NFS1

Summary

NFS1 (NFS1 cysteine desulfurase, HGNC:15910) is a protein-coding gene on chromosome 20q11.22, encoding Cysteine desulfurase (Q9Y697). Cysteine desulfurase, of the core iron-sulfur cluster (ISC) assembly complex, that catalyzes the desulfuration of L-cysteine to L-alanine, as component of the cysteine desulfurase complex, leading to the formation of a cysteine persulfide intermediate at the active site cysteine…. It is a common-essential gene (DepMap: required in 99.7% of cancer cell lines).

Iron-sulfur clusters are required for the function of many cellular enzymes. The proteins encoded by this gene supply inorganic sulfur to these clusters by removing the sulfur from cysteine, creating alanine in the process. This gene uses alternate in-frame translation initiation sites to generate mitochondrial forms and cytoplasmic/nuclear forms. Selection of the alternative initiation sites is determined by the cytosolic pH. The encoded proteins belong to the class-V family of pyridoxal phosphate-dependent aminotransferases. Alternatively spliced transcript variants have been described.

Source: NCBI Gene 9054 — RefSeq curated summary.

At a glance

• Gene–disease (curated): combined oxidative phosphorylation deficiency 52 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 195 total
• Phenotypes (HPO): 26
• Cancer dependency (DepMap): dependent in 99.7% of screened cell lines (common-essential)
• MANE Select transcript: NM_021100

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15910
Approved symbol	NFS1
Name	NFS1 cysteine desulfurase
Location	20q11.22
Locus type	gene with protein product
Status	Approved
Aliases	NifS, IscS
Ensembl gene	ENSG00000244005
Ensembl biotype	protein_coding
OMIM	603485
Entrez	9054

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 17 protein_coding, 3 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000306750, ENST00000374085, ENST00000374092, ENST00000397425, ENST00000413203, ENST00000419569, ENST00000421540, ENST00000440385, ENST00000456462, ENST00000471137, ENST00000480655, ENST00000489163, ENST00000498084, ENST00000541387, ENST00000874532, ENST00000874533, ENST00000874534, ENST00000874535, ENST00000874536, ENST00000874537, ENST00000874538, ENST00000874539, ENST00000874540, ENST00000966806, ENST00000966807

RefSeq mRNA: 2 — MANE Select: NM_021100 NM_001198989, NM_021100

CCDS: CCDS13262, CCDS56185

Canonical transcript exons

ENST00000374092 — 13 exons

Exon	Start	End
ENSE00001462438	35668052	35669685
ENSE00003483005	35699192	35699352
ENSE00003500778	35681888	35681981
ENSE00003511682	35690413	35690565
ENSE00003543354	35674512	35674617
ENSE00003594979	35680737	35680871
ENSE00003596611	35675045	35675202
ENSE00003696644	35698481	35698590
ENSE00003697275	35696377	35696460
ENSE00003698899	35697684	35697800
ENSE00003705338	35672755	35672844
ENSE00003706405	35674350	35674431
ENSE00003707552	35673601	35673684

Expression profiles

Bgee: expression breadth ubiquitous, 269 present calls, max score 95.88.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.3505 / max 72.6247, expressed in 1800 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
187084	11.5231	1791
187083	2.0927	1331
187082	0.4434	217
187081	0.2325	123
187079	0.0331	5
187080	0.0257	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland cortex	UBERON:0035827	95.88	gold quality
right adrenal gland	UBERON:0001233	95.72	gold quality
adrenal tissue	UBERON:0018303	95.22	gold quality
left adrenal gland	UBERON:0001234	95.10	gold quality
left adrenal gland cortex	UBERON:0035825	94.73	gold quality
right lobe of liver	UBERON:0001114	93.98	gold quality
adrenal gland	UBERON:0002369	93.86	gold quality
adrenal cortex	UBERON:0001235	93.84	gold quality
apex of heart	UBERON:0002098	93.28	gold quality
right testis	UBERON:0004534	93.20	gold quality
left testis	UBERON:0004533	93.16	gold quality
mucosa of transverse colon	UBERON:0004991	93.08	gold quality
right frontal lobe	UBERON:0002810	92.93	gold quality
anterior cingulate cortex	UBERON:0009835	92.46	gold quality
cingulate cortex	UBERON:0003027	92.35	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.31	gold quality
heart left ventricle	UBERON:0002084	92.30	gold quality
prefrontal cortex	UBERON:0000451	91.81	gold quality
cardiac ventricle	UBERON:0002082	91.73	gold quality
gastrocnemius	UBERON:0001388	91.61	gold quality
caudate nucleus	UBERON:0001873	91.49	gold quality
adult mammalian kidney	UBERON:0000082	91.33	gold quality
nucleus accumbens	UBERON:0001882	91.24	gold quality
muscle of leg	UBERON:0001383	91.21	gold quality
putamen	UBERON:0001874	91.20	gold quality
Brodmann (1909) area 9	UBERON:0013540	91.11	gold quality
right uterine tube	UBERON:0001302	90.87	gold quality
testis	UBERON:0000473	90.74	gold quality
adenohypophysis	UBERON:0002196	90.70	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.68	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.67

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

45 targeting NFS1, 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-3925-3P	100.00	69.95	1237
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4743-3P	99.62	68.12	2095
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-17-3P	99.55	66.77	1311
HSA-MIR-199A-5P	99.51	69.71	1107
HSA-MIR-199B-5P	99.51	69.74	1098
HSA-MIR-5571-5P	99.49	66.99	1764
HSA-MIR-1912-3P	99.32	67.40	936
HSA-MIR-548V	99.29	69.47	1157
HSA-MIR-133A-3P	99.27	71.53	1270
HSA-MIR-133B	99.27	71.53	1270
HSA-MIR-149-5P	99.25	67.16	1315
HSA-MIR-1253	99.12	67.08	1688
HSA-MIR-4795-5P	99.11	66.90	876

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.7% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 20)

• the cytosolic form of ISCS is a functional cysteine desulfurase that can collaborate with cytosolic ISCU to promote de novo iron-sulfur cluster formation (PMID:16527810)
• Results show that human Nfs1 is required inside mitochondria for efficient maturation of cellular iron/sulfur proteins. (PMID:16847322)
• Nfs1 acts as a sulfur donor for MOCS3, a protein involved in molybdenum cofactor biosynthesis (PMID:18650437)
• Icp55 protease and its substrate Nfs1 appear to be dual distributed between the nucleus and mitochondria (PMID:19720832)
• Nfs1, the cysteine desulfurase responsible for providing sulfur for cluster formation, is required for the increased Isu stability occurring after disruption of cluster formation on or transfer from Isu (PMID:22689995)
• the interaction of NFS1 and MOCS3 in the cytosol of human cells, is reported. (PMID:23593335)
• NFS1 binds preferentially to the D-state of ISCU while mtHSP70 binds preferentially to the D-state of ISCU and HSC20 binds preferentially to the S-state of ISCU. (PMID:23940031)
• The data presented here show that the Isu1 suppressor mimics the frataxin effects on Nfs1, explaining the bypassing activity. (PMID:24217246)
• Our findings highlight that the ISD11 R68A/R68L mutation display reduced affinity to form a stable subcomplex with NFS1, and thereby fails to prevent NFS1 aggregation resulting in impairment of the Fe-S cluster biogenesis (PMID:26342079)
• Molecular dynamics flexible fitting of protein structures docked into the EM map of the model revealed a [FXN(42-210)]24.[NFS1]24.[ISD11]24.[ISCU]24 complex, consistent with the measured 1:1:1:1 stoichiometry of its four components. (PMID:27519411)
• FDX1 and FDX2 both bind NFS1 and donate electrons for iron-sulfur cluster biosynthesis. (PMID:28001042)
• The NFS1/ISD11 complex further interacts with scaffold protein ISCU and regulator protein frataxin, thereby forming a quaternary complex for Fe-S cluster formation. (PMID:28271877)
• analysis of the NFS1-ISD11-ACP (SDA) complex forms the core of the iron-sulfur (Fe-S) assembly complex and associates with assembly proteins ISCU2, frataxin (FXN), and ferredoxin to synthesize Fe-S clusters (PMID:28634302)
• human NFS1 was almost fully able to complement the role of IscS in Moco biosynthesis when its specific interaction partner protein MOCS3 from humans was also present. (PMID:28766335)
• NFS1 maintains the iron sulfur clusters in proteins that are essential for protecting them from oxidative damage; inactivating NFS1 or iron sulfur clusters can trigger ferroptosis, a non-apoptotic form of cell death, in cancer cells (PMID:29168506)
• The molecular structure of the human mitochondrial cysteine desulfurase complex consisting of two copies each of NFS1, ISD11, and acyl carrier protein has been described. (PMID:29983374)
• FXN binds the NFS1-ISD11-ACP-ISCU complex (SDAU), to activate the desulfurase activity and Fe-S cluster biosynthesis. In the absence of FXN, the NFS1-ISD11-ACP (SDA) complex was reportedly inhibited by binding of recombinant ISCU (PMID:30031876)
• By different methods, this study identified a MOCS3-independent novel localization of NFS1 at the centrosome. (PMID:30817134)
• Study reports 3.2 A resolution cryo-electron microscopy structure of the FXN-bound active human iron-sulfur clusters biosynthesis complex. FXN binds at the interface of two NFS1 and one ISCU subunits, modifying the local environment of a bound zinc ion that would otherwise inhibit NFS1 activity in complexes without FXN. (PMID:31101807)
• Phosphorylated NFS1 weakens oxaliplatin-based chemosensitivity of colorectal cancer by preventing PANoptosis. (PMID:35221331)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	nfs1	ENSDARG00000062237
mus_musculus	Nfs1	ENSMUSG00000027618
rattus_norvegicus	Nfs1	ENSRNOG00000045686
drosophila_melanogaster	Nfs1	FBGN0032393
caenorhabditis_elegans	nfs-1	WBGENE00015021

Paralogs (1): SCLY (ENSG00000132330)

Protein

Protein identifiers

Cysteine desulfurase — Q9Y697 (reviewed: Q9Y697)

All UniProt accessions (7): A2A2M1, Q9Y697, F2Z2E7, F8WB23, F8WER8, Q5QP19, Q8WV90

UniProt curated annotations — full annotation on UniProt →

Function. Cysteine desulfurase, of the core iron-sulfur cluster (ISC) assembly complex, that catalyzes the desulfuration of L-cysteine to L-alanine, as component of the cysteine desulfurase complex, leading to the formation of a cysteine persulfide intermediate at the active site cysteine residue and participates in the [2Fe-2S] clusters assembly on the scaffolding protein ISCU. The persulfide is then transferred on the flexible Cys loop from the catalytic site of NFS1 to the surface of NFS1. After the NFS1-linked persulfide sulfur is transferred to one of the conserved Cys residues of the scaffold, a reaction assisted by FXN. The core iron-sulfur cluster (ISC) assembly complex is involved in the de novo synthesis of a [2Fe-2S] cluster, the first step of the mitochondrial iron-sulfur protein biogenesis. This process is initiated by the cysteine desulfurase complex (NFS1:LYRM4:NDUFAB1) that produces persulfide which is delivered on the scaffold protein ISCU in a FXN-dependent manner. Then this complex is stabilized by FDX2 which provides reducing equivalents to accomplish the [2Fe-2S] cluster assembly. Finally, the [2Fe-2S] cluster is transferred from ISCU to chaperone proteins, including HSCB, HSPA9 and GLRX5. May catalyze the desulfuration of L-cysteine to L-alanine as component of the cysteine desulfurase complex (NFS1:LYRM4), leading to the formation of a cysteine persulfide intermediate. Acts as a sulfur donor for MOCS3 by transferring the sulfur of the cysteine persulfide intermediate on MOCS3.

Subunit / interactions. Homodimer. Component of the mitochondrial core iron-sulfur cluster (ISC) complex composed of NFS1, LYRM4, NDUFAB1, ISCU, FXN, and FDX2; this complex is a heterohexamer containing two copies of each monomer. Component of cyteine desulfurase complex composed of NFS1, LYRM4 and NDUFAB1; this complex contributes to the activation of cysteine desulfurase activity and NFS1 stabilization. Interacts (homodimer form) with ISCU (D-state); each monomer interacts with the C-terminal regions of each NFS1 monomer. Interacts with HSPA9. Interacts (via homodimer form) with FDX2. Interacts (via homodimer form) with FXN. Interacts with LYRM4. Component of a complex composed of FXN, NFS1, LYRM4 and ISCU. Monomer. Homodimer. Oligomer. Interacts with ISCU. Component of the cysteine desulfurase complex composed of NFS1 and LYRM4; this complex contributes to the activation of cysteine desulfurase activity. Interacts with MOCS3.

Subcellular location. Mitochondrion Cytoplasm. Cytosol. Nucleus. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome.

Tissue specificity. Predominantly expressed in heart and skeletal muscle. Also found in brain, liver and pancreas.

Post-translational modifications. N-gluconoylated. Cysteine persulfide intermediate is reduced by thiol-containing molecules like glutathione and L-cysteine. Persulfide reduction is a rate-limiting step of cysteine desulfurase catalytic cycle.

Disease relevance. Combined oxidative phosphorylation deficiency 52 (COXPD52) [MIM:619386] An autosomal recessive mitochondrial disorder with onset in infancy, characterized by lactic acidemia, hypotonia, respiratory chain complex II and III deficiency, multisystem organ failure and abnormal mitochondria. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Active only in complex with LYRM4.

Similarity. Belongs to the class-V pyridoxal-phosphate-dependent aminotransferase family. NifS/IscS subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9Y697-1	Mitochondrial	yes
Q9Y697-2	Cytosolic
Q9Y697-3	3

RefSeq proteins (2): NP_001185918, NP_066923* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000192	Aminotrans_V_dom	Domain
IPR010240	Cys_deSase_IscS	Family
IPR015421	PyrdxlP-dep_Trfase_major	Homologous_superfamily
IPR015422	PyrdxlP-dep_Trfase_small	Homologous_superfamily
IPR015424	PyrdxlP-dep_Trfase	Homologous_superfamily
IPR016454	Cysteine_dSase	Family
IPR020578	Aminotrans_V_PyrdxlP_BS	Binding_site

Pfam: PF00266

Enzyme classification (BRENDA):

• EC 2.8.1.7 — cysteine desulfurase (BRENDA: 35 organisms, 87 substrates, 24 inhibitors, 32 Km, 18 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
L-CYSTEINE	0.043–5.1	14
L-SELENOCYSTEINE	0.13–4.17	10
L-CYSTEINE SULFINIC ACID	0.28–190	7
[SUFU]-CYSTEINE	0.003	1

Catalyzed reactions (Rhea), 2 shown:

• L-cysteinyl-[cysteine desulfurase] + L-cysteine = S-sulfanyl-L-cysteinyl-[cysteine desulfurase] + L-alanine (RHEA:17457)
• (sulfur carrier)-H + L-cysteine = (sulfur carrier)-SH + L-alanine (RHEA:43892)

UniProt features (58 total): helix 17, strand 11, turn 9, binding site 8, sequence conflict 5, modified residue 2, splice variant 2, transit peptide 1, chain 1, sequence variant 1, active site 1

Structure

Experimental structures (PDB)

20 structures.

PDB	Method	Resolution (Å)
6UXE	X-RAY DIFFRACTION	1.57
6W1D	X-RAY DIFFRACTION	1.79
6WIH	X-RAY DIFFRACTION	1.9
6WI2	X-RAY DIFFRACTION	1.95
8TVT	X-RAY DIFFRACTION	2
8RMC	ELECTRON MICROSCOPY	2.26
8RMF	ELECTRON MICROSCOPY	2.33
8RMG	ELECTRON MICROSCOPY	2.46
8PK8	ELECTRON MICROSCOPY	2.49
8RME	ELECTRON MICROSCOPY	2.49
7RTK	X-RAY DIFFRACTION	2.5
8RMD	ELECTRON MICROSCOPY	2.52
8PK9	ELECTRON MICROSCOPY	2.58
5WGB	X-RAY DIFFRACTION	2.75
8PKA	ELECTRON MICROSCOPY	2.75
5USR	X-RAY DIFFRACTION	3.09
5WKP	X-RAY DIFFRACTION	3.15
6NZU	ELECTRON MICROSCOPY	3.2
5WLW	X-RAY DIFFRACTION	3.32
5KZ5	ELECTRON MICROSCOPY	14.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y697-F1	89.34	0.82

Functional residue map

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

Catalytic / active sites (1): 381 (cysteine persulfide intermediate)

Ligand- & substrate-binding residues (8): 381; 127; 128; 235; 255; 257; 295; 381 (via persulfide group)

Post-translational modifications (2): 258, 381

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1362409	Mitochondrial iron-sulfur cluster biogenesis
R-HSA-947581	Molybdenum cofactor biosynthesis
R-HSA-9854311	Maturation of TCA enzymes and regulation of TCA cycle
R-HSA-9865881	Complex III assembly

MSigDB gene sets: 183 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, TAATAAT_MIR126, NIKOLSKY_BREAST_CANCER_20Q11_AMPLICON, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, SHIRAISHI_PLZF_TARGETS_UP, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOCC_CENTROSOME, SENESE_HDAC1_TARGETS_UP, RUAN_RESPONSE_TO_TROGLITAZONE_UP, WONG_MITOCHONDRIA_GENE_MODULE, RUAN_RESPONSE_TO_TNF_DN, chr20q11, DANG_BOUND_BY_MYC, GOCC_TRANSFERASE_COMPLEX

GO Biological Process (4): Mo-molybdopterin cofactor biosynthetic process (GO:0006777), iron-sulfur cluster assembly (GO:0016226), [2Fe-2S] cluster assembly (GO:0044571), [4Fe-4S] cluster assembly (GO:0044572)

GO Molecular Function (8): pyridoxal phosphate binding (GO:0030170), cysteine desulfurase activity (GO:0031071), protein homodimerization activity (GO:0042803), metal ion binding (GO:0046872), iron-sulfur cluster binding (GO:0051536), sulfur carrier activity (GO:0097163), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (10): nucleus (GO:0005634), nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), centrosome (GO:0005813), cytosol (GO:0005829), mitochondrial [2Fe-2S] assembly complex (GO:0099128), iron-sulfur cluster assembly complex (GO:1990229), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Metabolism	1
Metabolism of water-soluble vitamins and cofactors	1
Citric acid cycle (TCA cycle)	1
Respiratory electron transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	3
iron-sulfur cluster assembly	2
intracellular membrane-bounded organelle	2
molybdenum incorporation into molybdenum-molybdopterin complex	1
Mo-molybdopterin cofactor metabolic process	1
molybdopterin cofactor biosynthetic process	1
GTP 3’,8’-cyclase activity	1
cyclic pyranopterin monophosphate synthase activity	1
metallo-sulfur cluster assembly	1
anion binding	1
vitamin B6 binding	1
sulfurtransferase activity	1
identical protein binding	1
protein dimerization activity	1
cation binding	1
metal cluster binding	1
molecular carrier activity	1
binding	1
catalytic activity	1
nuclear lumen	1
mitochondrion	1
intracellular organelle lumen	1
centriole	1
microtubule organizing center	1
mitochondrial protein-containing complex	1
L-cysteine desulfurase complex	1
iron-sulfur cluster assembly complex	1
protein-containing complex	1
intracellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

2466 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NFS1	ISCU	Q9H1K1	999
NFS1	LYRM4	Q9HD34	999
NFS1	FXN	Q16595	998
NFS1	ACO1	P21399	937
NFS1	MOCS3	O95396	899
NFS1	IREB2	P48200	892
NFS1	ACO2	Q99798	887
NFS1	HSPA9	P30036	878
NFS1	CTU1	Q7Z7A3	833
NFS1	URM1	Q9BTM9	821
NFS1	MPST	P25325	816
NFS1	NFU1	Q9UMS0	816
NFS1	ISCA1	Q9BUE6	811
NFS1	GLRX5	Q86SX6	810
NFS1	FDX2	Q6P4F2	810

IntAct

87 interactions, top by confidence:

A	B	Type	Score
ZWINT	NDC80	psi-mi:“MI:0914”(association)	0.940
DLD	PDHX	psi-mi:“MI:0914”(association)	0.880
RB1CC1	ATG13	psi-mi:“MI:0914”(association)	0.820
PHC1	CBX4	psi-mi:“MI:0914”(association)	0.790
LYRM4	NFS1	psi-mi:“MI:0407”(direct interaction)	0.770
LYRM4	NFS1	psi-mi:“MI:0915”(physical association)	0.770
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
COQ8A	COQ9	psi-mi:“MI:0914”(association)	0.670
LYRM4	NDUFAB1	psi-mi:“MI:0914”(association)	0.640
KLHL22	TMEM223	psi-mi:“MI:0914”(association)	0.640
GPX7	GAK	psi-mi:“MI:0914”(association)	0.640
KLHL22	METTL15	psi-mi:“MI:0914”(association)	0.640
ISCU	acpP	psi-mi:“MI:0915”(physical association)	0.570
acpP	ISCU	psi-mi:“MI:0915”(physical association)	0.570
PICK1	ILVBL	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
ACAD9	PPL	psi-mi:“MI:0914”(association)	0.530
NDUFAB1	GLDC	psi-mi:“MI:0914”(association)	0.530

BioGRID (195): NFS1 (Affinity Capture-MS), NFS1 (Affinity Capture-MS), NFS1 (Affinity Capture-MS), NFS1 (Affinity Capture-MS), NFS1 (Affinity Capture-MS), NFS1 (Affinity Capture-MS), NFS1 (Affinity Capture-MS), ISCU (Reconstituted Complex), NFS1 (Affinity Capture-Western), ABCC1 (Co-fractionation), ACADM (Co-fractionation), NFS1 (Co-fractionation), NFS1 (Co-fractionation), NFS1 (Co-fractionation), SUCLA2 (Co-fractionation)

ESM2 similar proteins: A3KG59, A4IFH5, B9N1F9, D3ZVR9, O04059, O35331, O35621, O46560, P11172, P24298, P37111, Q03154, Q04609, Q15124, Q17QK3, Q2R483, Q501L1, Q5E9T8, Q5I0K3, Q5NAY4, Q5R514, Q5R5C9, Q5RDE7, Q5RDN7, Q5RFB0, Q5RFI8, Q6AY30, Q6AYS7, Q6K2E8, Q6PTT0, Q6Q0N1, Q6ZV70, Q7TSV4, Q7X7L3, Q8BZF8, Q8CG45, Q8CG76, Q8IYS1, Q8K183, Q8N0X4

Diamond homologs: A0R5M7, A5I4Z9, A7FWJ9, B4UCP2, B8F356, B8JC53, C1FTC4, O49543, O69668, P25374, Q2INI7, Q5RDE7, Q7D515, Q8SQS2, Q99P39, Q9Y697, Q9YAB6, Q9Z1J3, Q9Z5X5, A1KUK1, A2VDS1, A4WDB1, A6TCF1, A7H804, A7MU48, A7ZPX4, A8A336, A8EYH9, A8F204, A8GHY3, A8GNU0, A8GSG4, A8GWB2, A9M029, A9MHJ4, A9N1X5, B0BXX6, B0YLW6, B1IWD1, B1LNI6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NFS1	“form complex”	“Mitochondrial Fe-S Cluster Assembly Complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 100 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
Complex I biogenesis	6	12.7×	8e-04
Mitochondrial protein degradation	8	11.7×	2e-04
Mitochondrial protein import	5	10.8×	5e-03
Respiratory electron transport	7	8.5×	1e-03
Aerobic respiration and respiratory electron transport	7	7.9×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
iron-sulfur cluster assembly	5	33.1×	1e-04
mitochondrial electron transport, NADH to ubiquinone	5	19.7×	8e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	78
Likely benign	70
Benign	24

Top pathogenic / likely-pathogenic (0)

SpliceAI

2378 predictions. Top by Δscore:

Variant	Effect	Δscore
20:35672750:TATA:T	donor_loss	1.0000
20:35672751:ATACC:A	donor_loss	1.0000
20:35672752:TACC:T	donor_loss	1.0000
20:35672753:A:C	donor_loss	1.0000
20:35672754:C:CT	donor_loss	1.0000
20:35672756:T:TA	donor_gain	1.0000
20:35672841:AAACC:A	acceptor_loss	1.0000
20:35672842:AACC:A	acceptor_loss	1.0000
20:35672843:ACC:A	acceptor_loss	1.0000
20:35672844:CCT:C	acceptor_loss	1.0000
20:35672845:C:CA	acceptor_loss	1.0000
20:35672846:T:C	acceptor_loss	1.0000
20:35673595:A:AC	donor_gain	1.0000
20:35673596:C:CC	donor_gain	1.0000
20:35673596:CTGA:C	donor_gain	1.0000
20:35673683:CA:C	acceptor_gain	1.0000
20:35673685:C:CC	acceptor_gain	1.0000
20:35674348:ACCTC:A	donor_gain	1.0000
20:35674349:CCTCC:C	donor_gain	1.0000
20:35674352:C:A	donor_gain	1.0000
20:35674371:T:TA	donor_gain	1.0000
20:35674506:CCATA:C	donor_loss	1.0000
20:35674507:CATA:C	donor_loss	1.0000
20:35674508:ATAC:A	donor_loss	1.0000
20:35674509:TA:T	donor_loss	1.0000
20:35674510:A:AT	donor_loss	1.0000
20:35674528:AGGGT:A	donor_gain	1.0000
20:35674613:TCATA:T	acceptor_gain	1.0000
20:35674614:CATA:C	acceptor_gain	1.0000
20:35674614:CATAC:C	acceptor_gain	1.0000

AlphaMissense

2957 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:35672764:C:G	R434P	1.000
20:35672767:A:G	L433P	1.000
20:35673601:C:A	R407M	1.000
20:35673655:G:A	S389F	1.000
20:35673678:G:C	C381W	1.000
20:35673680:A:G	C381R	1.000
20:35673684:A:C	S379R	1.000
20:35673684:A:T	S379R	1.000
20:35674351:T:G	S379R	1.000
20:35674353:C:T	G378E	1.000
20:35674354:C:A	G378W	1.000
20:35674389:A:G	L366P	1.000
20:35674399:C:G	G363R	1.000
20:35674399:C:T	G363R	1.000
20:35680762:A:C	S255R	1.000
20:35680762:A:T	S255R	1.000
20:35680764:T:G	S255R	1.000
20:35690500:A:C	C158W	1.000
20:35669634:C:A	W454C	0.999
20:35669634:C:G	W454C	0.999
20:35669636:A:G	W454R	0.999
20:35669636:A:T	W454R	0.999
20:35669685:G:C	S437R	0.999
20:35669685:G:T	S437R	0.999
20:35672756:T:G	S437R	0.999
20:35672839:C:T	G409E	0.999
20:35673601:C:G	R407T	0.999
20:35673607:G:A	S405F	0.999
20:35673607:G:T	S405Y	0.999
20:35673608:A:G	S405P	0.999

dbSNP variants (sampled 300 via entrez): RS1000022492 (20:35695868 C>T), RS1000117711 (20:35682508 G>C), RS1000146925 (20:35679571 A>G), RS1000394315 (20:35692128 G>C), RS1000417678 (20:35676541 G>T), RS1000464279 (20:35689695 G>A), RS1000610222 (20:35685508 C>A,T), RS1000629951 (20:35682510 C>G,T), RS1000723841 (20:35689394 G>A), RS1000792453 (20:35685165 C>T), RS1001071775 (20:35696745 G>C), RS1001318876 (20:35672542 T>C), RS1001416296 (20:35668083 A>G), RS1001470725 (20:35675907 T>C), RS1001470926 (20:35668960 C>T)

Disease associations

OMIM: gene MIM:603485 | disease phenotypes: MIM:619386

GenCC curated gene-disease

Disease	Classification	Inheritance
combined oxidative phosphorylation deficiency 52	Strong	Autosomal recessive
severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency	Supportive	Autosomal recessive

Mondo (2): combined oxidative phosphorylation deficiency 52 (MONDO:0030311), (MONDO:0018337)

Orphanet (0):

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000846	Adrenal insufficiency
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001397	Hepatic steatosis
HP:0001522	Death in infancy
HP:0001639	Hypertrophic cardiomyopathy
HP:0001733	Pancreatitis
HP:0001942	Metabolic acidosis
HP:0001943	Hypoglycemia
HP:0002039	Anorexia
HP:0002151	Increased circulating lactate concentration
HP:0002154	Hyperglycinemia
HP:0002878	Respiratory failure
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003348	Hyperalaninemia
HP:0003355	Aminoaciduria
HP:0003648	Lacticaciduria
HP:0005521	Disseminated intravascular coagulation
HP:0008314	Decreased activity of mitochondrial complex II
HP:0011924	Decreased activity of mitochondrial complex III
HP:0031956	Elevated circulating aspartate aminotransferase concentration
HP:0031964	Elevated circulating alanine aminotransferase concentration
HP:0410288	Hyperamylasemia

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST010002_66	Refractive error	2.000000e-20
GCST012227_1101	Hip circumference adjusted for BMI	5.000000e-09
GCST012227_1130	Hip circumference adjusted for BMI	1.000000e-11
GCST012227_1146	Hip circumference adjusted for BMI	1.000000e-15

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	4
sodium arsenite	decreases expression, increases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
TAK-243	increases sumoylation	1
bisphenol A	affects expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluorooctanoic acid	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
perfluoro-n-nonanoic acid	decreases expression	1
perfluorohexanesulfonic acid	decreases expression	1
abrine	decreases expression	1
bisphenol S	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Indomethacin	decreases expression, affects cotreatment	1
Lipopolysaccharides	increases expression, affects cotreatment	1
Selenium	decreases expression	1
Thiram	decreases expression	1
Tretinoin	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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