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): 115 total — 8 pathogenic, 1 likely-pathogenic
• Regional missense constraint (gnomAD): 1 of 5 regions constrained (≈3% of expected missense variation)
• GTEx eGene: eQTL in 36 tissues, sQTL in 2 (q < 0.05)
• Phenotypes (HPO): 17
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.63 (unconstrained)
• 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: 28 — 19 protein_coding, 5 retained_intron, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

MANE Select: ENST00000290649

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 4, TSL 3: 1, TSL 4: 3, TSL 5: 2

ENST00000290649, ENST00000492830, ENST00000563285, ENST00000563664, ENST00000564283, ENST00000565445, ENST00000566334, ENST00000566757, ENST00000567738, ENST00000568325, ENST00000568657, ENST00000568762, ENST00000861439, ENST00000861440, ENST00000861441, ENST00000861442, ENST00000861443, ENST00000861444, ENST00000861445, ENST00000861446, ENST00000861447, ENST00000957771, ENST00000957772, ENST00001003182, ENST00001003184, ENST00001037990, ENST00001117316, ENST00001138547

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.

Highest expression (Bgee): stromal cell of endometrium, adrenal tissue, testis, gastrocnemius, muscle of leg.

Genetic regulation across tissues (GTEx eQTL / sQTL)

AMFR is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 36 tissues and its splicing (sQTL) in 2 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 38 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Testis	sqtl	5.3e-30	-1.72	16:56350775:G:T
Cells Cultured fibroblasts	eqtl	5.1e-17	+0.25	16:56450908:C:T
Artery Tibial	eqtl	5.9e-12	+0.21	16:56399034:TA:T
Muscle Skeletal	eqtl	1.9e-09	+0.11	16:56413374:T:C
Spleen	eqtl	3.9e-09	-0.30	16:56445386:G:A
Cells EBV-transformed lymphocytes	eqtl	7.9e-09	-0.40	16:56445386:G:A
Brain Frontal Cortex BA9	eqtl	5.9e-08	+0.37	16:56445386:G:A
Lung	eqtl	1.6e-07	-0.19	16:56453533:C:G
Artery Aorta	eqtl	2.3e-07	-0.16	16:56350808:T:C
Brain Hippocampus	eqtl	3.1e-07	+0.31	16:56367064:C:T
Brain Putamen basal ganglia	eqtl	3.6e-07	+0.38	16:56445386:G:A
Esophagus Muscularis	eqtl	7.2e-07	+0.14	16:56450908:C:T
Skin Sun Exposed Lower leg	eqtl	7.4e-07	-0.14	16:56362574:C:T
Brain Nucleus accumbens basal ganglia	eqtl	1.6e-06	+0.29	16:56521876:T:A
Brain Caudate basal ganglia	eqtl	3.5e-06	+0.31	16:56367064:C:T
Brain Hypothalamus	eqtl	6.0e-06	+0.28	16:56367064:C:T
Testis	eqtl	8.1e-06	-0.17	16:56456637:G:A
Nerve Tibial	eqtl	3.2e-05	-0.11	16:56453533:C:G
Artery Coronary	eqtl	3.3e-05	-0.21	16:56453533:C:G
Esophagus Gastroesophageal Junction	eqtl	4.2e-05	+0.16	16:56380333:AC:A

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

showing 100 of 299 tissues 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
esophagus mucosa	UBERON:0002469	94.31	gold quality
sural nerve	UBERON:0015488	94.28	gold quality
nucleus accumbens	UBERON:0001882	94.27	gold quality
anterior cingulate cortex	UBERON:0009835	94.23	gold quality
cingulate cortex	UBERON:0003027	94.21	gold quality
thoracic aorta	UBERON:0001515	94.10	gold quality
ascending aorta	UBERON:0001496	94.08	gold quality
right ovary	UBERON:0002118	94.07	gold quality
mucosa of stomach	UBERON:0001199	94.02	gold quality
caudate nucleus	UBERON:0001873	94.01	gold quality
ganglionic eminence	UBERON:0004023	93.96	gold quality
aorta	UBERON:0000947	93.92	gold quality
popliteal artery	UBERON:0002250	93.92	gold quality
tibial artery	UBERON:0007610	93.92	gold quality
body of uterus	UBERON:0009853	93.87	gold quality
esophagus	UBERON:0001043	93.85	gold quality
left uterine tube	UBERON:0001303	93.80	gold quality
right frontal lobe	UBERON:0002810	93.66	gold quality
cortical plate	UBERON:0005343	93.64	gold quality
descending thoracic aorta	UBERON:0002345	93.57	gold quality
putamen	UBERON:0001874	93.56	gold quality
skeletal muscle organ	UBERON:0014892	93.53	gold quality
muscle organ	UBERON:0001630	93.52	gold quality
adenohypophysis	UBERON:0002196	93.43	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.41	gold quality
Brodmann (1909) area 9	UBERON:0013540	93.40	gold quality
amygdala	UBERON:0001876	93.32	gold quality
lower esophagus	UBERON:0013473	93.30	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.28	gold quality
apex of heart	UBERON:0002098	93.23	gold quality
small intestine Peyer’s patch	UBERON:0003454	93.23	gold quality
body of pancreas	UBERON:0001150	93.16	gold quality
left coronary artery	UBERON:0001626	93.09	gold quality
skin of leg	UBERON:0001511	93.08	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.03	gold quality
pancreas	UBERON:0001264	92.85	gold quality
monocyte	CL:0000576	92.78	gold quality
coronary artery	UBERON:0001621	92.64	gold quality
small intestine	UBERON:0002108	92.57	gold quality
minor salivary gland	UBERON:0001830	92.54	gold quality
right atrium auricular region	UBERON:0006631	92.49	gold quality
corpus callosum	UBERON:0002336	92.48	gold quality
leukocyte	CL:0000738	92.47	gold quality
adult mammalian kidney	UBERON:0000082	92.40	gold quality
mononuclear cell	CL:0000842	92.36	gold quality
lymph node	UBERON:0000029	92.26	gold quality
transverse colon	UBERON:0001157	92.16	gold quality
right lung	UBERON:0002167	92.03	gold quality
upper lobe of left lung	UBERON:0008952	91.92	gold quality
right lobe of thyroid gland	UBERON:0001119	91.85	gold quality
skin of abdomen	UBERON:0001416	91.78	gold quality
omental fat pad	UBERON:0010414	91.70	gold quality
peritoneum	UBERON:0002358	91.67	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	91.67	gold quality
body of stomach	UBERON:0001161	91.64	gold quality
mucosa of transverse colon	UBERON:0004991	91.61	gold quality
gluteal muscle	UBERON:0002000	91.57	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	91.56	gold quality
left lobe of thyroid gland	UBERON:0001120	91.51	gold quality
upper lobe of lung	UBERON:0008948	91.50	gold quality
liver	UBERON:0002107	91.28	gold quality
stomach	UBERON:0000945	91.25	gold quality
mouth mucosa	UBERON:0003729	91.22	gold quality
renal medulla	UBERON:0000362	91.19	gold quality
pituitary gland	UBERON:0000007	91.12	gold quality
right uterine tube	UBERON:0001302	91.00	gold quality
adipose tissue of abdominal region	UBERON:0007808	90.99	gold quality
neocortex	UBERON:0001950	90.97	gold quality
hypothalamus	UBERON:0001898	90.95	gold quality
duodenum	UBERON:0002114	90.89	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

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Choroid plexus	tissue	154.3
Caudate putamen	tissue	115.1
Skeletal muscle	tissue	106.2	medium
Locus coeruleus	tissue	101.1
Nucleus accumbens	tissue	98.5
Frontal cortex	tissue	88.4
Hippocampus	tissue	82.3	high
Testis	tissue	78.2	high
Spinal cord	tissue	73.5
Postcentral gyrus	tissue	72.7
Liver	tissue	70.4	medium
Hypothalamus	tissue	68.8
Parathyroid gland	tissue	66.4	medium
Thalamus	tissue	66.1
Pons	tissue	65.2
Midbrain	tissue	64.6
Septum	tissue	63.8
Putamen	tissue	63.7
Substantia nigra	tissue	63.1
Medulla oblongata	tissue	62.9
Basal ganglia	tissue	62.8	high
Superior colliculi	tissue	62.7
Hippocampal formation	tissue	62.0
Periaqueductal gray	tissue	61.8
Kidney	tissue	60.4	high
Ventral forebrain	tissue	59.8
Cerebral cortex	tissue	58.5	high
Motor cortex	tissue	58.5
Prefrontal cortex	tissue	57.9
Somatosensory cortex	tissue	55.4
Entorhinal cortex	tissue	55.0
Corpus callosum	tissue	54.6
Retina	tissue	53.4
Amygdala	tissue	53.0
Tongue	tissue	52.8
Occipital cortex	tissue	52.7
Retrosplenial and cingulate cortex	tissue	52.5
Temporal cortex	tissue	52.5
Insular cortex	tissue	51.8
Retrosplenial cortex	tissue	51.7
Adrenal gland	tissue	50.0	high
Epididymis	tissue	48.6	high
Olfactory bulb	tissue	44.9
Duodenum	tissue	44.6	high
Esophagus	tissue	41.5	medium
Cerebellum	tissue	41.3	high
Tonsil	tissue	40.7	high
Placenta	tissue	38.5	high
Lymph node	tissue	37.5	medium
Ovary	tissue	35.5	high
Seminal vesicle	tissue	35.3	high
Bone marrow	tissue	34.8	medium
Small intestine	tissue	33.8	high
Cervix	tissue	32.3	medium
Thyroid gland	tissue	31.7	high
Smooth muscle	tissue	31.6	medium
Endometrium 1	tissue	31.5	high
Heart muscle	tissue	30.1	medium
Fallopian tube	tissue	29.7	high
Vagina	tissue	28.0	low

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Dorsal funiculus (white matter) (145.6), Anterior funiculus (white matter) (132.4), Cervical spinal cord, ventral horn (129.3), Lateral funiculus (white matter) (128.8), Area postrema (121.2).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting AMFR by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 89 miRNAs:

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

Functional genomics

gnomAD constraint: pLI 0.000624, LOEUF 0.633, missense Z 1.63 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000290649 splits into 5 regions with different missense tolerance; 1 is missense-constrained (≈3% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
16:56,362,912–56,385,974	235 / 272.2	0.86	no
16:56,385,975–56,389,196	6 / 28.9	0.21	yes (p 2.0e-05)
16:56,389,197–56,409,472	280 / 352.5	0.79	no
16:56,409,473–56,409,563	14 / 36.5	0.38	no
16:56,409,564–56,425,327	176 / 173.2	1.02	no

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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1345634) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 15 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal liver morphology	1
abnormal hepatocyte morphology	1
obese	1
liver inflammation	1
hepatic steatosis	1
decreased circulating alanine transaminase level	1
decreased circulating alkaline phosphatase level	1
liver cirrhosis	1
liver fibrosis	1
decreased circulating total protein level	1
decreased lactate dehydrogenase level	1
decreased circulating aspartate transaminase level	1
increased liver tumor incidence	1
increased physiological sensitivity to xenobiotic	1
decreased circulating fructosamine level	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	Q0II22	92.5%	Diamond
Arabidopsis thaliana	Q500V2	83.4%	Diamond
Oryza sativa Japonica Group	Q5Z880	70.5%	Diamond
Drosophila melanogaster	Q95SP2	67.3%	Diamond
Schizosaccharomyces pombe 972h-	Q9Y7K6	47.7%	Diamond
Saccharomyces cerevisiae S288C	Q08109	41.1%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
NUDT21	protein-coding	11051
GNAO1-AS1	ncRNA	26077
GNAO1	protein-coding	2775
GNAO1-DT	ncRNA	283856
MIR3935	ncRNA	100500891
OGFOD1	protein-coding	55239
BBS2	protein-coding	583
MT4	protein-coding	84560

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 (47 total): transmembrane region 7, helix 7, mutagenesis site 6, strand 6, sequence variant 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 by resolution:

PDB	Title	Method	Resolution (Å)
4G3O	Crystal structure of the CUE domain of the E3 ubiquitin ligase AMFR (gp78)	X-RAY DIFFRACTION	1.6
3H8K	Crystal structure of Ube2g2 complxed with the G2BR domain of gp78 at 1.8-A resolution	X-RAY DIFFRACTION	1.8
3TIW	Crystal structure of p97N in complex with the C-terminus of gp78	X-RAY DIFFRACTION	1.8
8T0S	Crystal structure of UBE2G2 adduct with phenethyl isothiocyanate (PEITC) at the Cys48 …	X-RAY DIFFRACTION	1.95
4LAD	Crystal Structure of the Ube2g2:RING-G2BR complex	X-RAY DIFFRACTION	2.3
3FSH	Crystal structure of the ubiquitin conjugating enzyme Ube2g2 bound to the G2BR domain of …	X-RAY DIFFRACTION	2.76
2EJS	Solution structure of RUH-076, a human CUE domain	SOLUTION NMR
2LVN	Structure of the gp78 CUE domain	SOLUTION NMR
2LVO	Structure of the gp78CUE domain bound to monubiquitin	SOLUTION NMR
2LVP	gp78CUE domain bound to the distal ubiquitin of K48-linked diubiquitin	SOLUTION NMR
2LVQ	gp78CUE domain bound to the proximal ubiquitin of K48-linked diubiquitin	SOLUTION NMR
2LXH	NMR structure of the RING domain in ubiquitin ligase gp78	SOLUTION NMR
2LXP	NMR structure of two domains in ubiquitin ligase gp78, RING and G2BR, bound to its …	SOLUTION NMR

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Metabolic proteins, Transporters, Accessory Factors Involved in Transport, Predicted membrane proteins, Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): endoplasmic reticulum; golgi apparatus

Antibody reliability (HPA): IH approved · IF supported

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)

Type	Positions
Phosphoserine	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

2 curated (TAS) of 6; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

6 pathways:

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

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 (17): 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), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), protein unfolding (GO:0043335), 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), 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 (12): ubiquitin ligase complex (GO:0000151), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), 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

5 top-level categories:

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

showing 60 of 61 GO namespaces:

Category	Terms
cellular anatomical structure	4
protein ubiquitination	3
protein binding	3
cytoplasm	3
cellular process	2
response to endoplasmic reticulum stress	2
proteasomal protein catabolic process	2
protein polyubiquitination	2
modification-dependent protein catabolic process	1
cell communication	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
response to chemical	1
intracellular signaling cassette	1
ubiquitin-dependent protein catabolic process	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
protease binding	1
binding	1
catalytic activity	1
cation binding	1
intracellular protein-containing complex	1
transferase complex	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
neuron projection	1
dendritic tree	1
site of polarized growth	1
distal axon	1
cellular_component	1
endoplasmic reticulum membrane	1
membrane protein complex	1
endoplasmic reticulum protein-containing complex	1
somatodendritic compartment	1
cell body	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 24 of 43 annotations. The rest are phylogenetic / computational / electronic (IEA).

24 experimentally-supported GO terms:

GO term	NS	Evidence
ERAD pathway	BP	direct assay
endoplasmic reticulum unfolded protein response	BP	mutant phenotype
negative regulation of canonical Wnt signaling pathway	BP	mutant phenotype
non-canonical NF-kappaB signal transduction	BP	direct assay
protein K27-linked ubiquitination	BP	direct assay
protein K48-linked ubiquitination	BP	direct assay
protein autoubiquitination	BP	direct assay
protein polyubiquitination	BP	direct assay
ubiquitin-dependent protein catabolic process	BP	mutant phenotype
Derlin-1 retrotranslocation complex	CC	direct assay
endoplasmic reticulum	CC	direct assay
endoplasmic reticulum membrane	CC	direct assay
membrane	CC	high-throughput assay
perinuclear region of cytoplasm	CC	direct assay
protein-containing complex	CC	direct assay
BAT3 complex binding	MF	direct assay
identical protein binding	MF	physical interaction
protein-folding chaperone binding	MF	physical interaction
protein-macromolecule adaptor activity	MF	mutant phenotype
signaling receptor activity	MF	physical interaction
ubiquitin protein ligase activity	MF	direct assay
ubiquitin-protein transferase activity	MF	direct assay
ubiquitin-specific protease binding	MF	physical interaction
ubiquitin-ubiquitin ligase activity	MF	direct assay

Protein interactions and networks

IntAct

Human interaction partners of AMFR in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

22 partners by confidence:

Partner	Interaction type	MIscore	Records
VCP	physical association	0.870	8
UBE2G2	direct interaction	0.840	20
ERLIN2	association	0.660	7
ERLIN1	physical association	0.560	1
TMUB1	physical association	0.560	1
UBE2D1	physical association	0.550	2
UBE2D2	physical association	0.550	2
UBE2D3	physical association	0.550	2
UBE2D4	physical association	0.550	2
UBE2N	physical association	0.550	2
UBE2W	physical association	0.550	2
INSIG1	physical association	0.500	1
HERPUD1	direct interaction	0.440	1
UBAC2	colocalization	0.430	1
CD3D	physical association	0.400	1
DGAT2	physical association	0.400	1
SLC9B1	physical association	0.400	1
CRMP1	physical association	0.370	1
TOM1L1	physical association	0.370	1
UBE2T	physical association	0.370	1
PSMA7	association	0.350	1
PSMD14	association	0.350	1

BioGRID (552 interactions; top human partners by supporting records): VCP (Two-hybrid; 36 records), UBE2G2 (Reconstituted Complex; 23 records), UBC (Reconstituted Complex; 15 records), BAG6 (Affinity Capture-Western; 11 records), FAF2 (Affinity Capture-MS; 11 records), HERPUD1 (Biochemical Activity; 10 records), INSIG1 (Affinity Capture-Western; 8 records), UBAC2 (Affinity Capture-MS; 7 records), UBE2G1 (Reconstituted Complex; 7 records), ERLIN2 (Affinity Capture-MS; 6 records), HMGCR (Affinity Capture-MS; 6 records), MGRN1 (Affinity Capture-Western; 6 records), SYVN1 (Affinity Capture-Western; 6 records), TMUB1 (Affinity Capture-MS; 6 records), CCL1 (Affinity Capture-Western; 5 records)

SIGNOR signaling

14 signaling 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

Protein complexes (CORUM) (4)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

4 complexes by size:

Complex	Subunits	Members
AMFR-DERL1-VCP complex	3	AMFR, DERL1, VCP
AMFR-ERLIN2-TMUB1 complex	3	AMFR, ERLIN2, TMUB1
AMFR-STING-INSIG1 complex, herpes simplex virus 1 induced	3	STING1, AMFR, INSIG1
AMFR-BAG6-FAF2 complex	3	AMFR, BAG6, FAF2

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 22 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
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	5	96.9×	1e-07
Defective CFTR causes cystic fibrosis	5	57.8×	7e-07
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha	5	51.8×	8e-07
E3 ubiquitin ligases ubiquitinate target proteins	5	50.9×	8e-07
AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	5	50.9×	8e-07
FCERI mediated NF-kB activation	5	41.2×	2e-06
Downstream TCR signaling	6	40.5×	3e-07
CLEC7A (Dectin-1) signaling	5	37.6×	3e-06

GO biological processes:

GO term	Partners	Fold	FDR
ERAD pathway	6	49.4×	9e-08
protein K48-linked ubiquitination	6	46.0×	1e-07
protein polyubiquitination	7	36.7×	4e-08
ubiquitin-dependent protein catabolic process	8	27.0×	4e-08
proteasome-mediated ubiquitin-dependent protein catabolic process	7	16.6×	3e-06
protein ubiquitination	5	9.4×	1e-03

Disease & clinical

Genetic variants

Variant evidence for AMFR: 115 ClinVar records (9 pathogenic / likely pathogenic); 2 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	1
Uncertain significance	79
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (9)

Showing all 9 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
3252670	NM_001144.6(AMFR):c.1092T>A (p.Cys364Ter)	Pathogenic	criteria provided, single submitter	1
3362782	NM_001144.6(AMFR):c.707+1G>A	Likely pathogenic	criteria provided, single submitter	8
3243644	NC_000016.9:g.(?56226148)(57286179_?)del	Pathogenic	criteria provided, single submitter	1
2502908	NM_001144.6(AMFR):c.12del (p.Phe5fs)	Pathogenic	no assertion criteria provided	1
2502909	NM_001144.6(AMFR):c.254G>A (p.Trp85Ter)	Pathogenic	no assertion criteria provided	1
2502910	NM_001144.6(AMFR):c.369G>A (p.Trp123Ter)	Pathogenic	no assertion criteria provided	1
2502911	NM_001144.6(AMFR):c.871_874dup (p.Leu292fs)	Pathogenic	no assertion criteria provided	1
2502912	NM_001144.6(AMFR):c.1086-97_1380+375del	Pathogenic	no assertion criteria provided	1
1705883	GRCh37/hg19 16q12.2(chr16:55103496-56391061)x1	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore AMFR’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 27 predictions of 1,423):

Position(s)	Effect	Δscore	Sites
16:56364114	acceptor_gain	1.0000
16:56364119	acceptor_gain	1.0000
16:56385917–56385918	donor_loss	1.0000	5
16:56386023	acceptor_gain	1.0000
16:56386023–56386024	acceptor_loss	1.0000	3
16:56401725	donor_gain	1.0000
16:56401844–56401845	acceptor_loss	1.0000	4
16:56402983–56402984	donor_loss	1.0000	5
16:56403119–56403120	acceptor_loss	1.0000	5
16:56403120	acceptor_gain	1.0000

AlphaMissense

1,997 missense substitutions predicted likely pathogenic (of 4,228 scored), across 431 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M279	9	0.970	0.998
M348	9	0.936	0.999
M289	9	0.918	0.998
M296	9	0.900	0.995
M322	9	0.889	0.991
M467	9	0.851	0.994
H358	8	1.000	1.000
H361	8	0.999	1.000
F360	8	0.998	1.000
F134	8	0.996	1.000
D479	8	0.996	0.999
F132	8	0.992	0.999
D339	8	0.992	0.999
F127	8	0.990	0.998
F424	8	0.990	0.999
F107	8	0.989	0.997
D372	8	0.989	0.998
F468	8	0.987	0.999
F218	8	0.986	0.998
F422	8	0.982	0.998

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Disease associations

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

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
spastic paraplegia 89, autosomal recessive	Strong	Autosomal recessive	3

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (3 panels, 3 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

3 panels:

Panel	Rating
DDG2P	green
Hereditary spastic paraplegia, childhood onset	green
Paediatric disorders	green

Mondo (1): spastic paraplegia 89, autosomal recessive (MONDO:0957274)

HPO phenotypes

17 phenotypes (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:

Study	Trait	p-value
GCST010241_386	Apolipoprotein A1 levels	2e-10
GCST004988_455	Breast cancer	4e-8

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0004614	apolipoprotein A 1 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

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	decreases expression, increases expression	2
NMS-873	affects binding, increases reaction	1
lasiocarpine	decreases expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	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	increases expression, affects cotreatment	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)

Via MONDO — disease-level, not drug-specific.

13 trials:

NCT	Phase	Status	Title
NCT03414970	Phase 3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT00461344	Phase 2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	Phase 2	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	Phase 1/2	SUSPENDED	High Intensity Focused Ultrasound Tumor Treatment for Pancreatic Cancer Pain
NCT02779855	Phase 1/2	COMPLETED	Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
NCT01753908	Early Phase 1	COMPLETED	Broccoli Sprout Extract in Treating Patients With Breast Cancer
NCT01796041	Early Phase 1	COMPLETED	Intraoperative Imaging of Breast Cancer With Indocyanine Green
NCT07628634	Early Phase 1	RECRUITING	Feasibility Study on the Effect of a Methionine-Reduced Diet on Serum Levels in Pts w/ Solid Tumors
NCT01208974	Not specified	COMPLETED	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