AMFR

Summary

AMFR (autocrine motility factor receptor, HGNC:463) is a protein-coding gene on chromosome 16q13, encoding E3 ubiquitin-protein ligase AMFR (Q9UKV5). E3 ubiquitin-protein ligase that mediates the polyubiquitination of lysine and cysteine residues on target proteins, such as CD3D, CYP3A4, CFTR, INSIG1, SOAT2/ACAT2 and APOB for proteasomal degradation.

This locus encodes a glycosylated transmembrane receptor. Its ligand, autocrine motility factor, is a tumor motility-stimulating protein secreted by tumor cells. The encoded receptor is also a member of the E3 ubiquitin ligase family of proteins. It catalyzes ubiquitination and endoplasmic reticulum-associated degradation of specific proteins.

Source: NCBI Gene 267 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spastic paraplegia 89, autosomal recessive (Strong, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 113 total — 8 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 17
• MANE Select transcript: NM_001144

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:463
Approved symbol	AMFR
Name	autocrine motility factor receptor
Location	16q13
Locus type	gene with protein product
Status	Approved
Aliases	RNF45, gp78
Ensembl gene	ENSG00000159461
Ensembl biotype	protein_coding
OMIM	603243
Entrez	267

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 16 protein_coding, 5 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000290649, ENST00000492830, ENST00000563285, ENST00000563664, ENST00000564283, ENST00000565445, ENST00000566334, ENST00000566757, ENST00000567738, ENST00000568325, ENST00000568657, ENST00000568762, ENST00000861439, ENST00000861440, ENST00000861441, ENST00000861442, ENST00000861443, ENST00000861444, ENST00000861445, ENST00000861446, ENST00000861447, ENST00000957771, ENST00000957772

RefSeq mRNA: 3 — MANE Select: NM_001144 NM_001144, NM_001323511, NM_001323512

CCDS: CCDS10758

Canonical transcript exons

ENST00000290649 — 14 exons

Exon	Start	End
ENSE00001045776	56402985	56403118
ENSE00001045783	56389185	56389375
ENSE00001108656	56404909	56405041
ENSE00001108659	56407964	56408116
ENSE00001108663	56405204	56405244
ENSE00001204531	56361452	56363056
ENSE00001233636	56425073	56425545
ENSE00003373462	56385919	56386022
ENSE00003413886	56367444	56367527
ENSE00003543756	56363921	56364105
ENSE00003597038	56401733	56401843
ENSE00003608109	56369193	56369327
ENSE00003611280	56414252	56414344
ENSE00003687814	56409424	56409588

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 98.82.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.9321 / max 133.0981, expressed in 1817 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
157476	22.7088	1814
157475	0.3985	205
157477	0.3491	150
157474	0.2026	88
157472	0.1344	54
157473	0.0693	24
157470	0.0324	9
157469	0.0214	7
157471	0.0136	4
157466	0.0019	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	98.82	gold quality
adrenal tissue	UBERON:0018303	98.29	gold quality
right testis	UBERON:0004534	98.06	gold quality
left testis	UBERON:0004533	98.01	gold quality
gastrocnemius	UBERON:0001388	97.76	gold quality
muscle of leg	UBERON:0001383	97.61	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.17	gold quality
metanephros cortex	UBERON:0010533	97.15	gold quality
right adrenal gland cortex	UBERON:0035827	96.83	gold quality
calcaneal tendon	UBERON:0003701	96.62	gold quality
ventricular zone	UBERON:0003053	96.42	gold quality
lower esophagus mucosa	UBERON:0035834	96.37	gold quality
right adrenal gland	UBERON:0001233	96.33	gold quality
left adrenal gland	UBERON:0001234	96.11	gold quality
left adrenal gland cortex	UBERON:0035825	95.92	gold quality
colonic epithelium	UBERON:0000397	95.84	gold quality
adrenal gland	UBERON:0002369	95.77	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.75	gold quality
right lobe of liver	UBERON:0001114	95.52	gold quality
adrenal cortex	UBERON:0001235	95.30	gold quality
endocervix	UBERON:0000458	95.09	gold quality
gall bladder	UBERON:0002110	95.02	gold quality
islet of Langerhans	UBERON:0000006	94.96	gold quality
tibial nerve	UBERON:0001323	94.94	gold quality
testis	UBERON:0000473	94.90	gold quality
ectocervix	UBERON:0012249	94.81	gold quality
right coronary artery	UBERON:0001625	94.73	gold quality
prefrontal cortex	UBERON:0000451	94.70	gold quality
spinal cord	UBERON:0002240	94.59	gold quality
left ovary	UBERON:0002119	94.47	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	10649.53
E-ANND-3	yes	8.42
E-GEOD-70580	no	296.53
E-MTAB-9067	no	5.86
E-GEOD-83139	no	2.80

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

89 targeting AMFR, 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-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
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-5193	100.00	67.26	1744
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-6499-3P	99.90	66.38	1212

Literature-anchored findings (GeneRIF, showing 40)

• hippocampal expression of NLK and its receptor gp78 is associated with maze learning in rats. (PMID:11902125)
• In a prospective study we have also analyzed AMF receptor protein expression in primary tumors of 54 skin melanoma patients using IHC (PMID:12067203)
• demonstrate that GP78 is a bona fide E3 ligase in the apoB ER-associated degradation pathway (PMID:12670940)
• Autocrine motility factor receptor may contribute to tumor progression and AMF-R gene expression can serve as a useful prognostic marker in non-small cell lung cancers (NSCLC). (PMID:12962414)
• data provide evidence that the AMFR sequence coding for a seven-transmembrane domain E3 ubiquitin ligase codes for the gp78/AMFR protein recognized by the 3F3A mAb; the 3F3A mAb selectively recognizes a subpopulation of AMFR localized to an ER subdomain (PMID:15303277)
• Results identify gp78 as the E3 that initiates sterol-accelerated degradation of reductase, and Insig-1 as a bridge between gp78/VCP and the reductase substrate. (PMID:16168377)
• AMFR expression predicts an unfavourable surgical outcome in patients with stage I pulmonary adenocarcinomas (PMID:16184720)
• gp78-mediated ubiquitylation is an early step in endoplasmic reticulum -associated degradation (PMID:16407162)
• N-glyco side-chain of AMFR is a trigger and that interaction between the 117-C-terminal part of AMF and the extracellular core protein of AMFR is needed during AMF-AMFR interactions (PMID:16563432)
• These data indicate that gp78 assumes multiple unique quality control roles over ATZ, including the facilitation of degradation and inhibition of aggregation of ATZ. (PMID:16979136)
• Insig-1 sterol-regulated degradation is mediated by the membrane-bound ubiquitin ligase gp78 (PMID:17043353)
• the receptor molecule for AMF/NLK/MF in leukemic differentiation is not gp78 (PMID:17071500)
• Findings suggest a strong correlation between the expression of AMFR and RhoC and a correlation between them and invasion and metastasis of hepatocellular carcinoma. (PMID:17265125)
• Ube2g2/gp78-mediated polyubiquitination involves preassembly of Lys 48-linked ubiquitin chains at the catalytic cysteine of Ube2g2 (PMID:17310145)
• This study identifies Ufd1 as a cofactor of gp78, reveals an unappreciated function of Ufd1 in the ubiquitination reaction during endoplasmic reticulum -associated degradation, and illustrates that Ufd1 plays a critical role in cholesterol metabolism. (PMID:17681147)
• SVIP is an endogenous inhibitor of ERAD that acts through regulating the assembly of the gp78-p97/VCP-Derlin1 complex. (PMID:17872946)
• gp78 promotes sarcoma metastasis by targeting KAI1 for degradation (PMID:18037895)
• both UBC7/gp78 and UbcH5a/CHIP may be involved in CYP3A4 ER-associated degradation, although their relative physiological contribution remains to be established (PMID:19103148)
• The G2BR domain within the E3 gp78 binds selectively and with high affinity to the E2 Ube2g2. (PMID:19560420)
• Gp78 promotes SOD1 and ataxin-3 degradation in endoplasmic reticulum. (PMID:19661182)
• The results support that gp78 is an E3 targeting CFTRDeltaF508 for degradation and Hrd1 inhibits CFTRDeltaF508 degradation by acting as an E3 for gp78. (PMID:19828134)
• Hrd1 targets gp78 for proteasomal degradation independent of the ubiquitin ligase activity of gp78, without evidence of a reciprocal effect. (PMID:19835843)
• These data demonstrate a role of the E3 ubiquitin ligases in CTA1 retro-translocation. (PMID:19864457)
• KAI1 has a role in promotion of cell proliferation and mammary gland hyperplasia by the gp78 ubiquitin ligase (PMID:20089858)
• AMFR pathway promotes invasion of esophageal squamous cell cancer cells (PMID:20504226)
• cell surface expression of AMFR is associated with progression in Chronic lymphocytic leukemia (PMID:20574759)
• identify two ER membrane proteins, SPFH2 and TMUB1, as associated proteins of gp78, a membrane-bound ubiquitin ligase that mediates sterol-accelerated ERAD of the cholesterol biosynthetic enzyme HMG-CoA reductase. (PMID:21343306)
• Delivery of ubiquitylated substrate to the central ER was regulated by ubiquitin chain elongation and opposing actions of gp78 CUE domain interactions and p97 recruitment. (PMID:22328510)
• This review summarizes the structure and function of GP78, and its importance in both physiological and pathological processes.[review] (PMID:22812524)
• The GP78 CUE domain functions to both facilitate substrate binding and enable switching between adjacent ubiquitin molecules of a growing chain to enable processivity in ubiquitination. (PMID:23123110)
• A novel role for the endoplasmic reticulum-associated Gp78 ubiquitin ligase and the Mfn1 mitochondrial fusion factor in mitophagy. (PMID:23427266)
• gp78 is expressed specifically in human prostate cancer rather than normal prostate tissues, it could be a putative biomarker for prostate cancer diagnosis. (PMID:23666464)
• gp78 is a ubiquitination machine where multiple E2-binding sites coordinately facilitate processive ubiquitination. (PMID:23942235)
• data thus implicate two parallel pathways by which Gp78 regulates MAVS signaling (PMID:24285545)
• The authors identify USP13 as a gp78-associated deubiquitinase that eliminates ubiquitin conjugates from Ubl4A to maintain the functionality of Bag6. (PMID:24424410)
• High AMFR expression is associated with invasion depth and lymph node metastasis in gastric cancer. (PMID:24568530)
• The ubiquitin ligase gp78, known for its role in protein quality control, is critical for unglycosylated PrP ubiquitylation and degradation. (PMID:24714645)
• Our data uncovers a previously unknown functional link between gp78 and TRIM25 and provides mechanistic insight into gp78-mediated protein ubiquitylation. (PMID:24810856)
• DGAT2 is regulated by gp78-associated endoplasmic-reticulum-associated degradation at the post-translational level. (PMID:24820123)
• Data show that autocrine motility factor receptor (AMFR) and NOTCH1 protein are the direct target genes of microRNA miR-139-5p in colorectal cancer (CRC). (PMID:25149074)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	amfra	ENSDARG00000020218
danio_rerio	amfrb	ENSDARG00000105578
mus_musculus	Amfr	ENSMUSG00000031751
rattus_norvegicus	Amfr	ENSRNOG00000055446
caenorhabditis_elegans	hrdl-1	WBGENE00009164

Paralogs (4): RNF145 (ENSG00000145860), SYVN1 (ENSG00000162298), RNF139 (ENSG00000170881), DZIP3 (ENSG00000198919)

Protein

Protein identifiers

E3 ubiquitin-protein ligase AMFR — Q9UKV5 (reviewed: Q9UKV5)

Alternative names: Autocrine motility factor receptor, RING finger protein 45, gp78

All UniProt accessions (5): Q9UKV5, H3BQM3, H3BRK9, H3BSK3, R4GNG2

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that mediates the polyubiquitination of lysine and cysteine residues on target proteins, such as CD3D, CYP3A4, CFTR, INSIG1, SOAT2/ACAT2 and APOB for proteasomal degradation. Component of a VCP/p97-AMFR/gp78 complex that participates in the final step of endoplasmic reticulum-associated degradation (ERAD). The VCP/p97-AMFR/gp78 complex is involved in the sterol-accelerated ERAD degradation of HMGCR through binding to the HMGCR-INSIG1 complex at the ER membrane. In addition, interaction of AMFR with AUP1 facilitates interaction of AMFR with ubiquitin-conjugating enzyme UBE2G2 and ubiquitin ligase RNF139, leading to sterol-induced HMGCR ubiquitination. The ubiquitinated HMGCR is then released from the ER into the cytosol for subsequent destruction. In addition to ubiquitination on lysine residues, catalyzes ubiquitination on cysteine residues: together with INSIG1, mediates polyubiquitination of SOAT2/ACAT2 at ‘Cys-277’, leading to its degradation when the lipid levels are low. Catalyzes ubiquitination and subsequent degradation of INSIG1 when cells are depleted of sterols. Mediates polyubiquitination of INSIG2 at ‘Cys-215’ in some tissues, leading to its degradation. Also regulates ERAD through the ubiquitination of UBL4A a component of the BAG6/BAT3 complex. Also acts as a scaffold protein to assemble a complex that couples ubiquitination, retranslocation and deglycosylation. Mediates tumor invasion and metastasis as a receptor for the GPI/autocrine motility factor. In association with LMBR1L and UBAC2, negatively regulates the canonical Wnt signaling pathway in the lymphocytes by promoting the ubiquitin-mediated degradation of CTNNB1 and Wnt receptors FZD6 and LRP6. Regulates NF-kappa-B and MAPK signaling pathways by mediating ‘Lys-27’-linked polyubiquitination of TAB3 and promoting subsequent TAK1/MAP3K7 activation. Required for proper lipid homeostasis.

Subunit / interactions. Interacts with RNF5. Also forms an ERAD complex containing VCP/p97, NGLY1; PSMC1; SAKS1 and RAD23B required for coupling retrotranslocation, ubiquitination and deglycosylation. Interacts with DERL1. Interacts (through a region distinct from the RING finger) with UBE2G2/UBC7. Component of the VCP/p97-AMFR/gp78 complex that enhances VCP/p97 binding to polyubiquitinated proteins for their degradation by the endoplasmic reticulum-associated degradation (ERAD) pathway. Interacts (via the VIM) with VCP/p97. Interacts (via its membrane domain) with INSIG1; the interaction initiates the sterol-mediated ubiquitination and degradation of HMGCR by the ERAD pathway. Interacts with AUP1, UBE2G2 and RNF139/TRC8; interaction with AUP1 facilitates interaction of AMFR with ubiquitin-conjugating enzyme UBE2G2 and ubiquitin ligase RNF139, leading to sterol-induced ubiquitination of HMGCR and its subsequent proteasomal degradation. Interacts with BAG6. Interacts with USP13 (via UBA 2 domain); the interaction is direct. Interacts with LMBR1L. Interacts with UBAC2 and CTNNB1. Interacts with C18orf32. (Microbial infection) Interacts with Staphylococcus aureus HIgB; this interaction regulates AMFR-mediated inflammation by promoting TAB3 ubiquitination to promote TAB3-TAK1 complex formation.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Widely expressed.

Post-translational modifications. Palmitoylation of the RING-type zing finger by ZDHHC6 promotes localization to the peripheral endoplasmic reticulum.

Disease relevance. Spastic paraplegia 89, autosomal recessive (SPG89) [MIM:620379] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or weakness and stiffness may spread to other parts of the body. SPG89 affected individuals show delayed motor development, abnormal spastic gait, and hyperreflexia of the lower limbs. Some patients may have mildly impaired intellectual development or learning difficulties. SPG89 disease onset is in the first years of life. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The CUE domain is required for recognition of misfolded proteins such as mutant CFTR. The VCP/p97-interacting motif (VIM) is sufficient for binding VCP/p97 to form a complex capable of transferring VCP/p97 from the cytosol to microsomes.

Pathway. Protein modification; protein ubiquitination.

RefSeq proteins (3): NP_001135, NP_001310440, NP_001310441 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR003892	CUE	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR040675	AMFR_Ube2g2-bd	Domain
IPR057992	TPR_SYVN1_N	Domain

Pfam: PF02845, PF13639, PF18442, PF25563

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 (46 total): transmembrane region 7, helix 7, mutagenesis site 6, sequence variant 5, strand 5, region of interest 4, sequence conflict 4, modified residue 3, compositionally biased region 2, chain 1, domain 1, zinc finger region 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
4G3O	X-RAY DIFFRACTION	1.6
3H8K	X-RAY DIFFRACTION	1.8
3TIW	X-RAY DIFFRACTION	1.8
8T0S	X-RAY DIFFRACTION	1.95
4LAD	X-RAY DIFFRACTION	2.3
3FSH	X-RAY DIFFRACTION	2.76
2EJS	SOLUTION NMR
2LVN	SOLUTION NMR
2LVO	SOLUTION NMR
2LVP	SOLUTION NMR
2LVQ	SOLUTION NMR
2LXH	SOLUTION NMR
2LXP	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UKV5-F1	73.30	0.27

Functional residue map

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

Post-translational modifications (3): 516, 523, 542

Mutagenesis-validated functional residues (6):

Position	Phenotype
341–344	decreased palmitoylation.
346	abolished binding to tab3.
356	decreased palmitoylation. no degradation of hmgcr.
364	decreased palmitoylation.
375–378	decreased palmitoylation.
379	abolished binding to tab3.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

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

MSigDB gene sets: 280 (showing top): MORF_RAGE, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_COGNITION, GOBP_BEHAVIOR, PAX4_01, MORF_MSH3, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, MORF_BRCA1, MORF_ATRX, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, MORF_ESR1, IIZUKA_LIVER_CANCER_PROGRESSION_L1_G1_UP, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS

GO Biological Process (16): protein polyubiquitination (GO:0000209), ubiquitin-dependent protein catabolic process (GO:0006511), signal transduction (GO:0007165), learning or memory (GO:0007611), Wnt signaling pathway (GO:0016055), endoplasmic reticulum unfolded protein response (GO:0030968), ERAD pathway (GO:0036503), non-canonical NF-kappaB signal transduction (GO:0038061), protein K27-linked ubiquitination (GO:0044314), protein autoubiquitination (GO:0051865), protein K48-linked ubiquitination (GO:0070936), negative regulation of canonical Wnt signaling pathway (GO:0090090), endoplasmic reticulum mannose trimming (GO:1904380), regulation of SREBP signaling pathway (GO:2000638), canonical NF-kappaB signal transduction (GO:0007249), protein ubiquitination (GO:0016567)

GO Molecular Function (14): ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), protein-macromolecule adaptor activity (GO:0030674), ubiquitin-ubiquitin ligase activity (GO:0034450), signaling receptor activity (GO:0038023), identical protein binding (GO:0042802), ubiquitin binding (GO:0043130), protein-folding chaperone binding (GO:0051087), ubiquitin protein ligase activity (GO:0061630), BAT3 complex binding (GO:1904288), ubiquitin-specific protease binding (GO:1990381), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (13): ubiquitin ligase complex (GO:0000151), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), cytosol (GO:0005829), membrane (GO:0016020), dendrite (GO:0030425), growth cone (GO:0030426), protein-containing complex (GO:0032991), Derlin-1 retrotranslocation complex (GO:0036513), neuronal cell body (GO:0043025), endoplasmic reticulum quality control compartment (GO:0044322), perinuclear region of cytoplasm (GO:0048471)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Asparagine N-linked glycosylation	1
Calnexin/calreticulin cycle	1
Post-translational protein modification	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
cytoplasm	4
cellular anatomical structure	4
protein ubiquitination	3
protein binding	3
response to endoplasmic reticulum stress	2
intracellular signaling cassette	2
protein polyubiquitination	2
endomembrane system	2
intracellular membrane-bounded organelle	2
modification-dependent protein catabolic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
behavior	1
cognition	1
cell surface receptor signaling pathway	1
cellular response to unfolded protein	1
intracellular signal transduction	1
proteasomal protein catabolic process	1
response to chemical	1
negative regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
protein alpha-1,2-demannosylation	1
endoplasmic reticulum quality control compartment	1
SREBP signaling pathway	1
regulation of cellular response to stress	1
regulation of intracellular signal transduction	1
protein modification by small protein conjugation	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
molecular adaptor activity	1
ubiquitin protein ligase activity	1
molecular transducer activity	1
ubiquitin-like protein binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
protein-containing complex binding	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

196 interactions, top by confidence:

A	B	Type	Score
AMFR	VCP	psi-mi:“MI:0915”(physical association)	0.870
VCP	AMFR	psi-mi:“MI:0407”(direct interaction)	0.870
VCP	AMFR	psi-mi:“MI:0915”(physical association)	0.870
UBE2G2	AMFR	psi-mi:“MI:0407”(direct interaction)	0.840
AMFR	UBE2G2	psi-mi:“MI:0407”(direct interaction)	0.840
AMFR	UBE2G2	psi-mi:“MI:0915”(physical association)	0.840
AMFR	Ube2g2	psi-mi:“MI:0915”(physical association)	0.820
Ube2g2	AMFR	psi-mi:“MI:0407”(direct interaction)	0.820

BioGRID (549): AMFR (Affinity Capture-Western), HSPA5 (Affinity Capture-Western), AMFR (Two-hybrid), AMFR (Reconstituted Complex), VCP (Protein-peptide), VCP (Reconstituted Complex), CYP3A4 (Biochemical Activity), UBE2G1 (Reconstituted Complex), UBE2G2 (Reconstituted Complex), HERPUD1 (Biochemical Activity), UBC (Reconstituted Complex), AMFR (Affinity Capture-Western), AMFR (Biochemical Activity), UBE2D2 (Reconstituted Complex), AMFR (Affinity Capture-Western)

ESM2 similar proteins: A0A1L8FG46, A0A1L8FM16, A0A1L8FZ98, A0A1L8H814, A1L3G9, A8X0L4, B0JYZ2, B1AUE5, B9X187, C0HKD7, E7F4V8, E7FE40, F1QB30, F1S5L4, O88177, P24392, P28328, P32800, P55098, P97564, Q00940, Q05568, Q059Y8, Q06438, Q19189, Q19337, Q28EH9, Q3U213, Q3UF64, Q5GJ77, Q5RAG4, Q5SNQ7, Q5Z880, Q61586, Q642F4, Q68F70, Q6DFK1, Q6INN0, Q6NPT7, Q6NZ21

Diamond homologs: A0A3L6DPG1, A5WWA0, A6HD62, D3ZSP7, F1QB30, G3X9R7, O13797, O16259, O35814, O54981, O88196, P31948, P53041, P53042, P53804, Q06003, Q0JL44, Q14B02, Q29RU0, Q2TA44, Q388N2, Q3U2C5, Q3ZBZ8, Q496Y0, Q4R8N7, Q54DA8, Q566M8, Q5DTZ6, Q5QLR5, Q5R8D8, Q5RF74, Q5SPX3, Q5XEP2, Q5Z880, Q5ZHY5, Q60676, Q60864, Q6AY01, Q6DGE9, Q6NPT7

SIGNOR signaling

14 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	AMFR	ubiquitination
TRIM25	“down-regulates quantity by destabilization”	AMFR	polyubiquitination
AMFR	“down-regulates quantity by destabilization”	GPI	polyubiquitination
AMFR	“down-regulates quantity by destabilization”	CD3D	polyubiquitination
AMFR	“down-regulates quantity by destabilization”	SERPINI1	polyubiquitination
AMFR	“down-regulates activity”	UBL4A	polyubiquitination
CDK5	“down-regulates quantity by destabilization”	AMFR	phosphorylation
AMFR	“down-regulates quantity by destabilization”	INSIG1	ubiquitination
AMFR	“down-regulates quantity by destabilization”	HMGCR	ubiquitination
AMFR	“down-regulates quantity by destabilization”	APOB	ubiquitination
GPI	up-regulates	AMFR	binding
UFD1	“up-regulates activity”	AMFR	binding
AMFR	“down-regulates quantity by destabilization”	MFN1	polyubiquitination
AMFR	“down-regulates quantity by destabilization”	MFN2	polyubiquitination

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
TICAM1, RIP1-mediated IKK complex recruitment	5	24.0×	6e-05
IKK complex recruitment mediated by RIP1	5	19.9×	1e-04
Defective CFTR causes cystic fibrosis	11	19.3×	1e-09
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	6	17.7×	5e-05
PINK1-PRKN Mediated Mitophagy	6	17.1×	6e-05
N-glycan trimming in the ER and Calnexin/Calreticulin cycle	5	16.9×	2e-04
AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	10	15.5×	1e-07
Hh mutants are degraded by ERAD	7	13.6×	4e-05

GO biological processes:

GO term	Partners	Fold	FDR
retrograde protein transport, ER to cytosol	5	31.2×	5e-05
regulation of intracellular pH	7	26.5×	1e-06
sodium ion import across plasma membrane	5	19.6×	5e-04
ERAD pathway	16	18.2×	4e-13
transmembrane transport	15	15.9×	1e-11
protein monoubiquitination	6	13.0×	6e-04
protein K11-linked ubiquitination	5	12.3×	4e-03
protein K48-linked ubiquitination	9	9.5×	5e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	1
Uncertain significance	78
Likely benign	6
Benign	0

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
1705883	GRCh37/hg19 16q12.2(chr16:55103496-56391061)x1	Pathogenic
2502908	NM_001144.6(AMFR):c.12del (p.Phe5fs)	Pathogenic
2502909	NM_001144.6(AMFR):c.254G>A (p.Trp85Ter)	Pathogenic
2502910	NM_001144.6(AMFR):c.369G>A (p.Trp123Ter)	Pathogenic
2502911	NM_001144.6(AMFR):c.871_874dup (p.Leu292fs)	Pathogenic
2502912	NM_001144.6(AMFR):c.1086-97_1380+375del	Pathogenic
3243644	NC_000016.9:g.(?56226148)(57286179_?)del	Pathogenic
3252670	NM_001144.6(AMFR):c.1092T>A (p.Cys364Ter)	Pathogenic
3362782	NM_001144.6(AMFR):c.707+1G>A	Likely pathogenic

SpliceAI

2335 predictions. Top by Δscore:

Variant	Effect	Δscore
16:56363054:CGT:C	acceptor_gain	1.0000
16:56363919:A:AC	donor_gain	1.0000
16:56363920:C:CC	donor_gain	1.0000
16:56363920:CTTG:C	donor_gain	1.0000
16:56363951:CG:C	donor_gain	1.0000
16:56364101:TCGGT:T	acceptor_gain	1.0000
16:56364102:CGGT:C	acceptor_gain	1.0000
16:56364102:CGGTC:C	acceptor_gain	1.0000
16:56364104:GT:G	acceptor_gain	1.0000
16:56364106:C:CC	acceptor_gain	1.0000
16:56364111:C:CT	acceptor_gain	1.0000
16:56364113:C:CT	acceptor_gain	1.0000
16:56364114:G:T	acceptor_gain	1.0000
16:56364118:C:CT	acceptor_gain	1.0000
16:56364119:A:T	acceptor_gain	1.0000
16:56385913:CCTTA:C	donor_loss	1.0000
16:56385914:CTTAC:C	donor_loss	1.0000
16:56385917:A:AC	donor_gain	1.0000
16:56385918:C:CC	donor_gain	1.0000
16:56385918:C:CT	donor_loss	1.0000
16:56386019:GACC:G	acceptor_gain	1.0000
16:56386020:ACC:A	acceptor_gain	1.0000
16:56386021:CC:C	acceptor_gain	1.0000
16:56386021:CCC:C	acceptor_gain	1.0000
16:56386022:CC:C	acceptor_gain	1.0000
16:56386023:C:CC	acceptor_gain	1.0000
16:56386023:C:T	acceptor_gain	1.0000
16:56401725:G:C	donor_gain	1.0000
16:56401731:A:AC	donor_gain	1.0000
16:56401732:C:CC	donor_gain	1.0000

AlphaMissense

4228 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:56363971:T:A	R578S	1.000
16:56363971:T:G	R578S	1.000
16:56363992:G:C	F571L	1.000
16:56363992:G:T	F571L	1.000
16:56363994:A:G	F571L	1.000
16:56369242:G:C	T489R	1.000
16:56369242:G:T	T489K	1.000
16:56369269:A:G	L480P	1.000
16:56369269:A:T	L480H	1.000
16:56385986:A:T	V438D	1.000
16:56386003:C:A	W432C	1.000
16:56386003:C:G	W432C	1.000
16:56386005:A:G	W432R	1.000
16:56386005:A:T	W432R	1.000
16:56389324:T:A	R379S	1.000
16:56389324:T:G	R379S	1.000
16:56389325:C:A	R379I	1.000
16:56389325:C:G	R379T	1.000
16:56389327:G:C	C378W	1.000
16:56389328:C:A	C378F	1.000
16:56389328:C:G	C378S	1.000
16:56389328:C:T	C378Y	1.000
16:56389329:A:G	C378R	1.000
16:56389329:A:T	C378S	1.000
16:56389334:G:C	P376R	1.000
16:56389334:G:T	P376Q	1.000
16:56389335:G:A	P376S	1.000
16:56389335:G:T	P376T	1.000
16:56389336:A:C	C375W	1.000
16:56389337:C:A	C375F	1.000

dbSNP variants (sampled 300 via entrez): RS1000179520 (16:56368948 T>A), RS1000201500 (16:56417795 T>C), RS1000274406 (16:56384411 C>G,T), RS1000291185 (16:56366020 T>C), RS1000333898 (16:56378583 G>T), RS1000434259 (16:56417533 C>A,T), RS1000476935 (16:56424466 G>A), RS1000513221 (16:56404347 C>T), RS1000630089 (16:56398525 T>C), RS1000673632 (16:56410904 G>T), RS1000779347 (16:56424220 A>G), RS1000876435 (16:56382992 A>G), RS1001022499 (16:56389464 A>G), RS1001299927 (16:56401161 T>C), RS1001392690 (16:56383324 C>T)

Disease associations

OMIM: gene MIM:603243 | disease phenotypes: MIM:620379

GenCC curated gene-disease

Disease	Classification	Inheritance
spastic paraplegia 89, autosomal recessive	Strong	Autosomal recessive

Mondo (3): breast ductal adenocarcinoma (MONDO:0005590), spastic paraplegia 89, autosomal recessive (MONDO:0957274), primary amenorrhea (MONDO:1060208)

Orphanet (0):

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000009	Functional abnormality of the bladder
HP:0000252	Microcephaly
HP:0000750	Delayed speech and language development
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001256	Mild intellectual disability
HP:0001258	Spastic paraplegia
HP:0001270	Motor delay
HP:0001511	Intrauterine growth retardation
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)
HP:0002376	Developmental regression
HP:0002395	Lower limb hyperreflexia
HP:0003593	Infantile onset
HP:0008936	Axial hypotonia
HP:0011463	Childhood onset
HP:0033725	Thin corpus callosum

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST004988_637	Breast cancer	4.000000e-08
GCST010241_413	Apolipoprotein A1 levels	2.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004614	apolipoprotein A 1 measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression, increases reaction, increases methylation	3
Benzo(a)pyrene	increases expression, increases methylation	2
Doxorubicin	affects cotreatment, affects response to substance, decreases expression	2
Tretinoin	increases expression, decreases expression	2
NMS-873	affects binding, increases reaction	1
lasiocarpine	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
trichostatin A	decreases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	increases expression	1
coumarin	increases phosphorylation	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	decreases response to substance	1
Vorinostat	decreases expression	1
Acetaminophen	increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Caffeine	decreases phosphorylation	1
Coumestrol	affects cotreatment, increases expression	1
Curcumin	increases expression	1
Cyclophosphamide	affects cotreatment, affects response to substance	1
Estradiol	increases expression, increases reaction	1
Fluorouracil	affects cotreatment, affects response to substance	1
Lead	affects expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT00461344	PHASE2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	PHASE2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT00637364	PHASE1/PHASE2	SUSPENDED	High Intensity Focused Ultrasound Tumor Treatment for Pancreatic Cancer Pain
NCT02779855	PHASE1/PHASE2	COMPLETED	Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
NCT01753908	EARLY_PHASE1	COMPLETED	Broccoli Sprout Extract in Treating Patients With Breast Cancer
NCT01796041	EARLY_PHASE1	COMPLETED	Intraoperative Imaging of Breast Cancer With Indocyanine Green
NCT01208974	Not specified	ACTIVE_NOT_RECRUITING	Nipple-Areola Complex (NAC) Irradiation After Nipple-Sparing Mastectomy and Reconstruction
NCT01875198	Not specified	TERMINATED	Oncologic Impact of Splenectomy-omitting Radical Pancreatectomy in Well-selected Left-sided Pancreatic Cancer
NCT03543397	Not specified	UNKNOWN	MRI in Ductal Carcinoma in Situ (DCIS)
NCT03834532	Not specified	COMPLETED	Living Well After Breast Surgery
NCT07164248	Not specified	COMPLETED	Evaluation of Bone Mineral Density Indications and Outcomes in Female Adolescents: Implications for Early Detection of Osteopenia/Osteoporosis and Gynecologic Practice