MARCH6 (Affinity Capture-MS), MARCH6 (Affinity Capture-MS), MARCH6 (Affinity Capture-MS), MARCH6 (Affinity Capture-MS)

ESM2 similar proteins: A2AF53, A4FV75, A4K2N5, A4K2W1, A5A6S6, A6QL84, A6ZIQ8, A9JRA0, B1AZA5, D3ZEH5, D3ZXD8, E1BD52, O60337, P58749, Q08DE2, Q108U3, Q2TBU2, Q3SYY9, Q3TMP8, Q4R5E3, Q58DA4, Q5BJW3, Q5JZQ8, Q5R8H8, Q5R9W1, Q5RBJ7, Q5RFE0, Q5ZII3, Q62302, Q6UWH6, Q6ZQ89, Q78S06, Q7SYC7, Q7ZUA6, Q86W33, Q8CIF6, Q8K0B2, Q8N2H4, Q8NBJ9, Q8NFB2

Diamond homologs: A0JN69, A6NNE9, A6P320, F4JKK0, O60103, O60337, P40318, P90489, P90495, Q0IH10, Q0P496, Q0VD59, Q1LVZ2, Q28EX7, Q32L65, Q3TZ87, Q5I0I2, Q5PQ35, Q5R9W1, Q5T0T0, Q5XIE5, Q5XIV2, Q68FA7, Q6NZQ8, Q6ZQ89, Q80TE3, Q86UD3, Q86YJ5, Q8BRX9, Q8CBH7, Q8TCQ1, Q99M02, Q9DBD2, Q9P0N8, Q9P2E8, Q0X0A5, Q28IK8, Q3KNM2, Q3ZC24, Q5R9W2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	MARCHF6	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	84
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
635281	NM_005885.4(MARCHF6):c.19+2427TTTAT[641]	Pathogenic
694446	NC_000005.10:g.10356348_10356407TTTTA[(9_?)]TTTCA[(791_1035)]	Pathogenic

SpliceAI

3865 predictions. Top by Δscore:

Variant	Effect	Δscore
5:10353913:GGAAG:G	donor_gain	1.0000
5:10353914:GAAGG:G	donor_gain	1.0000
5:10353918:G:GG	donor_gain	1.0000
5:10353918:GT:G	donor_loss	1.0000
5:10353919:T:A	donor_loss	1.0000
5:10377790:A:AG	acceptor_gain	1.0000
5:10377790:ATT:A	acceptor_gain	1.0000
5:10377790:ATTG:A	acceptor_gain	1.0000
5:10377791:T:G	acceptor_gain	1.0000
5:10377792:T:A	acceptor_gain	1.0000
5:10377793:G:A	acceptor_gain	1.0000
5:10377794:GCAG:G	acceptor_loss	1.0000
5:10377795:CA:C	acceptor_loss	1.0000
5:10377796:A:AG	acceptor_gain	1.0000
5:10377796:A:C	acceptor_loss	1.0000
5:10377797:G:GC	acceptor_gain	1.0000
5:10377797:GA:G	acceptor_gain	1.0000
5:10377797:GAC:G	acceptor_gain	1.0000
5:10377797:GACA:G	acceptor_gain	1.0000
5:10377797:GACAT:G	acceptor_gain	1.0000
5:10377890:GAATG:G	donor_gain	1.0000
5:10377893:TGGT:T	donor_loss	1.0000
5:10377895:G:GC	donor_loss	1.0000
5:10377895:G:GG	donor_gain	1.0000
5:10377896:TAAGT:T	donor_loss	1.0000
5:10378757:A:AG	acceptor_gain	1.0000
5:10378758:G:GC	acceptor_gain	1.0000
5:10378758:GCTT:G	acceptor_gain	1.0000
5:10378758:GCTTA:G	acceptor_gain	1.0000
5:10378829:CCAA:C	donor_gain	1.0000

AlphaMissense

5904 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:10377801:T:A	I8K	1.000
5:10377803:T:A	C9S	1.000
5:10377803:T:C	C9R	1.000
5:10377803:T:G	C9G	1.000
5:10377804:G:A	C9Y	1.000
5:10377804:G:C	C9S	1.000
5:10377804:G:T	C9F	1.000
5:10377805:T:G	C9W	1.000
5:10377806:A:G	R10G	1.000
5:10377807:G:C	R10T	1.000
5:10377807:G:T	R10I	1.000
5:10377808:A:C	R10S	1.000
5:10377808:A:T	R10S	1.000
5:10377809:G:A	V11M	1.000
5:10377809:G:C	V11L	1.000
5:10377809:G:T	V11L	1.000
5:10377810:T:A	V11E	1.000
5:10377810:T:C	V11A	1.000
5:10377812:T:A	C12S	1.000
5:10377812:T:C	C12R	1.000
5:10377812:T:G	C12G	1.000
5:10377813:G:A	C12Y	1.000
5:10377813:G:C	C12S	1.000
5:10377813:G:T	C12F	1.000
5:10377814:T:G	C12W	1.000
5:10377815:C:G	R13G	1.000
5:10377815:C:T	R13W	1.000
5:10377816:G:A	R13Q	1.000
5:10377816:G:C	R13P	1.000
5:10377816:G:T	R13L	1.000

dbSNP variants (sampled 300 via entrez): RS1000012748 (5:10405999 G>A), RS1000029495 (5:10380216 A>G), RS1000031936 (5:10423553 T>G), RS1000032448 (5:10380361 G>A,T), RS1000054202 (5:10368124 G>T), RS1000066431 (5:10407848 CG>C), RS1000070795 (5:10374177 T>G), RS1000143603 (5:10369324 G>T), RS1000183395 (5:10433426 C>G,T), RS1000190644 (5:10417332 C>G,T), RS1000217017 (5:10426222 C>T), RS1000217385 (5:10359116 T>C), RS1000235625 (5:10375257 C>T), RS1000262376 (5:10352602 T>C), RS1000307308 (5:10414171 T>C)

Disease associations

OMIM: gene MIM:613297 | disease phenotypes: MIM:613608

GenCC curated gene-disease

Disease	Classification	Inheritance
benign adult familial myoclonic epilepsy	Supportive	Autosomal dominant

Mondo (2): epilepsy, familial adult myoclonic, 3 (MONDO:0013322), benign adult familial myoclonic epilepsy (MONDO:0019448)

Orphanet (1): Familial adult myoclonic epilepsy (Orphanet:86814)

HPO phenotypes

20 total (20 of 20 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001249	Intellectual disability
HP:0001288	Gait disturbance
HP:0001312	Giant somatosensory evoked potentials
HP:0001336	Myoclonus
HP:0001337	Tremor
HP:0001340	Enhancement of the C-reflex
HP:0001351	Jerk-locked premyoclonus spikes
HP:0002069	Bilateral tonic-clonic seizure
HP:0002197	Generalized-onset seizure
HP:0002315	Headache
HP:0002353	EEG abnormality
HP:0002378	Hand tremor
HP:0003596	Middle age onset
HP:0003621	Juvenile onset
HP:0003680	Nonprogressive
HP:0007359	Focal-onset seizure
HP:0010852	EEG with photoparoxysmal response
HP:0011462	Young adult onset
HP:0100576	Amaurosis fugax

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001448_3	Body mass index	4.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567098	Epilepsy, Familial Adult Myoclonic, 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

43 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression	3
aristolochic acid I	decreases expression	1
CB-5083	increases stability	1
bisphenol F	increases expression, affects cotreatment	1
2,4,6-tribromophenol	decreases expression	1
bisphenol A	decreases expression	1
25-hydroxycholesterol	increases stability	1
decabromobiphenyl ether	decreases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
tetrabromobisphenol A	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	increases stability	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
2,6-diaminopyridine-3,5-bis(thiocyanate)	increases stability	1
Irinotecan	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Vorinostat	decreases expression	1
Arsenic	affects methylation	1
Betaine	decreases stability, decreases reaction	1
Cholesterol	increases stability, increases reaction, decreases reaction, decreases stability, increases degradation (+1 more)	1
Curcumin	increases expression	1
Desmosterol	increases stability	1
Dexamethasone	affects cotreatment, increases expression	1
Diethylstilbestrol	increases expression	1

Clinical trials (associated diseases)

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