GFER

Summary

GFER (growth factor, augmenter of liver regeneration, HGNC:4236) is a protein-coding gene on chromosome 16p13.3, encoding FAD-linked sulfhydryl oxidase ALR (P55789). FAD-dependent sulfhydryl oxidase that regenerates the redox-active disulfide bonds in CHCHD4/MIA40, a chaperone essential for disulfide bond formation and protein folding in the mitochondrial intermembrane space. It is a selective cancer dependency (DepMap: 80.5% of cell lines).

The hepatotrophic factor designated augmenter of liver regeneration (ALR) is thought to be one of the factors responsible for the extraordinary regenerative capacity of mammalian liver. It has also been called hepatic regenerative stimulation substance (HSS). The gene resides on chromosome 16 in the interval containing the locus for polycystic kidney disease (PKD1). The putative gene product is 42% similar to the scERV1 protein of yeast. The yeast scERV1 gene had been found to be essential for oxidative phosphorylation, the maintenance of mitochondrial genomes, and the cell division cycle. The human gene is both the structural and functional homolog of the yeast scERV1 gene.

Source: NCBI Gene 2671 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 184 total — 8 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 18
• Druggable target: yes — 11 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 80.5% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_005262

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4236
Approved symbol	GFER
Name	growth factor, augmenter of liver regeneration
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Aliases	HSS, ERV1, ALR, HERV1, HPO1, HPO2
Ensembl gene	ENSG00000127554
Ensembl biotype	protein_coding
OMIM	600924
Entrez	2671

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 retained_intron

ENST00000248114, ENST00000561710, ENST00000565658, ENST00000567719, ENST00000569451

RefSeq mRNA: 1 — MANE Select: NM_005262 NM_005262

CCDS: CCDS32368

Canonical transcript exons

ENST00000248114 — 3 exons

Exon	Start	End
ENSE00001340601	1985866	1987749
ENSE00001388901	1984747	1984943
ENSE00002605178	1984193	1984476

Expression profiles

Bgee: expression breadth ubiquitous, 197 present calls, max score 95.55.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.9501 / max 131.4429, expressed in 1814 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
152154	24.1010	1811
152153	1.2617	826
152151	0.7169	404
152150	0.3162	153
152152	0.2725	106
152157	0.0802	39
152149	0.0717	31
152158	0.0648	34
152156	0.0424	23
152155	0.0228	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
olfactory bulb	UBERON:0002264	95.55	silver quality
type B pancreatic cell	CL:0000169	94.69	gold quality
vena cava	UBERON:0004087	94.25	silver quality
mucosa of transverse colon	UBERON:0004991	93.95	gold quality
body of pancreas	UBERON:0001150	93.05	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.67	gold quality
tongue squamous epithelium	UBERON:0006919	91.82	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	91.64	gold quality
transverse colon	UBERON:0001157	90.40	gold quality
small intestine Peyer’s patch	UBERON:0003454	90.07	gold quality
granulocyte	CL:0000094	89.96	gold quality
body of tongue	UBERON:0011876	89.91	silver quality
right lobe of liver	UBERON:0001114	89.80	gold quality
right testis	UBERON:0004534	89.53	gold quality
gastrocnemius	UBERON:0001388	89.50	gold quality
left testis	UBERON:0004533	89.46	gold quality
muscle of leg	UBERON:0001383	89.15	gold quality
apex of heart	UBERON:0002098	89.12	gold quality
pharyngeal mucosa	UBERON:0000355	88.95	silver quality
cardia of stomach	UBERON:0001162	88.80	silver quality
small intestine	UBERON:0002108	88.63	gold quality
lateral nuclear group of thalamus	UBERON:0002736	88.48	silver quality
pericardium	UBERON:0002407	88.26	silver quality
pancreas	UBERON:0001264	88.17	gold quality
dorsal plus ventral thalamus	UBERON:0001897	88.07	silver quality
subthalamic nucleus	UBERON:0001906	88.07	silver quality
pylorus	UBERON:0001166	87.88	silver quality
pons	UBERON:0000988	87.35	silver quality
body of stomach	UBERON:0001161	87.28	gold quality
saliva-secreting gland	UBERON:0001044	87.23	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.31

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPB, FOXA2, HNF4A, SP1

miRNA regulators (miRDB)

45 targeting GFER, 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-651-3P	99.94	73.48	5177
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4325	99.49	72.20	1342
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-3085-3P	99.26	66.16	1490
HSA-MIR-3064-5P	99.26	66.13	1497
HSA-MIR-6504-5P	99.26	65.95	1487
HSA-MIR-149-5P	99.25	67.16	1315
HSA-MIR-4477B	99.23	70.49	1733
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-520G-3P	98.91	67.38	1914
HSA-MIR-520H	98.91	67.38	1914
HSA-MIR-4755-3P	98.77	65.59	1915
HSA-MIR-6885-5P	98.71	64.33	902
HSA-MIR-6894-5P	98.70	63.78	809
HSA-MIR-7977	98.65	66.18	2590
HSA-MIR-12120	98.05	68.44	1768
HSA-MIR-6801-3P	98.04	64.64	805
HSA-MIR-506-5P	98.02	67.41	1065
HSA-MIR-6810-3P	97.96	64.57	1023

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 80.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Hepatopoietin acts as an autocrine growth factor in hepatoma cells (PMID:11879572)
• A novel isoform of hHPO (HPO-205) was isolated from hepatic-derived cells and distinguished from the previous HPO that lacked the N-terminal 80 amino acids. (PMID:11925624)
• HPO has 2 isoforms at 15 kDa (nucleus) and 23 kDa (cytoplasm) in liver cells. The capacity of HPO to form both homodimers and heterodimers with the alternatively spliced forms might contribute to the existence of various HPO complexes in hepatic cells. (PMID:12180965)
• regulation of expression (PMID:12681483)
• interaction with cell proliferation-related proteins, MIF and GFER (PMID:12681488)
• hepatopoietin association with thioredoxin constitutes a redox signal transduction in activation of AP-1/NF-kappaB (PMID:15894171)
• Findings suggest an important role for ALR in hepatocellular regeneration in liver cirrhosis as well as in hepatocarcinogenesis and therefore its potential value in the clinical diagnosis of hepatic cirrhosis and cancer. (PMID:15982324)
• Additionally, ALR treatment induced mRNA expression of ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase, both key enzymes of polyamine biosynthesis. (PMID:16677602)
• Purified hALR has the ability to stimulate DNA synthesis of adult rat hepatocytes in primary culture and HepG2 cells in vitro, and can provide evidence for its clinical application. (PMID:16865786)
• review of the molecular biology of ALR [review] (PMID:16937489)
• After passage across the translocase of the mitochondrial outer membrane Erv1 interacts via disulfide bonds with Mia40. (PMID:17336303)
• ALR is critically important for the survival of hepatocytes by its association with mitochondria and regulation of ATP synthesis. (PMID:18272248)
• results suggested that Sp1 activates hHSS basal expression, but HNF4alpha inhibits hHSS gene expression (PMID:18513187)
• Serum ALR level is helpful in estimating the survival time of patients with hepatic failure. (PMID:19335987)
• Catalysis involves a flow of reducing equivalents from the reduced CxC cysteine motif of Mia40 to distal and then proximal CxxC motifs of long-form ALR to the flavin ring and, finally, to cytochrome c or molecular oxygen. (PMID:19397338)
• Mutation in the GFER gene causes an infantile mitochondrial disorder. GFER mutation in patient’s muscle causes: a reduction in complex I, II, and IV activity; abnormal morphology of the mitochondria; and mtDNA multiple deletions. (PMID:19409522)
• The human ALR is important for hepatoma cell viability and involved in the protection of hepatoma cells against irradiation-induced damage by its association with mitochondria. (PMID:19616613)
• Demonstrate that Alrp improves SH-SY5Y cells survival in H(2)O(2)-induced apoptosis. (PMID:19629817)
• HPPCn is a novel hepatic growth factor that can be secreted to culture medium and suppresses apoptosis of hepatocellular carcinoma cells by up-regulating Mcl-1 expression. (PMID:20066738)
• these results indicate that ALR is regulated by Foxa2, and this regulation may be amplified by IL-6. (PMID:20382118)
• [review] Chronic lack of action by hepatic insulin-sensitizing substance (HISS) results in a progressive and predictable series of homeostatic dysfunctions typical of type 2 diabetes. (PMID:20393596)
• the major impact of the seemingly conservative R194H mutation on the stability of dimeric ALR (PMID:20593814)
• Transcription of hHSS triggered by EGF (epidermal growth factor) and the role of C/EBPbeta (CCAAT/enhancer-binding protein beta) as a potential core factor responsible for hHSS transcription in HepG2 cells, was investigated. (PMID:20690902)
• This paper demonstrates the necessity of the conserved CXXC catalytic motif (C62-C65) for the mitochondria-targeted anti-apoptotic activity of HSS. (PMID:20816831)
• Data indicate that cytosolic ALR reduces hepatoma cell migration, augments epithelial growth and, therefore, may act as an antimetastatic and EMT reversing protein. (PMID:21152698)
• Molecular recognition and substrate mimicry drive the electron-transfer process between MIA40 and ALR. (PMID:21383138)
• The role for Gfer is the restriction of unwarranted proliferation in HSCs through the inhibition of Jab1 and subsequent stabilization and nuclear retention of p27kip1. (PMID:21636978)
• The study shows the mechanism of the electron flux within ALR, characterizing at the atomic level the ALR intermediates that allow electrons to rapidly flow to cytochrome c. (PMID:22224850)
• ALR level in serum may indicate hepatocyte proliferation or liver regeneration. High ALR level in serum in early stage of acute-on-chrinic liver failure may mean a good prognosis. (PMID:22246190)
• The role of ALR is activated caspase-3, ROS, apoptotic cell number and mitochondrial degeneration. (PMID:22476097)
• overexpression of hALR results in influencing the sperm morphology and quantity and the eventual reduction in male fertility. (PMID:22863717)
• refined 2.4 A resolution of ALR structure is in good agreement with both the X-ray data (R(cryst) of 0.165, R(free) of 0.211) (PMID:22948913)
• The unstructured domain performs a dual function in two cellular compartments: it acts (i) as a mitochondrial targeting signal in the cytosol and (ii) as a crucial recognition site in the disulfide relay system of intermembrane space. (PMID:23207295)
• Small molecule MitoBloCK-6 inhibits Erv1/ALR and thus mitochondrial protein import in human embryonic stem cells. (PMID:23597483)
• Import and oxidative folding of proteins are kinetically and functionally coupled and depend on the expression of Mia40, ALR, and the intracellular glutathione pool. (PMID:23676665)
• protects Jurkat T leukemia cells from vincristine-induced cell death (PMID:23810409)
• Nrf2 activates ALR via antioxidant response element and links oxidative stress to liver regeneration. (PMID:23887691)
• ALR, Bcl-2 protein, clusterin and reactive oxygen species expression in muscle tissue biopsies from mitochondrial myopathy-affected patients, was determined. (PMID:23916837)
• this work studies the catalytic mechanism of the short, cytokine form of augmenter of liver regeneration using model thiol substrates of the enzyme (PMID:24147449)
• These results collectively suggest that the Hippo pathway negatively regulates the actin-binding activity of Amot family members through direct phosphorylation. (PMID:24225952)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	gfer	ENSDARG00000070061
mus_musculus	Gfer	ENSMUSG00000040888
rattus_norvegicus	Gfer	ENSRNOG00000013370
drosophila_melanogaster	Alr	FBGN0031068
caenorhabditis_elegans	F56C11.3	WBGENE00018955

Protein

Protein identifiers

FAD-linked sulfhydryl oxidase ALR — P55789 (reviewed: P55789)

Alternative names: Augmenter of liver regeneration, Hepatopoietin

All UniProt accessions (4): P55789, H3BQQ4, H3BRD2, H3BRW3

UniProt curated annotations — full annotation on UniProt →

Function. FAD-dependent sulfhydryl oxidase that regenerates the redox-active disulfide bonds in CHCHD4/MIA40, a chaperone essential for disulfide bond formation and protein folding in the mitochondrial intermembrane space. The reduced form of CHCHD4/MIA40 forms a transient intermolecular disulfide bridge with GFER/ERV1, resulting in regeneration of the essential disulfide bonds in CHCHD4/MIA40, while GFER/ERV1 becomes re-oxidized by donating electrons to cytochrome c or molecular oxygen. May act as an autocrine hepatotrophic growth factor promoting liver regeneration.

Subunit / interactions. Homodimer; disulfide-linked. May form heterodimers of isoform 1 and isoform 2. Interacts with CHCHD4/MIA40.

Subcellular location. Mitochondrion intermembrane space. Mitochondrion Cytoplasm. Secreted.

Tissue specificity. Ubiquitously expressed. Highest expression in the testis and liver and low expression in the muscle.

Disease relevance. Myopathy, mitochondrial progressive, with congenital cataract, hearing loss and developmental delay (MPMCD) [MIM:613076] A disease characterized by progressive myopathy and partial combined respiratory-chain deficiency, congenital cataract, sensorineural hearing loss, and developmental delay. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
P55789-1	1, HPO-205, lfALR	yes
P55789-2	2, HPO-125, sfALR

RefSeq proteins (1): NP_005253* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR017905	ERV/ALR_sulphydryl_oxidase	Domain
IPR036774	ERV/ALR_sulphydryl_oxid_sf	Homologous_superfamily
IPR039799	ALR/ERV	Family

Pfam: PF04777

Enzyme classification (BRENDA):

• EC 1.8.3.2 — thiol oxidase (BRENDA: 39 organisms, 163 substrates, 41 inhibitors, 94 Km, 60 kcat entries)

Substrate kinetics (BRENDA)

25 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
DITHIOTHREITOL	0.03–52.2	16
GLUTATHIONE	0.02–41.2	11
O2	0.0001–0.77	10
GSH	0.09–20	8
L-CYS	0.42–10.9	7
RNASE A	0.014–0.36	5
DTT	0.14–12.5	4
2-MERCAPTOETHANOL	7.9–54	3
CYSTEAMINE	1.25–30	3
D-CYS	1.33–13.1	3
N-ACETYL-L-CYS	1.13–3.85	3
REDUCED RIBONUCLEASE	0.0174–0.115	2
2-NITRO-5-THIOBENZOIC ACID	100	1
GLY-GLY-L-CYS	6.31	1
N-ACETYL-EAQCGTS	1.72	1

Catalyzed reactions (Rhea), 2 shown:

• 2 R’C(R)SH + O2 = R’C(R)S-S(R)CR’ + H2O2 (RHEA:17357)
• [protein]-dithiol + O2 = [protein]-disulfide + H2O2 (RHEA:59116)

UniProt features (29 total): helix 7, binding site 5, disulfide bond 4, sequence conflict 3, sequence variant 2, compositionally biased region 2, chain 1, domain 1, modified residue 1, splice variant 1, region of interest 1, strand 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
3U5S	X-RAY DIFFRACTION	1.5
3TK0	X-RAY DIFFRACTION	1.61
3MBG	X-RAY DIFFRACTION	1.85
3O55	X-RAY DIFFRACTION	1.9
3U2L	X-RAY DIFFRACTION	1.95
3U2M	X-RAY DIFFRACTION	2
4LDK	X-RAY DIFFRACTION	2.04

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P55789-F1	78.50	0.56

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 (5): 99–107; 111; 140; 171–183; 194–195

Post-translational modifications (1): 59

Disulfide bonds (4): 95, 142–145, 171–188, 204

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1268020	Mitochondrial protein import
R-HSA-9609507	Protein localization

MSigDB gene sets: 183 (showing top): GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GGGNRMNNYCAT_UNKNOWN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOMF_GROWTH_FACTOR_ACTIVITY, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_PROTEIN_MATURATION, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4, BYSTRYKH_HEMATOPOIESIS_STEM_CELL_AND_BRAIN_QTL_CIS, GOCC_MITOCHONDRIAL_ENVELOPE, GOBP_PROTEIN_FOLDING, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE, AFFAR_YY1_TARGETS_UP, SPIELMAN_LYMPHOBLAST_EUROPEAN_VS_ASIAN_UP, GOBP_PROTEIN_TRANSMEMBRANE_TRANSPORT, GOBP_PROTEIN_LOCALIZATION_TO_MITOCHONDRION

GO Biological Process (3): liver development (GO:0001889), protein import into the intermembrane space via the disulfide relay system (GO:0160203), signal transduction (GO:0007165)

GO Molecular Function (7): growth factor activity (GO:0008083), protein-disulfide reductase activity (GO:0015035), flavin-dependent sulfhydryl oxidase activity (GO:0016971), flavin adenine dinucleotide binding (GO:0050660), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), thiol oxidase activity (GO:0016972)

GO Cellular Component (5): extracellular region (GO:0005576), mitochondrion (GO:0005739), mitochondrial intermembrane space (GO:0005758), cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Protein localization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
disulfide oxidoreductase activity	2
cytoplasm	2
gland development	1
hepaticobiliary system development	1
protein import into mitochondrial intermembrane space	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
receptor ligand activity	1
catalytic activity, acting on a protein	1
protein-disulfide reductase activity	1
thiol oxidase activity	1
nucleotide binding	1
anion binding	1
binding	1
catalytic activity	1
oxidoreductase activity, acting on a sulfur group of donors, oxygen as acceptor	1
intracellular membrane-bounded organelle	1
mitochondrial envelope	1
organelle envelope lumen	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1826 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GFER	SAV1	Q9H4B6	990
GFER	CHCHD4	Q8N4Q1	966
GFER	QSOX2	Q6ZRP7	892
GFER	QSOX1	O00391	870
GFER	MOB1A	Q9H8S9	765
GFER	CYCS	P00001	757
GFER	DIAPH1	O60610	747
GFER	POU5F1	P31359	747
GFER	WWC1	Q8IX03	747
GFER	NANOG	Q9H9S0	733
GFER	TIMM10	P62072	730
GFER	MOB1B	Q7L9L4	726
GFER	TIMM9	Q9Y5J7	722
GFER	COX17	Q14061	714
GFER	TIMM13	P62206	711

IntAct

103 interactions, top by confidence:

A	B	Type	Score
rep	AP2A2	psi-mi:“MI:0914”(association)	0.660
GFER	rep	psi-mi:“MI:0915”(physical association)	0.660
MAPK14	RPS6KA5	psi-mi:“MI:0914”(association)	0.660
KLHL22	TMEM223	psi-mi:“MI:0914”(association)	0.640
FAM136A	RBFOX3	psi-mi:“MI:0914”(association)	0.640
TUBB	PLD2	psi-mi:“MI:0914”(association)	0.640
CHCHD4	SSNA1	psi-mi:“MI:0914”(association)	0.640
CDK4	HSP90AA1	psi-mi:“MI:0914”(association)	0.640
GPS1	GFER	psi-mi:“MI:0403”(colocalization)	0.600
GFER	COPS2	psi-mi:“MI:0403”(colocalization)	0.600
GFER	COPS8	psi-mi:“MI:0403”(colocalization)	0.600
COPS5	GFER	psi-mi:“MI:0403”(colocalization)	0.600
COPS5	GFER	psi-mi:“MI:0915”(physical association)	0.600
COPS8	GFER	psi-mi:“MI:0915”(physical association)	0.600
GPS1	GFER	psi-mi:“MI:0915”(physical association)	0.600
GFER	COPS2	psi-mi:“MI:0915”(physical association)	0.600
GFER	COPS5	psi-mi:“MI:0915”(physical association)	0.600
GFER	GPS1	psi-mi:“MI:0915”(physical association)	0.600
GFER	COPS5	psi-mi:“MI:0403”(colocalization)	0.600
COPS8	GFER	psi-mi:“MI:0403”(colocalization)	0.600

BioGRID (136): PLEKHF2 (Two-hybrid), GFER (Affinity Capture-MS), GFER (Affinity Capture-MS), GFER (Affinity Capture-MS), GFER (Affinity Capture-MS), GFER (Affinity Capture-MS), GFER (Affinity Capture-MS), GFER (Affinity Capture-MS), GRHPR (Co-fractionation), PCBP1 (Co-fractionation), GFER (Affinity Capture-MS), GFER (Affinity Capture-MS), GFER (Affinity Capture-MS), GFER (Affinity Capture-MS), GFER (Affinity Capture-MS)

ESM2 similar proteins: A2BD09, A4IFM1, A4IIA2, A6QLD2, B1AL88, G3X992, H2N4I1, O00391, O08841, O54828, O75949, O93279, P04004, P12843, P13384, P18065, P24853, P47876, P47877, P49705, P49805, P51693, P55108, P55789, P56213, Q1LZ89, Q29400, Q3V1G4, Q4ACU6, Q5EGE1, Q5QQ56, Q5XHC5, Q63042, Q68BL7, Q68BL8, Q6AYG1, Q6IUU3, Q766D5, Q76KP1, Q7TSG2

Diamond homologs: O14144, P27882, P55789, P56213, Q10Q80, Q12284, Q5UQV6, Q63042, Q8GXX0, Q91FH7, Q9Y806

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
CEBPB	“down-regulates quantity by repression”	GFER	“transcriptional regulation”
HNF4A	“down-regulates quantity by repression”	GFER	“transcriptional regulation”
SP1	“up-regulates quantity by expression”	GFER	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 99 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
Mitochondrial protein import	6	15.7×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	4
Uncertain significance	76
Likely benign	72
Benign	14

Top pathogenic / likely-pathogenic (12)

Variant ID	HGVS	Classification
1184607	NM_005262.3(GFER):c.575A>G (p.Asp192Gly)	Pathogenic
1455115	NC_000016.9:g.(?2034220)(2136892_?)del	Pathogenic
1455610	NC_000016.9:g.(?2029297)(2096295_?)del	Pathogenic
1696839	NC_000016.10:g.1903155_2093402del	Pathogenic
1808105	GRCh37/hg19 16p13.3(chr16:2021144-2146432)x1	Pathogenic
2423309	NC_000016.9:g.(?2034220)(2152787_?)del	Pathogenic
521763	NM_005262.3(GFER):c.566C>G (p.Ser189Ter)	Pathogenic
8691	NM_005262.3(GFER):c.581G>A (p.Arg194His)	Pathogenic
4819609	NM_005262.3(GFER):c.226G>T (p.Asp76Tyr)	Likely pathogenic
666364	NM_005262.3(GFER):c.259-25_259-24del	Likely pathogenic
807351	NM_005262.3(GFER):c.502C>T (p.Gln168Ter)	Likely pathogenic
916074	NM_005262.3(GFER):c.559G>T (p.Asp187Tyr)	Likely pathogenic

SpliceAI

300 predictions. Top by Δscore:

Variant	Effect	Δscore
16:1985861:CACA:C	acceptor_loss	0.9900
16:1985864:A:AG	acceptor_gain	0.9900
16:1985864:A:C	acceptor_loss	0.9900
16:1985865:G:GG	acceptor_gain	0.9900
16:1985865:GGCT:G	acceptor_gain	0.9900
16:1986007:G:GT	donor_gain	0.9900
16:1984745:AGC:A	acceptor_gain	0.9700
16:1984746:GCG:G	acceptor_gain	0.9700
16:1985862:ACAG:A	acceptor_gain	0.9700
16:1986034:G:GA	donor_gain	0.9700
16:1985864:AG:A	acceptor_gain	0.9600
16:1985865:GG:G	acceptor_gain	0.9600
16:1986033:T:TA	donor_gain	0.9600
16:1984940:AAAGG:A	donor_loss	0.9500
16:1984942:AGG:A	donor_loss	0.9500
16:1984943:GGT:G	donor_loss	0.9500
16:1984944:G:C	donor_loss	0.9500
16:1984945:T:G	donor_loss	0.9500
16:1984472:AGAAG:A	donor_loss	0.9400
16:1984473:GAAG:G	donor_gain	0.9400
16:1984474:AAG:A	donor_loss	0.9400
16:1984475:AG:A	donor_loss	0.9400
16:1984476:GGTG:G	donor_loss	0.9400
16:1984477:G:C	donor_loss	0.9400
16:1984478:T:G	donor_loss	0.9400
16:1984745:A:AG	acceptor_gain	0.9400
16:1984745:AGCG:A	acceptor_gain	0.9400
16:1984746:G:GG	acceptor_gain	0.9400
16:1984746:GCGG:G	acceptor_gain	0.9400
16:1985863:C:G	acceptor_gain	0.9400

AlphaMissense

1344 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:1984809:G:C	W107C	0.999
16:1984809:G:T	W107C	0.999
16:1984804:A:C	S106R	0.998
16:1984806:C:A	S106R	0.998
16:1984806:C:G	S106R	0.998
16:1984807:T:A	W107R	0.998
16:1984807:T:C	W107R	0.998
16:1984819:C:G	H111D	0.998
16:1985993:T:A	W195R	0.998
16:1985993:T:C	W195R	0.998
16:1985995:G:C	W195C	0.998
16:1985995:G:T	W195C	0.998
16:1984913:G:A	C142Y	0.996
16:1985917:G:C	W169C	0.996
16:1985917:G:T	W169C	0.996
16:1985921:T:A	C171S	0.996
16:1985922:G:C	C171S	0.996
16:1985930:C:G	H174D	0.996
16:1985966:T:C	F186L	0.996
16:1985968:C:A	F186L	0.996
16:1985968:C:G	F186L	0.996
16:1984829:C:A	A114D	0.995
16:1984837:T:G	Y117D	0.995
16:1985915:T:A	W169R	0.995
16:1985915:T:C	W169R	0.995
16:1985921:T:C	C171R	0.995
16:1985928:T:C	L173P	0.995
16:1985997:G:C	R196P	0.995
16:1984819:C:A	H111N	0.994
16:1984906:T:G	Y140D	0.994

dbSNP variants (sampled 300 via entrez): RS1000015313 (16:1984196 C>T), RS1000407179 (16:1986372 G>A,T), RS1000521284 (16:1982785 C>T), RS1001437970 (16:1982394 G>A,C), RS1001448390 (16:1987136 G>A,C), RS1001655581 (16:1985214 G>A), RS1001685389 (16:1985524 A>G), RS1002443332 (16:1983549 G>A), RS1002509390 (16:1982895 G>A), RS1002691909 (16:1987791 A>G), RS1003355020 (16:1984298 T>C), RS1003357467 (16:1986459 G>A), RS1004515353 (16:1986877 G>A), RS1004735340 (16:1983582 C>A,T), RS1005019398 (16:1982203 C>T)

Disease associations

OMIM: gene MIM:600924 | disease phenotypes: MIM:613076, MIM:613254

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Mondo (3): congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome (MONDO:0013116), tuberous sclerosis 2 (MONDO:0013199), mitochondrial disease (MONDO:0044970)

Orphanet (3): Congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome (Orphanet:330054), Tuberous sclerosis complex (Orphanet:805), Mitochondrial disease (Orphanet:68380)

HPO phenotypes

18 total (18 of 18 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0000408	Progressive sensorineural hearing impairment
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000519	Developmental cataract
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001315	Reduced tendon reflexes
HP:0001324	Muscle weakness
HP:0001583	Rotary nystagmus
HP:0002079	Hypoplasia of the corpus callosum
HP:0003128	Lactic acidosis
HP:0003198	Myopathy
HP:0008936	Axial hypotonia
HP:0008972	Decreased activity of mitochondrial respiratory chain
HP:0012343	Decreased circulating ferritin concentration
HP:0030089	Abnormal muscle fiber protein expression

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C567769	Myopathy, Mitochondrial Progressive, With Congenital Cataract, Hearing Loss, And Developmental Delay (supp.)
C566021	Tuberous Sclerosis 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1741189 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

11 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 195,194 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1026	FENOLDOPAM MESYLATE	4	2,560
CHEMBL1200469	PROMAZINE HYDROCHLORIDE	4	2,273
CHEMBL1200750	PROMETHAZINE HYDROCHLORIDE	4	9,776
CHEMBL1200895	PHENELZINE SULFATE	4	5,019
CHEMBL1356238	PYRITHIONE	4	15,582
CHEMBL1557	DOPAMINE HYDROCHLORIDE	4	42,025
CHEMBL1712842	MEPAZINE ACETATE	4	11
CHEMBL1713	CHLORPROMAZINE HYDROCHLORIDE	4	13,209
CHEMBL715	OLANZAPINE	4	40,057
CHEMBL165	RESVERATROL	3	60,144
CHEMBL83527	PTEROSTILBENE	2	4,538

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

ChEMBL bioactivities

1273 potent at pChembl≥5 of 1431 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.30	AC50	5	nM	CHEMBL2001554
8.30	AC50	5	nM	CHEMBL3194699
8.15	AC50	7	nM	CHEMBL1314092
8.10	AC50	8	nM	CHEMBL1334528
8.10	AC50	8	nM	CHEMBL1590507
8.05	AC50	9	nM	CHEMBL1994372
8.05	AC50	9	nM	CHEMBL538542
8.05	AC50	9	nM	CHEMBL1451763
8.05	AC50	9	nM	CHEMBL1321939
8.05	AC50	9	nM	CHEMBL1383770
8.00	AC50	10	nM	CHEMBL1384636
8.00	AC50	10	nM	CHEMBL1421202
8.00	AC50	10	nM	CHEMBL1345455
8.00	AC50	10	nM	CHEMBL1393642
8.00	AC50	10	nM	CHEMBL1568298
7.96	AC50	11	nM	CHEMBL1608601
7.96	AC50	11	nM	CHEMBL3197392
7.89	AC50	13	nM	CHEMBL3197936
7.89	AC50	13	nM	CHEMBL1727288
7.82	AC50	15	nM	CHEMBL1509716
7.80	AC50	16	nM	CHEMBL52101
7.80	AC50	16	nM	CHEMBL1391665
7.77	AC50	17	nM	CHEMBL1726783
7.75	AC50	18	nM	CHEMBL1461059
7.70	AC50	20	nM	CHEMBL1353098
7.70	AC50	20	nM	CHEMBL3209857
7.68	AC50	21	nM	CHEMBL1580609
7.66	AC50	22	nM	CHEMBL1549086
7.66	AC50	22	nM	CHEMBL1730847
7.62	AC50	24	nM	CHEMBL1362247
7.60	AC50	25	nM	CHEMBL2005764
7.60	AC50	25	nM	CHEMBL1708249
7.60	AC50	25	nM	CHEMBL3199692
7.57	AC50	27	nM	CHEMBL1376053
7.57	AC50	27	nM	CHEMBL1491555
7.55	AC50	28	nM	CHEMBL3208276
7.55	AC50	28	nM	CHEMBL3210311
7.51	AC50	31	nM	CHEMBL1411640
7.51	AC50	31	nM	CHEMBL1093074
7.50	AC50	32	nM	CHEMBL1462827
7.48	AC50	33	nM	CHEMBL1586957
7.47	AC50	34	nM	CHEMBL1412545
7.46	AC50	35	nM	CHEMBL2369291
7.46	AC50	35	nM	CHEMBL1409203
7.46	AC50	35	nM	CHEMBL1387497
7.42	AC50	38	nM	CHEMBL1610977
7.41	AC50	39	nM	CHEMBL3196427
7.41	AC50	39	nM	CHEMBL1599886
7.40	AC50	40	nM	CHEMBL1491577
7.37	AC50	43	nM	CHEMBL1712248

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases methylation	2
aristolochic acid I	increases expression	1
sodium arsenite	decreases expression, affects cotreatment	1
cobaltous chloride	increases expression	1
perfluorooctanoic acid	increases expression	1
abrine	increases expression	1
(+)-JQ1 compound	decreases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Caffeine	decreases phosphorylation	1
Carbon Tetrachloride	affects response to substance	1
Cisplatin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Hydrogen Peroxide	affects response to substance	1
Methotrexate	decreases expression	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Testosterone	decreases expression	1
Toluene	decreases expression	1
Tretinoin	affects cotreatment, decreases expression	1
Cyclosporine	increases expression	1
Copper Sulfate	decreases expression	1
tert-Butylhydroperoxide	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1738573	Binding	PUBCHEM_BIOASSAY: HTS-Luminescent assay for inhibitors of ALR by detection of hydrogen peroxide production Measured in Biochemical System Using Plate Reader - 2036-02_Inhibitor_Dose_CherryPick_Activity. (Class of assay: confirmatory) [Relat	PubChem BioAssay data set

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_W371	HepG2 hALR	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
NCT02201212	PHASE2	COMPLETED	Everolimus for Cancer With TSC1 or TSC2 Mutation
NCT05103358	PHASE2	ACTIVE_NOT_RECRUITING	Phase 2 Basket Trial of Nab-sirolimus in Patients With Malignant Solid Tumors With Pathogenic Alterations in TSC1/TSC2 Genes (PRECISION 1)
NCT02398201	PHASE2	COMPLETED	A Study of Bezafibrate in Mitochondrial Myopathy
NCT02473445	PHASE2	TERMINATED	A Long-term Extension of Study RP103-MITO-001 (NCT02023866) to Assess Cysteamine Bitartrate Delayed-release Capsules (RP103) in Children With Inherited Mitochondrial Disease
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT02805790	PHASE2	COMPLETED	Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT02976038	PHASE2	TERMINATED	Open-Label Extension Trial to Characterize the Long-term Safety and Tolerability of Elamipretide in Subjects With Genetically Confirmed Primary Mitochondrial Myopathy (PMM)
NCT03177798	PHASE2	COMPLETED	Mitochondria and Chronic Kidney Disease
NCT03866954	PHASE2	WITHDRAWN	Trial of Erythrocyte Encapsulated Thymidine Phosphorylase In Mitochondrial Neurogastrointestinal Encephalomyopathy
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04604548	PHASE2	COMPLETED	The KHENEREXT Study
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT04846036	PHASE2	SUSPENDED	The KHENERGYC Study
NCT05650229	PHASE2	RECRUITING	Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease
NCT05972954	PHASE2	COMPLETED	OMT-28 in Patients With Primary Mitochondrial Disease (PMD) (PMD-OPTION)
NCT06017869	PHASE2	RECRUITING	Evaluate the Safety and Therapeutic Effects of a Single Intravenous Infusion (IV) of Autologous CD34+ Cells Enriched With Allogenic Placenta-derived Mitochondria in Patients With a Diagnosis of Pearson Syndrome (PS)
NCT07514338	PHASE2	NOT_YET_RECRUITING	Open Label Extension to Assess Long Term Safety and Efficacy of KL1333 in Patients With Primary Mitochondrial Disease
NCT00060515	PHASE1	TERMINATED	RG2133 (2’,3’,5’-Tri-O-Acetyluridine) in Mitochondrial Disease
NCT02348125	PHASE1	UNKNOWN	Does Clinical Treatment of Mitochondrial Dysfunction Impact Autism Spectrum Disorder (ASD)?
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT03888716	PHASE1	COMPLETED	A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease
NCT04086329	PHASE1	RECRUITING	Validation of Oxygen Nanosensor in Mitochondrial Myopathy
NCT04643249	PHASE1	COMPLETED	Drug-drug Interaction Study of KL1333 in Healthy Subjects
NCT05241262	PHASE1	RECRUITING	Study of N-acetylcysteine in the Treatment of Patients With the m.3243A>G Mutation and Low Brain Glutathione Levels
NCT05569122	PHASE1	RECRUITING	Applying pGz in Mitochondrial Disease
NCT06819683	PHASE1	RECRUITING	Validation of Nanosensor Oxygen Measurement
NCT07258667	PHASE1	NOT_YET_RECRUITING	Pilot Study of the Efficacy of Nicotinamide (Vitamin B3) in Leber’s Hereditary Optic Neuropathy
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT03817515	Not specified	APPROVED_FOR_MARKETING	Expanded Access for ABI-009 in Patients With Advanced PEComa and Patients With a Malignancy With Relevant Genetic Mutations or mTOR Pathway Activation
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01642056	PHASE1/PHASE2	COMPLETED	EPI-743 for Metabolism or Mitochondrial Disorders
NCT03384420	PHASE1/PHASE2	COMPLETED	A Study to Evaluate the Safety and Therapeutic Effects of Transplantation of MNV-BM-BLD in Pediatric Patients With Pearson Syndrome
NCT06051448	PHASE1/PHASE2	COMPLETED	Promoting Resilience in Stress Management (PRISM) and Clinical-focused Narrative (CFN) Pilot in Adults With Primary Mitochondrial Disease (PMD).
NCT01252979	EARLY_PHASE1	COMPLETED	Ketones & Mitochondrial Heteroplasmy
NCT00786539	Not specified	COMPLETED	Mitochondria Inborn Errors of Metabolism and ANT Defects in Mitochondria Diseases