FDXR

Summary

FDXR (ferredoxin reductase, HGNC:3642) is a protein-coding gene on chromosome 17q25.1, encoding NADPH:adrenodoxin oxidoreductase, mitochondrial (P22570). Serves as the first electron transfer protein in all the mitochondrial P450 systems including cholesterol side chain cleavage in all steroidogenic tissues, steroid 11-beta hydroxylation in the adrenal cortex, 25-OH-vitamin D3-24 hydroxylation in the kidney, and sterol C-27 hydro…. In precision oncology, AR AR-V7 confers sensitivity to Galeterone + Enzalutamide in Prostate Cancer (CIViC Level B); 10 further curated variant–drug associations are listed below. It is a selective cancer dependency (DepMap: 66.1% of cell lines).

This gene encodes a mitochondrial flavoprotein that initiates electron transport for cytochromes P450 receiving electrons from NADPH. Multiple alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 2232 — RefSeq curated summary.

At a glance

• Gene–disease (curated): FDXR-related optic atrophy mitochondrial dysfunction syndrome (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 215 total — 7 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 292
• Precision-oncology evidence (CIViC): 11 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 14 cancer types
• Cancer dependency (DepMap): dependent in 66.1% of screened cell lines
• MANE Select transcript: NM_024417

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3642
Approved symbol	FDXR
Name	ferredoxin reductase
Location	17q25.1
Locus type	gene with protein product
Status	Approved
Aliases	ADR, AR
Ensembl gene	ENSG00000161513
Ensembl biotype	protein_coding
OMIM	103270
Entrez	2232

Gene structure

Transcript identifiers

Ensembl transcripts: 45 — 35 protein_coding, 6 nonsense_mediated_decay, 2 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000293195, ENST00000413947, ENST00000420580, ENST00000442102, ENST00000544854, ENST00000577509, ENST00000577932, ENST00000578473, ENST00000579482, ENST00000579543, ENST00000579893, ENST00000580492, ENST00000581219, ENST00000581530, ENST00000581969, ENST00000582710, ENST00000582944, ENST00000583881, ENST00000583917, ENST00000610946, ENST00000868974, ENST00000868975, ENST00000868976, ENST00000868977, ENST00000868978, ENST00000868979, ENST00000868980, ENST00000933576, ENST00000933577, ENST00000933578, ENST00000933579, ENST00000933580, ENST00000933581, ENST00000946587, ENST00000946588, ENST00000946589, ENST00000946590, ENST00000946591, ENST00000946592, ENST00000946593, ENST00000946594, ENST00000946595, ENST00000946596, ENST00000946597, ENST00000946598

RefSeq mRNA: 7 — MANE Select: NM_024417 NM_001258012, NM_001258013, NM_001258014, NM_001258015, NM_001258016, NM_004110, NM_024417

CCDS: CCDS11707, CCDS58591, CCDS58592, CCDS58593, CCDS58594, CCDS58595, CCDS58596

Canonical transcript exons

ENST00000293195 — 12 exons

Exon	Start	End
ENSE00002719423	74872866	74872994
ENSE00003461582	74866131	74866244
ENSE00003485718	74863896	74864067
ENSE00003497290	74864480	74864564
ENSE00003522271	74865719	74865820
ENSE00003541727	74866446	74866568
ENSE00003542523	74864824	74864931
ENSE00003589823	74866784	74866876
ENSE00003620500	74863076	74863246
ENSE00003638235	74872036	74872133
ENSE00003638826	74864148	74864347
ENSE00003688402	74862497	74862947

Expression profiles

Bgee: expression breadth ubiquitous, 208 present calls, max score 99.39.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.2885 / max 542.0126, expressed in 1766 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
168018	24.2797	1762
168019	0.5643	319
168017	0.4153	227
168016	0.0291	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland cortex	UBERON:0035827	99.39	gold quality
right adrenal gland	UBERON:0001233	99.28	gold quality
left adrenal gland cortex	UBERON:0035825	99.12	gold quality
left adrenal gland	UBERON:0001234	99.09	gold quality
adrenal cortex	UBERON:0001235	99.07	gold quality
adrenal gland	UBERON:0002369	98.06	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	97.75	gold quality
adrenal tissue	UBERON:0018303	97.39	gold quality
right testis	UBERON:0004534	94.47	gold quality
left testis	UBERON:0004533	94.21	gold quality
right uterine tube	UBERON:0001302	94.18	gold quality
testis	UBERON:0000473	92.74	gold quality
spleen	UBERON:0002106	89.94	gold quality
lower esophagus mucosa	UBERON:0035834	89.54	gold quality
left ovary	UBERON:0002119	88.74	gold quality
esophagus mucosa	UBERON:0002469	88.48	gold quality
right ovary	UBERON:0002118	87.91	gold quality
right hemisphere of cerebellum	UBERON:0014890	87.35	gold quality
cerebellar hemisphere	UBERON:0002245	87.00	gold quality
cerebellar cortex	UBERON:0002129	86.81	gold quality
gingival epithelium	UBERON:0001949	86.18	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	86.10	gold quality
ovary	UBERON:0000992	85.93	gold quality
cerebellum	UBERON:0002037	84.98	gold quality
skin of abdomen	UBERON:0001416	84.66	gold quality
gingiva	UBERON:0001828	84.56	gold quality
skin of leg	UBERON:0001511	84.51	gold quality
mucosa of transverse colon	UBERON:0004991	84.47	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.49	gold quality
apex of heart	UBERON:0002098	83.32	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6911	yes	257.76
E-GEOD-134144	yes	40.06
E-ANND-3	yes	3.39

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR5A1, TP53, TP63, TP73

miRNA regulators (miRDB)

8 targeting FDXR, 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-4530	99.69	66.47	1509
HSA-MIR-4777-3P	99.15	68.92	626
HSA-MIR-6734-3P	99.15	66.27	1627
HSA-MIR-2355-5P	98.83	65.51	1589
HSA-MIR-1301-3P	98.64	68.27	1071
HSA-MIR-5047	98.64	68.62	1035
HSA-MIR-338-3P	98.14	67.38	1137
HSA-MIR-3936	97.64	64.47	732

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 66.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 21)

• comparison of catalytic properties between conditions of limiting and saturating adrenodoxin reductase [cytochrome P450scc] (PMID:12137805)
• The ferredoxin reductase gene is regulated by the p53 family and sensitizes cells to oxidative stress-induced apoptosis (PMID:12370809)
• ADXR rate of hydroxylation was linear with incubation time. (PMID:12782149)
• results suggest that both FDX1 and FDX2 and their likely reductase partner, FDXR, contribute to iron-sulfur cluster biogenesis (PMID:22101253)
• These results indicated that abundant FDXR expression in these steroidogenic cells was maintained through SF-1 binding to the intronic enhancer of the FDXR gene (PMID:24321386)
• NOS-3 overexpression resulted in an increased sensitivity to anti-Fas induced cell death, independently of AR expression and CatD activity. (PMID:25712867)
• Using surface plasmon resonance, physiologically relevant concentrations of isatin (25-100 muM) were found to increase affinity of interactions between human recombinant ferrochelatase (FECH) and NADPH-dependent adrenodoxin reductase (ADR). (PMID:28905435)
• Mutation in FDXR gene is associated with Sensorial Neuropathies. (PMID:28965846)
• we identified a novel disease-causing gene FDXR associated with mitochondrial diseases. The biallelic FDXR mutations cause optic atrophy and neuropathy. we found that FDXR levels are significantly lower in the patient fibroblast cells with the homozygous mutations R392W. Fourteen missense or nonsense FDXR mutations were identified in this study and eight of them (I143F, V158M, T211A, I213F, K280*, R315*, C359Y, D374N) clu (PMID:29040572)
• These data provide further insight into the pathogenic mechanism of FDXR-mediated central neuropathy, and suggest an avenue for mechanistic studies that will ultimately inform treatment. (PMID:30250212)
• FDXR regulates TP73 tumor suppressor via IRP2 to modulate aging and tumor suppression. (PMID:32304229)
• In Vivo Validation of Alternative FDXR Transcripts in Human Blood in Response to Ionizing Radiation. (PMID:33113898)
• Substrate-induced modulation of protein-protein interactions within human mitochondrial cytochrome P450-dependent system. (PMID:33271253)
• Expanding the clinical and genetic spectrum of FDXR deficiency by functional validation of variants of uncertain significance. (PMID:33348459)
• Expanding the FDXR-Associated Disease Phenotype: Retinal Dystrophy Is a Recurrent Ocular Feature. (PMID:33938912)
• Characterization of a Cleavable Fusion of Human CYP24A1 with Adrenodoxin Reveals the Variable Role of Hydrophobics in Redox Partner Binding. (PMID:34979083)
• Four Genes Predictive for the Severity of Hematological Damage Reveal a Similar Response after X Irradiation and Chemotherapy. (PMID:36480042)
• FDXR-associated disease: a challenging differential diagnosis with inflammatory peripheral neuropathy. (PMID:37046037)
• FDXR-Associated Oculopathy: Congenital Amaurosis and Early-Onset Severe Retinal Dystrophy as Common Presenting Features in a Chinese Population. (PMID:37107710)
• FDXR-associated disease in a Chinese cohort: Unraveling expanded ocular phenotypes and genetic spectrum. (PMID:37481223)
• FDXR variants cause adrenal insufficiency and atypical sexual development. (PMID:38885337)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fdxr	ENSDARG00000089369
drosophila_melanogaster	dare	FBGN0015582
caenorhabditis_elegans		WBGENE00013376

Paralogs (2): DHODH (ENSG00000102967), DPYD (ENSG00000188641)

Protein

Protein identifiers

NADPH:adrenodoxin oxidoreductase, mitochondrial — P22570 (reviewed: P22570)

Alternative names: Ferredoxin–NADP(+) reductase

All UniProt accessions (14): A0A0A0MSZ4, A0A0A0MT64, A0A0A0MTN9, A0A0A0MTR6, A0A0C4DFN8, A0A0C4DGN7, P22570, J3KRG8, J3KS64, J3KTA3, J3QKZ8, J3QQW7, J3QQX3, J3QSF9

UniProt curated annotations — full annotation on UniProt →

Function. Serves as the first electron transfer protein in all the mitochondrial P450 systems including cholesterol side chain cleavage in all steroidogenic tissues, steroid 11-beta hydroxylation in the adrenal cortex, 25-OH-vitamin D3-24 hydroxylation in the kidney, and sterol C-27 hydroxylation in the liver. Also acts as a ferredoxin–NADP(+) reductase essential for coenzyme Q biosynthesis: together with FDX2, transfers the electrons required for the hydroxylation reaction performed by COQ6.

Subunit / interactions. Monomer. Interacts directly with FDX1.

Subcellular location. Mitochondrion. Mitochondrion inner membrane.

Disease relevance. Auditory neuropathy and optic atrophy (ANOA) [MIM:617717] An autosomal recessive disease characterized by hearing loss, visual impairment and optic atrophy, with onset in the first or second decades of life. Optic atrophy is caused by degeneration of nerve fibers which arise in the retina and converge to form the optic disk, optic nerve, optic chiasm and optic tracts. The disease is caused by variants affecting the gene represented in this entry. Multiple mitochondrial dysfunctions syndrome 9B (MMDS9B) [MIM:620887] An autosomal recessive disorder characterized by optic and/or auditory neuropathy with onset in the first two decades of life, in some cases associated with developmental delay or regression, global hypotonia, pyramidal, cerebellar signs, and seizures. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Steroid metabolism; cholesterol metabolism.

Miscellaneous. Represents 10-20% of all adrenodoxin reductase mRNAs and seems to be inactive.

Similarity. Belongs to the ferredoxin–NADP reductase type 1 family.

Isoforms (7)

UniProt ID	Names	Canonical?
P22570-1	Short	yes
P22570-2	Long
P22570-3	3
P22570-4	4
P22570-5	5
P22570-6	6
P22570-7	7

RefSeq proteins (7): NP_001244941, NP_001244942, NP_001244943, NP_001244944, NP_001244945, NP_004101, NP_077728* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR021163	Ferredox_Rdtase_adrenod	Family
IPR036188	FAD/NAD-bd_sf	Homologous_superfamily
IPR055275	Ferredox_Rdtase	Family

Pfam: PF13450

Catalyzed reactions (Rhea), 2 shown:

• 2 reduced [2Fe-2S]-[ferredoxin] + NADP(+) + H(+) = 2 oxidized [2Fe-2S]-[ferredoxin] + NADPH (RHEA:20125)
• 2 reduced [adrenodoxin] + NADP(+) + H(+) = 2 oxidized [adrenodoxin] + NADPH (RHEA:42312)

UniProt features (60 total): sequence variant 38, binding site 10, splice variant 7, modified residue 2, transit peptide 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P22570-F1	91.66	0.88

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 (10): 405–407; 405; 49; 69; 77; 113; 184–187; 228–229; 240; 398

Post-translational modifications (2): 310, 317

Function

Pathways and Gene Ontology

Reactome pathways

15 pathways

ID	Pathway
R-HSA-196108	Pregnenolone biosynthesis
R-HSA-211976	Endogenous sterols
R-HSA-2395516	Electron transport from NADPH to Ferredoxin
R-HSA-5579026	Defective CYP11A1 causes AICSR
R-HSA-1362409	Mitochondrial iron-sulfur cluster biogenesis
R-HSA-1430728	Metabolism
R-HSA-1643685	Disease
R-HSA-196071	Metabolism of steroid hormones
R-HSA-211859	Biological oxidations
R-HSA-211897	Cytochrome P450 - arranged by substrate type
R-HSA-211945	Phase I - Functionalization of compounds
R-HSA-556833	Metabolism of lipids
R-HSA-5579029	Metabolic disorders of biological oxidation enzymes
R-HSA-5668914	Diseases of metabolism
R-HSA-8957322	Metabolism of steroids

MSigDB gene sets: 1148 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, GSE45365_NK_CELL_VS_CD8A_DC_UP, MORF_RAGE, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_SINGLE_FERTILIZATION, MODULE_52, MODULE_92, GOBP_POSITIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MAMMARY_GLAND_MORPHOGENESIS, REACTOME_BIOLOGICAL_OXIDATIONS, FARMER_BREAST_CANCER_CLUSTER_7, GOBP_GLAND_MORPHOGENESIS

GO Biological Process (6): generation of precursor metabolites and energy (GO:0006091), steroid biosynthetic process (GO:0006694), ubiquinone biosynthetic process (GO:0006744), cholesterol metabolic process (GO:0008203), lipid metabolic process (GO:0006629), steroid metabolic process (GO:0008202)

GO Molecular Function (2): ferredoxin-NADP+ reductase activity (GO:0004324), oxidoreductase activity (GO:0016491)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Metabolism	3
Metabolism of steroid hormones	1
Cytochrome P450 - arranged by substrate type	1
Mitochondrial iron-sulfur cluster biogenesis	1
Metabolic disorders of biological oxidation enzymes	1
Metabolism of steroids	1
Phase I - Functionalization of compounds	1
Biological oxidations	1
Diseases of metabolism	1
Disease	1
Metabolism of lipids	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
metabolic process	1
steroid metabolic process	1
lipid biosynthetic process	1
ubiquinone metabolic process	1
quinone biosynthetic process	1
sterol metabolic process	1
secondary alcohol metabolic process	1
primary metabolic process	1
lipid metabolic process	1
ferredoxin-[NAD(P)H] reductase activity	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
mitochondrion	1
intracellular organelle lumen	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2220 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FDXR	FDX1	P10109	999
FDXR	CYP11A1	P05108	988
FDXR	FDX2	Q6P4F2	871
FDXR	FHIT	P49789	864
FDXR	CYP27A1	Q02318	833
FDXR	SCP2	P22307	796
FDXR	STAR	P49675	779
FDXR	NFS1	Q9Y697	766
FDXR	LYRM4	Q9HD34	766
FDXR	RFK	Q969G6	747
FDXR	CYP11B1	P15538	739
FDXR	ISCU	Q9H1K1	722
FDXR	FXN	Q16595	690
FDXR	IBA57	Q5T440	685
FDXR	COQ6	Q9Y2Z9	675

IntAct

44 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
BPNT1	GTPBP10	psi-mi:“MI:0914”(association)	0.530
EMILIN1	METTL15	psi-mi:“MI:0914”(association)	0.530
NPY2R	RTL8C	psi-mi:“MI:0914”(association)	0.530
OTC	RTL8C	psi-mi:“MI:0914”(association)	0.530
GATC	NME4	psi-mi:“MI:0914”(association)	0.530
YBEY	NME4	psi-mi:“MI:0914”(association)	0.530
C1QTNF9B	PLOD3	psi-mi:“MI:0914”(association)	0.530
EIPR1	LDHC	psi-mi:“MI:0914”(association)	0.530
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
NDUFS3	ACOT7	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
S100B	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
S100A2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
COQ3	TARS3	psi-mi:“MI:0914”(association)	0.350
UQCRFS1	VWA8	psi-mi:“MI:0914”(association)	0.350
MALSU1	VWA8	psi-mi:“MI:0914”(association)	0.350
PFDN5	GTPBP10	psi-mi:“MI:0914”(association)	0.350
TUBB4B	POTEF	psi-mi:“MI:0914”(association)	0.350
GLMP	RTL8C	psi-mi:“MI:0914”(association)	0.350
NIT1	NUDT19	psi-mi:“MI:0914”(association)	0.350
THBS3	APBB1	psi-mi:“MI:0914”(association)	0.350
ZNG1A	TCERG1	psi-mi:“MI:0914”(association)	0.350
A1BG	WDR62	psi-mi:“MI:0914”(association)	0.350
KLHL10	BCL2L11	psi-mi:“MI:0914”(association)	0.350
LMNB2	SPOP	psi-mi:“MI:0914”(association)	0.350
TBC1D22A	ACSL4	psi-mi:“MI:0914”(association)	0.350
ACSM5	CLUH	psi-mi:“MI:0914”(association)	0.350

BioGRID (109): FDXR (Affinity Capture-MS), FDXR (Affinity Capture-MS), FDXR (Affinity Capture-MS), FDXR (Affinity Capture-MS), FDXR (Affinity Capture-MS), FDXR (Co-fractionation), GSR (Co-fractionation), FDXR (Proximity Label-MS), FDXR (Affinity Capture-MS), FDXR (Affinity Capture-MS), FDXR (Affinity Capture-MS), FDXR (Affinity Capture-MS), FDXR (Affinity Capture-MS), FDXR (Affinity Capture-MS), FDXR (Affinity Capture-MS)

ESM2 similar proteins: A0LEF5, A1K1Q4, A2CDR8, A4JA22, A4SUS3, A4VS73, A5GPI1, A5GWP3, B1K1K2, B1ZWP4, B2JJL1, B2T7L1, B2UGW0, B4E581, C1D0A9, O32886, P08165, P22570, P56522, P82861, P9WIQ2, P9WIQ3, Q0ADD6, Q0BJM8, Q0I6D8, Q0K5L6, Q13SP0, Q1BR97, Q1GXL9, Q1LHJ8, Q2JI26, Q2JXG8, Q2L2T3, Q2Y5B4, Q39KY9, Q3AUG9, Q3IYH4, Q3J6M0, Q46VW9, Q5RB71

Diamond homologs: E1V8I0, O32886, O33064, O59710, P08165, P22570, P48360, P56522, P65529, P82861, P9WIQ2, P9WIQ3, P9WJI0, P9WJI1, Q03460, Q0JKD0, Q54KG7, Q61578, Q8U195, Q8VQF5, Q8W3L1, Q9LV03, Q9V3T9, O08340, O34399, P37127, P9WN18, P9WN19, Q12680, Q9C102, G9F1Y9, O09046, O60341, O87278, P09832, P0DXY1, P19410, P42593, Q05756, Q0DG35

SIGNOR signaling

0 interactions.

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 14 cancer types — BRCA, CHOL, COAD, DLBCLNOS, GBC, GBM, LMS, NPC, NSCLC, PCM, PRAD, PROSTATE…(+2 more).

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	15
Uncertain significance	105
Likely benign	27
Benign	31

Top pathogenic / likely-pathogenic (22)

Variant ID	HGVS	Classification
1803970	NM_024417.5(FDXR):c.564_575del (p.Leu189_Ala192del)	Pathogenic
1803971	NM_024417.5(FDXR):c.332T>C (p.Val111Ala)	Pathogenic
2263800	NM_024417.5(FDXR):c.778_779dup (p.Leu260fs)	Pathogenic
3252085	NM_024417.5(FDXR):c.178-86C>T	Pathogenic
3252092	c.1002+1G-A	Pathogenic
441238	NM_024417.5(FDXR):c.1255C>T (p.Gln419Ter)	Pathogenic
441239	NM_024417.5(FDXR):c.643C>G (p.Leu215Val)	Pathogenic
1176691	NM_024417.5(FDXR):c.1102G>A (p.Asp368Asn)	Likely pathogenic
1176693	NM_024417.5(FDXR):c.138_145del (p.Gly47fs)	Likely pathogenic
1185063	NM_024417.5(FDXR):c.368del (p.Gln123fs)	Likely pathogenic
1217114	NM_024417.5(FDXR):c.1208C>T (p.Pro403Leu)	Likely pathogenic
1491548	NM_024417.5(FDXR):c.507+1G>A	Likely pathogenic
3048648	NM_024417.5(FDXR):c.3G>A (p.Met1Ile)	Likely pathogenic
3775488	NM_024417.5(FDXR):c.173dup (p.His60fs)	Likely pathogenic
3779651	NM_024417.5(FDXR):c.80-135_80-134insA	Likely pathogenic
4081391	NM_024417.5(FDXR):c.803-2A>G	Likely pathogenic
4292118	NM_024417.5(FDXR):c.508-1G>A	Likely pathogenic
689759	NM_024417.5(FDXR):c.619A>T (p.Ile207Phe)	Likely pathogenic
689760	NM_024417.5(FDXR):c.472G>A (p.Val158Met)	Likely pathogenic
817643	NM_024417.5(FDXR):c.929del (p.Ser310fs)	Likely pathogenic
983267	NM_024417.5(FDXR):c.463C>T (p.Arg155Trp)	Likely pathogenic
986189	NM_024417.5(FDXR):c.394-1G>C	Likely pathogenic

SpliceAI

5503 predictions. Top by Δscore:

Variant	Effect	Δscore
17:74863060:G:C	donor_gain	1.0000
17:74863140:AG:A	donor_gain	1.0000
17:74863150:T:TA	donor_gain	1.0000
17:74863242:GAGGC:G	acceptor_gain	1.0000
17:74863244:GGC:G	acceptor_gain	1.0000
17:74863246:CCTGA:C	acceptor_loss	1.0000
17:74863247:C:CC	acceptor_gain	1.0000
17:74864146:ACCT:A	donor_gain	1.0000
17:74864147:CCTC:C	donor_gain	1.0000
17:74864346:CT:C	acceptor_gain	1.0000
17:74864478:AC:A	donor_gain	1.0000
17:74864479:CC:C	donor_gain	1.0000
17:74864564:CCT:C	acceptor_gain	1.0000
17:74864566:T:C	acceptor_gain	1.0000
17:74864566:T:TC	acceptor_gain	1.0000
17:74864572:G:C	acceptor_gain	1.0000
17:74864572:G:GC	acceptor_gain	1.0000
17:74864579:C:CT	acceptor_gain	1.0000
17:74864580:A:T	acceptor_gain	1.0000
17:74865714:CTCA:C	donor_loss	1.0000
17:74865715:TCA:T	donor_loss	1.0000
17:74865717:A:AC	donor_gain	1.0000
17:74865717:ACCT:A	donor_gain	1.0000
17:74865718:C:CC	donor_gain	1.0000
17:74865718:C:CG	donor_loss	1.0000
17:74865718:CCT:C	donor_gain	1.0000
17:74865718:CCTC:C	donor_gain	1.0000
17:74865816:TCCAG:T	acceptor_gain	1.0000
17:74865817:CCAG:C	acceptor_gain	1.0000
17:74865817:CCAGC:C	acceptor_gain	1.0000

AlphaMissense

3141 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:74863229:A:G	W398R	0.998
17:74863229:A:T	W398R	0.998
17:74863179:G:C	S414R	0.997
17:74863179:G:T	S414R	0.997
17:74863181:T:G	S414R	0.997
17:74863227:C:A	W398C	0.997
17:74863227:C:G	W398C	0.997
17:74865770:G:C	N186K	0.997
17:74865770:G:T	N186K	0.997
17:74866829:A:C	F75L	0.996
17:74866829:A:T	F75L	0.996
17:74866831:A:G	F75L	0.996
17:74865774:C:A	G185V	0.995
17:74865775:C:A	G185W	0.995
17:74863201:A:T	I407K	0.994
17:74863236:G:C	C395W	0.994
17:74863988:C:T	G361E	0.994
17:74863993:G:C	S359R	0.994
17:74863993:G:T	S359R	0.994
17:74863995:T:G	S359R	0.994
17:74865758:G:C	D190E	0.994
17:74865758:G:T	D190E	0.994
17:74865759:T:A	D190V	0.994
17:74866242:G:C	S132R	0.994
17:74866242:G:T	S132R	0.994
17:74866244:T:G	S132R	0.994
17:74866784:C:A	K90N	0.994
17:74866784:C:G	K90N	0.994
17:74872087:A:C	C42W	0.994
17:74863233:G:C	S396R	0.993

dbSNP variants (sampled 300 via entrez): RS1000102186 (17:74865428 A>C,G), RS1000536266 (17:74865162 T>C), RS1001220932 (17:74874744 AAAC>A), RS1001295874 (17:74868781 TCCTC>T), RS1001438184 (17:74870324 C>A), RS1002208991 (17:74869467 C>A,T), RS1002311465 (17:74873482 G>A,C,T), RS1002645820 (17:74873526 C>T), RS1002759970 (17:74868199 C>T), RS1002984292 (17:74873458 T>C), RS1003040349 (17:74863391 T>A,C), RS1003363641 (17:74873548 G>A), RS1003722405 (17:74874906 G>A,T), RS1003724875 (17:74872657 T>C), RS1003745829 (17:74869133 T>C)

Disease associations

OMIM: gene MIM:103270 | disease phenotypes: MIM:617717, MIM:620887, MIM:609129, MIM:261600

GenCC curated gene-disease

Disease	Classification	Inheritance
auditory neuropathy-optic atrophy syndrome	Strong	Autosomal recessive
optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
FDXR-related optic atrophy mitochondrial dysfunction syndrome	Definitive	AR

Mondo (7): auditory neuropathy-optic atrophy syndrome (MONDO:0060582), multiple mitochondrial dysfunctions syndrome 9b (MONDO:0971174), auditory neuropathy (MONDO:0021944), inherited retinal dystrophy (MONDO:0019118), optic atrophy (MONDO:0003608), phenylketonuria (MONDO:0009861), optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome (MONDO:0034092)

Orphanet (4): Auditory neuropathy-optic atrophy syndrome (Orphanet:542585), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome (Orphanet:543470), Phenylketonuria (Orphanet:716)

HPO phenotypes

292 total (30 of 292 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000023	Inguinal hernia
HP:0000027	Azoospermia
HP:0000028	Cryptorchidism
HP:0000029	Testicular atrophy
HP:0000037	Male pseudohermaphroditism
HP:0000047	Hypospadias
HP:0000048	Bifid scrotum
HP:0000051	Perineal hypospadias
HP:0000054	Micropenis
HP:0000062	Ambiguous genitalia
HP:0000066	Labial hypoplasia
HP:0000098	Tall stature
HP:0000135	Hypogonadism
HP:0000144	Decreased fertility
HP:0000151	Aplasia of the uterus
HP:0000153	Abnormality of the mouth
HP:0000175	Cleft palate
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000484	Hyperopic astigmatism
HP:0000486	Strabismus
HP:0000488	Retinopathy
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000510	Rod-cone dystrophy
HP:0000518	Cataract

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST012490_236	Femur bone mineral density x serum urate levels interaction	6.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D010661	Phenylketonurias	C10.228.140.163.100.687; C16.320.565.100.766; C16.320.565.189.687; C18.452.132.100.687; C18.452.648.100.766; C18.452.648.189.687
D058499	Retinal Dystrophies	C11.768.585.658
C538268	Auditory neuropathy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

Clinical evidence (CIViC)

Drug × variant × indication: 11 predictive associations from 17 curated evidence items; also 3 oncogenic, 1 functional, 1 prognostic.

Variant	Therapy	Indication	Effect	Level	CIViC
AR AR-V7	Galeterone + Enzalutamide	Prostate Cancer	Sensitivity/Response	CIViC B	EID9549
AR OVEREXPRESSION	Bicalutamide + Leuprolide	Salivary Gland Cancer	Sensitivity/Response	CIViC B	EID6953
AR AR-V7	Abiraterone + Enzalutamide	Prostate Cancer	Resistance	CIViC B	EID12463 +5
AR AR-V7	Enzalutamide + Abiraterone	Prostate Cancer	Resistance	CIViC B	EID12464 +1
AR AR-V7	Cabazitaxel	Prostate Cancer	Resistance	CIViC B	EID9552
AR AR-V7	Enzalutamide	Prostate Cancer	Resistance	CIViC B	EID9554
AR Mutation	Flutamide + Cyproterone Acetate + Nilutamide + Bicalutamide	Prostate Cancer	Resistance	CIViC B	EID1521
AR AR-V7	Abiraterone Acetate	Salivary Gland Cancer	Resistance	CIViC C	EID6954
AR OVEREXPRESSION	Dactolisib	Breast Cancer	Sensitivity/Response	CIViC D	EID859
AR F877L	Enzalutamide + Apalutamide	Prostate Cancer	Resistance	CIViC D	EID447
AR W742	Bicalutamide	Prostate Carcinoma	Resistance	CIViC D	EID448

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression	9
Fluorouracil	increases expression, affects reaction, increases reaction	6
Aflatoxin B1	affects reaction, affects expression, increases expression	6
bisphenol A	affects expression, decreases expression, increases expression	5
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	5
Cisplatin	decreases expression, affects cotreatment, increases expression	4
Cyclosporine	decreases expression	4
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance, increases expression	3
Doxorubicin	increases expression	3
Hydrogen Peroxide	affects cotreatment, decreases expression, increases expression	3
tungsten carbide	affects cotreatment, increases expression	2
entinostat	increases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	2
Acetaminophen	increases expression	2
Cobalt	affects cotreatment, increases expression	2
Methyl Methanesulfonate	increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
tert-Butylhydroperoxide	increases expression	2
Vitamin K 3	affects expression, increases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
sotorasib	affects cotreatment, increases expression	1
propionaldehyde	increases expression	1
nobiletin	decreases expression, decreases reaction	1
potassium perchlorate	decreases expression	1
sodium arsenate	decreases expression, decreases reaction	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, increases expression	1
hydroxyhydroquinone	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A5QA	COS-F2-130	Transformed cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01082328	PHASE4	COMPLETED	Response to Kuvan® in Subjects With Phenylketonuria (PKU) in a 4 Weeks Testing Period
NCT01617070	PHASE4	COMPLETED	Effects of Kuvan on Melatonin Secretion
NCT01965912	PHASE4	COMPLETED	Kuvan®’s Effect on the Cognition of Children With Phenylketonuria
NCT02677870	PHASE4	COMPLETED	The Effectiveness of Kuvan in Amish PKU Patients
NCT03788343	PHASE4	COMPLETED	Phenylalanine and Its Impact on Cognition
NCT04227080	PHASE4	UNKNOWN	BH4 Responsiveness in PAH Deficiency PKU Patients
NCT06780332	PHASE4	ACTIVE_NOT_RECRUITING	Rapid Drug Desensitization Study in Adults Experiencing Hypersensitivity Reactions to Palynziq
NCT06901323	PHASE4	ACTIVE_NOT_RECRUITING	Effect of L-carnitine Supplementation on Phenylalanine and Brain-derived Neurotrophic Factor Levels in Infants and Children With Phenylketonuria
NCT07477691	PHASE4	NOT_YET_RECRUITING	Immune Modulation During Palynziq® Treatment in Adults (IMPALA)
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT00104247	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Phenoptin™ in Subjects With Phenylketonuria Who Have Elevated Phenylalanine Levels
NCT00225615	PHASE3	COMPLETED	A Phase 3, Multicenter, Open-Label Extension Study of Phenoptin in Subjects With PKU Who Have Elevated Phenylalanine Levels
NCT00272792	PHASE3	COMPLETED	Study of Phenoptin to Increase Phenylalanine Tolerance in Phenylketonuric Children on a Phenylalanine-restricted Diet
NCT00332189	PHASE3	COMPLETED	Study of Phenoptin in Subjects With Phenylketonuria Who Participated in Protocols PKU-004 or PKU-006
NCT00838435	PHASE3	COMPLETED	Effect of Kuvan on Neurocognitive Function, Blood Phenylalanine Level, Safety, and Pharmacokinetics in Children With PKU
NCT01114737	PHASE3	COMPLETED	Safety and Therapeutic Effects of Sapropterin Dihydrochloride on Neuropsychiatric Symptoms in Phenylketonuria (PKU) Patients
NCT01376908	PHASE3	COMPLETED	Kuvan® in Phenylketonuria Patients Less Than 4 Years Old
NCT01732471	PHASE3	COMPLETED	Phase 3 Open-label Study to Evaluate the Response and Safety of Kuvan® in Subjects With Phenylketonuria
NCT01819727	PHASE3	COMPLETED	An Open-Label Phase 3 Study of BMN 165 for Adults With PKU Not Previously Treated w/ BMN 165
NCT01889862	PHASE3	COMPLETED	Phase 3 Study to Evaluate the Efficacy & Safety of Self-Administered Injections of BMN165 by Adults With PKU
NCT03694353	PHASE3	COMPLETED	Safety and Efficacy of Self Administered Injections of Pegvaliase (>40mg/Day Dose) in Adults With PKU
NCT05099640	PHASE3	COMPLETED	A Study of PTC923 in Participants With Phenylketonuria
NCT05166161	PHASE3	ACTIVE_NOT_RECRUITING	A Long-Term Safety Study of PTC923 in Participants With Phenylketonuria
NCT05270837	PHASE3	ACTIVE_NOT_RECRUITING	Study to Evaluate the Safety and Efficacy of Pegvaliase in Adolescents (Ages 12-17) With Phenylketonuria
NCT05764239	PHASE3	TERMINATED	Efficacy and Safety of SYNB1934 in Patients With PKU (SYNPHENY-3)
NCT06302348	PHASE3	RECRUITING	A Study of Sepiapterin in Participants With Phenylketonuria (PKU)
NCT06628128	PHASE3	RECRUITING	A Long-Term Study of JNT-517 in Participants With Phenylketonuria
NCT06971731	PHASE3	RECRUITING	A Study of JNT-517 in Participants With Phenylketonuria (PKU)
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT00104260	PHASE2	COMPLETED	Study to Evaluate the Response to and Safety of an 8-Day Course of Phenoptin™ Treatment in Subjects With Phenylketonuria
NCT00260000	PHASE2	COMPLETED	Study of BH4, a New and Simple Treatment of Mild PKU
NCT00841100	PHASE2	COMPLETED	Kuvan Therapy in Phenylketonuria (PKU): The Effect of Blood Phenylalanine Concentration on Kuvan Response
NCT00924703	PHASE2	COMPLETED	Long-Term Extension of Previous rAvPAL-PEG Protocols in Subjects With PKU (PAL-003)
NCT00925054	PHASE2	COMPLETED	Dose-Finding Study to Evaluate the Safety, Efficacy, & Tolerability of Multiple Doses of rAvPAL-PEG in Subjects With PKU
NCT01212744	PHASE2	COMPLETED	Safety, Tolerability, and Efficacy Study of rAvPAL-PEG Administered Daily in Subjects With Phenylketonuria (PKU)
NCT01395394	PHASE2	TERMINATED	Phenylketonuria, Oxidative Stress, and BH4
NCT01560286	PHASE2	COMPLETED	A Study to Evaluate Subcutaneously Administered rAvPAL-PEG in Patients With Phenylketonuria for 24 Weeks