FECH

Summary

FECH (ferrochelatase, HGNC:3647) is a protein-coding gene on chromosome 18q21.31, encoding Ferrochelatase, mitochondrial (P22830). Catalyzes the ferrous insertion into protoporphyrin IX and participates in the terminal step in the heme biosynthetic pathway. It is a selective cancer dependency (DepMap: 38.0% of cell lines).

The protein encoded by this gene is localized to the mitochondrion, where it catalyzes the insertion of the ferrous form of iron into protoporphyrin IX in the heme synthesis pathway. Mutations in this gene are associated with erythropoietic protoporphyria. Two transcript variants encoding different isoforms have been found for this gene. A pseudogene of this gene is found on chromosome 3.

Source: NCBI Gene 2235 — RefSeq curated summary.

At a glance

• Gene–disease (curated): protoporphyria, erythropoietic, 1 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 318 total — 58 pathogenic, 21 likely-pathogenic (top 10% of genes corpus-wide)
• GTEx eGene: eQTL in 43 tissues, sQTL in 18 (q < 0.05)
• Phenotypes (HPO): 16
• ChEMBL bioactivity: 34 clinical-phase molecules tested; no curated mechanism-of-action drug
• Cancer dependency (DepMap): dependent in 38.0% of screened cell lines
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.86 (unconstrained)
• MANE Select transcript: NM_000140
• Interaction hub: 1,760 STRING partners (top 10% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3647
Approved symbol	FECH
Name	ferrochelatase
Location	18q21.31
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000066926
Ensembl biotype	protein_coding
OMIM	612386
Entrez	2235

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 13 protein_coding, 6 nonsense_mediated_decay, 4 retained_intron, 3 protein_coding_CDS_not_defined

MANE Select: ENST00000262093

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

ENST00000262093, ENST00000382873, ENST00000585494, ENST00000585699, ENST00000585747, ENST00000585878, ENST00000591977, ENST00000592111, ENST00000592699, ENST00000651787, ENST00000651812, ENST00000652755, ENST00000682485, ENST00000878110, ENST00000878111, ENST00000878112, ENST00000932840, ENST00000972075, ENST00000972076, ENST00001052599, ENST00001052600, ENST00001052602, ENST00001085104, ENST00001085105, ENST00001085106, ENST00001130616

RefSeq mRNA: 5 — MANE Select: NM_000140 NM_000140, NM_001012515, NM_001371094, NM_001371095, NM_001374778

CCDS: CCDS11964, CCDS32836, CCDS92465

Canonical transcript exons

ENST00000262093 — 11 exons

Exon	Start	End
ENSE00000000116	57544377	57550846
ENSE00000669629	57571392	57571540
ENSE00003484710	57573246	57573365
ENSE00003487393	57566447	57566581
ENSE00003492409	57562874	57562980
ENSE00003517160	57551315	57551374
ENSE00003610599	57580073	57580199
ENSE00003632198	57554260	57554424
ENSE00003686289	57554845	57554952
ENSE00003687093	57559145	57559243
ENSE00003901550	57586554	57586702

Expression profiles

Bgee: expression breadth ubiquitous, 269 present calls, max score 98.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 28.8111 / max 1960.0814, expressed in 1816 samples.

Highest expression (Bgee): trabecular bone tissue, bone marrow, bone marrow cell, monocyte, mononuclear cell.

Genetic regulation across tissues (GTEx eQTL / sQTL)

FECH is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 43 tissues and its splicing (sQTL) in 18 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 61 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	sqtl	3.8e-68	-1.13	18:57559151:G:C
Cells Cultured fibroblasts	eqtl	2.7e-35	-0.78	18:57571588:A:G
Cells EBV-transformed lymphocytes	sqtl	1.7e-29	-1.28	18:57559151:G:C
Adipose Visceral Omentum	eqtl	1.2e-24	-0.70	18:57571588:A:G
Heart Atrial Appendage	eqtl	1.2e-22	-0.68	18:57571588:A:G
Heart Left Ventricle	eqtl	4.0e-20	-0.58	18:57571588:A:G
Esophagus Muscularis	eqtl	2.2e-18	-0.52	18:57571588:A:G
Brain Frontal Cortex BA9	eqtl	5.1e-17	-1.39	18:57571588:A:G
Esophagus Mucosa	eqtl	1.5e-15	-0.43	18:57571588:A:G
Testis	eqtl	3.0e-15	-0.52	18:57571588:A:G
Thyroid	eqtl	8.5e-13	-0.36	18:57571588:A:G
Muscle Skeletal	sqtl	8.9e-13	+0.50	18:57552144:G:A
Brain Nucleus accumbens basal ganglia	eqtl	1.1e-12	-1.02	18:57571588:A:G
Muscle Skeletal	eqtl	8.4e-12	-0.22	18:57573273:C:T
Artery Aorta	eqtl	5.1e-11	-0.46	18:57571588:A:G
Colon Transverse	eqtl	6.3e-11	-0.55	18:57571588:A:G
Cells EBV-transformed lymphocytes	eqtl	1.2e-10	-0.68	18:57571588:A:G
Artery Coronary	eqtl	1.3e-10	-0.73	18:57571588:A:G
Liver	eqtl	1.6e-10	-0.68	18:57571588:A:G
Artery Tibial	eqtl	9.7e-09	-0.42	18:57571588:A:G

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
172104	20.0730	1812
172102	7.5806	1687
172103	1.1574	722

Top tissues by expression

showing 100 of 295 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
trabecular bone tissue	UBERON:0002483	98.84	gold quality
bone marrow	UBERON:0002371	95.12	gold quality
bone marrow cell	CL:0002092	93.64	gold quality
monocyte	CL:0000576	91.99	gold quality
mononuclear cell	CL:0000842	91.80	gold quality
muscle of leg	UBERON:0001383	91.75	gold quality
gastrocnemius	UBERON:0001388	91.68	gold quality
gluteal muscle	UBERON:0002000	91.00	gold quality
leukocyte	CL:0000738	90.97	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	90.42	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.22	gold quality
muscle organ	UBERON:0001630	90.11	gold quality
skeletal muscle organ	UBERON:0014892	90.11	gold quality
adrenal tissue	UBERON:0018303	89.74	gold quality
biceps brachii	UBERON:0001507	89.67	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	89.12	gold quality
triceps brachii	UBERON:0001509	88.65	gold quality
blood	UBERON:0000178	88.48	gold quality
calcaneal tendon	UBERON:0003701	88.24	gold quality
adult mammalian kidney	UBERON:0000082	88.09	gold quality
right adrenal gland	UBERON:0001233	88.06	gold quality
right adrenal gland cortex	UBERON:0035827	87.90	gold quality
heart left ventricle	UBERON:0002084	87.72	gold quality
skeletal muscle tissue	UBERON:0001134	87.69	gold quality
left adrenal gland	UBERON:0001234	87.57	gold quality
cardiac ventricle	UBERON:0002082	87.44	gold quality
renal medulla	UBERON:0000362	87.41	gold quality
deltoid	UBERON:0001476	87.36	silver quality
right lobe of liver	UBERON:0001114	86.64	gold quality
left adrenal gland cortex	UBERON:0035825	86.59	gold quality
liver	UBERON:0002107	86.57	gold quality
nephron tubule	UBERON:0001231	86.55	gold quality
adrenal gland	UBERON:0002369	86.48	gold quality
corpus callosum	UBERON:0002336	86.30	gold quality
vastus lateralis	UBERON:0001379	86.26	silver quality
kidney	UBERON:0002113	86.24	gold quality
adrenal cortex	UBERON:0001235	85.88	gold quality
stromal cell of endometrium	CL:0002255	85.78	gold quality
muscle tissue	UBERON:0002385	85.67	gold quality
heart	UBERON:0000948	85.51	gold quality
tibialis anterior	UBERON:0001385	85.31	silver quality
islet of Langerhans	UBERON:0000006	85.27	gold quality
metanephros cortex	UBERON:0010533	85.26	gold quality
quadriceps femoris	UBERON:0001377	85.02	silver quality
right lobe of thyroid gland	UBERON:0001119	84.88	gold quality
esophagus mucosa	UBERON:0002469	84.61	gold quality
right atrium auricular region	UBERON:0006631	84.30	gold quality
esophagus	UBERON:0001043	84.29	gold quality
rectum	UBERON:0001052	84.28	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	84.10	gold quality
right uterine tube	UBERON:0001302	84.07	gold quality
lower esophagus muscularis layer	UBERON:0035833	84.05	gold quality
lower esophagus	UBERON:0013473	84.04	gold quality
left lobe of thyroid gland	UBERON:0001120	84.02	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	83.92	gold quality
body of pancreas	UBERON:0001150	83.73	gold quality
apex of heart	UBERON:0002098	83.73	gold quality
endothelial cell	CL:0000115	83.65	gold quality
muscle layer of sigmoid colon	UBERON:0035805	83.62	gold quality
prefrontal cortex	UBERON:0000451	83.59	gold quality
right ovary	UBERON:0002118	83.57	gold quality
right frontal lobe	UBERON:0002810	83.57	gold quality
left coronary artery	UBERON:0001626	83.46	gold quality
thyroid gland	UBERON:0002046	83.36	gold quality
descending thoracic aorta	UBERON:0002345	83.34	gold quality
thoracic aorta	UBERON:0001515	83.28	gold quality
left ovary	UBERON:0002119	83.27	gold quality
body of uterus	UBERON:0009853	83.27	gold quality
smooth muscle tissue	UBERON:0001135	83.26	gold quality
cortex of kidney	UBERON:0001225	83.15	gold quality
ascending aorta	UBERON:0001496	83.13	gold quality
pancreas	UBERON:0001264	83.11	gold quality
cardiac atrium	UBERON:0002081	83.11	gold quality
gall bladder	UBERON:0002110	83.08	gold quality
aorta	UBERON:0000947	82.99	gold quality
minor salivary gland	UBERON:0001830	82.95	gold quality
kidney epithelium	UBERON:0004819	82.93	gold quality
popliteal artery	UBERON:0002250	82.89	gold quality
tibial artery	UBERON:0007610	82.88	gold quality
right coronary artery	UBERON:0001625	82.85	gold quality
mucosa of stomach	UBERON:0001199	82.83	gold quality
spinal cord	UBERON:0002240	82.79	gold quality
coronary artery	UBERON:0001621	82.75	gold quality
left uterine tube	UBERON:0001303	82.65	gold quality
Brodmann (1909) area 9	UBERON:0013540	82.41	gold quality
ovary	UBERON:0000992	82.37	gold quality
putamen	UBERON:0001874	82.27	gold quality
transverse colon	UBERON:0001157	82.19	gold quality
tibial nerve	UBERON:0001323	82.13	gold quality
anatomical system	UBERON:0000467	82.10	gold quality
saliva-secreting gland	UBERON:0001044	82.04	gold quality
body of stomach	UBERON:0001161	82.03	gold quality
multicellular organism	UBERON:0000468	82.02	gold quality
caudate nucleus	UBERON:0001873	82.02	gold quality
endocervix	UBERON:0000458	82.01	gold quality
material anatomical entity	UBERON:0000465	82.00	gold quality
endometrium	UBERON:0001295	81.99	gold quality
mouth mucosa	UBERON:0003729	81.91	gold quality
ectocervix	UBERON:0012249	81.78	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.69	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-GEOD-130473	yes	786.09
E-HCAD-4	yes	155.62
E-CURD-112	yes	80.90
E-MTAB-10042	yes	50.29
E-MTAB-9221	yes	20.54
E-CURD-122	yes	18.60
E-HCAD-9	yes	10.09
E-MTAB-9388	yes	9.62
E-HCAD-10	yes	7.52
E-MTAB-9801	yes	3.76
E-CURD-98	no	638.82
E-MTAB-9067	no	5.08
E-MTAB-9467	no	2.30
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Caudate putamen	tissue	51.2
Frontal cortex	tissue	49.3
Bone marrow	tissue	36.8	low
Cerebellum	tissue	18.0	low
Basal ganglia	tissue	17.9	medium
Putamen	tissue	17.1
Medulla oblongata	tissue	16.8
Corpus callosum	tissue	16.8
Septum	tissue	16.8
Ventral forebrain	tissue	16.7
Superior colliculi	tissue	16.6
Hippocampal formation	tissue	16.5
Olfactory bulb	tissue	16.5
Cerebral cortex	tissue	16.3	low
Retrosplenial and cingulate cortex	tissue	16.3
Choroid plexus	tissue	16.2
Motor cortex	tissue	16.1
Somatosensory cortex	tissue	16.1
Retrosplenial cortex	tissue	16.0
Occipital cortex	tissue	16.0
Prefrontal cortex	tissue	15.9
Amygdala	tissue	15.9
Insular cortex	tissue	15.7
Entorhinal cortex	tissue	15.6
Periaqueductal gray	tissue	15.6
Temporal cortex	tissue	15.6
Thalamus	tissue	15.2
Hypothalamus	tissue	15.2
Substantia nigra	tissue	14.9
Midbrain	tissue	14.8
Spinal cord	tissue	14.8
Nucleus accumbens	tissue	14.7
Pons	tissue	13.9
Postcentral gyrus	tissue	13.8
Locus coeruleus	tissue	13.6
Hippocampus	tissue	12.5	medium
Skeletal muscle	tissue	10.1	low
Kidney	tissue	8.3	high
Tongue	tissue	6.9
Liver	tissue	5.2	medium
Thymus	tissue	4.3
Prostate	tissue	4.2	high
Salivary gland	tissue	3.9	medium
Parathyroid gland	tissue	3.9	medium
Pancreas	tissue	3.8	medium
Skin 1	tissue	3.3	low
Retina	tissue	3.1
Esophagus	tissue	3.0	low
Thyroid gland	tissue	3.0	medium
Epididymis	tissue	2.8	medium
Placenta	tissue	2.8	medium
Heart muscle	tissue	2.6	medium
Ovary	tissue	2.5	medium
Smooth muscle	tissue	2.5	not detected
Endometrium 1	tissue	2.5	low
Breast	tissue	2.4	low
Colon	tissue	2.4	low
Spleen	tissue	2.3	low
Stomach 1	tissue	2.2	medium
Seminal vesicle	tissue	2.2	medium

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Parieto-temporal junction (white matter) (22.3), Corpus callosum, genu (white matter) (22.2), Temporal white matter (21.0), Corpus callosum, splenium (white matter) (19.9), Area striata (white matter) (19.8).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR2, HIF1A, HNF1A, MYC, SP1

miRNA regulators (miRDB)

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

showing 30 of 182 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3688-3P	99.97	72.02	2834

Functional genomics

gnomAD constraint: pLI 1.01e-07, LOEUF 0.859, missense Z 1.64 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000262093 — one region, missense o/e 0.81. DepMap (CRISPR cell-line fitness): dependent in 38.0% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): Capan-1 (-2.869), HCC70 (-2.219), Panc 03.27 (-2.148), SU-DHL-8 (-2.024), UACC-893 (-1.91), HARA (-1.866), HUP-T4 (-1.789), OCI-AML3 (-1.639), NCI-H1869 (-1.617), NCI-N87 (-1.561), MFE-296 (-1.554), LK-2 (-1.52), NB-4 (-1.504), MDA-MB-453 (-1.494), KP-N-YN (-1.462).

Literature-anchored findings (GeneRIF, showing 40)

• Mutations in the FECH gene could not account the development of liver disease in the severe phenotype of erythropoietic protoporphyria(EPP). (PMID:11929052)
• Data indicate a significant genotype-phenotype correlation between “null allele” mutation and protoporphyrin related liver disease in erythropoietic protoporphyria. (PMID:11929053)
• Modulation of penetrance by the wild-type allele in dominantly inherited erythrohepatic and acute hepatic porphyrias was studied using FECH. (PMID:14669009)
• Mutation in ferrochelatase is associated with erythropoietic porphyria. (PMID:15046047)
• analysis of frataxin-mediated iron delivery to ferrochelatase in the final step of heme biosynthesis (PMID:15123683)
• Identification of autosomal recessive FECH mutations in erythropoietic protoporphyria patients with higher risk of severe liver disease in the United Kingdom. (PMID:15286165)
• data for 12 ferrochelatase wild-type/EPP mutant heterodimers show that some mutations result in heterodimers with the residual activity anticipated, whereas others result in heterodimers with significantly lower activity than would be predicted (PMID:15831704)
• mutation in promoter affects binding of a transcription factor and causes erythropoietic protoporphyria phenotype (PMID:15850836)
• A common single-nucleotide polymorphism of FECH gene contributes to the genetic predisposition for erythropoietic protoporphyria. (PMID:16385445)
• Patients with erythropoietic protoporphyria usually have a mutation in 1 Ferrochelatase allele that alters enzyme structure/function, together with a polymorphism in the nonmutant allele that causes low gene expression. (PMID:16819399)
• These data suggest that the first 62 amino acids of ferrochelatase allow targeting to mitochondria but do not contain sufficient information for efficient processing of the protein. (PMID:16844398)
• Mutations and a low-expressed allele IVS3-48c (in trans to the mutation) of the ferrochelatase (FECH) gene are responsible for erythropoietic protoporphyria (EPP) which is characterized clinically by cutaneous photosensitivity. (PMID:17196862)
• Substrate is bound deep within an enclosed pocket, and the binding sites with protoporphyrin IX are mapped in detail. (PMID:17261801)
• results highlight a novel, profilin2-dependent pathway, regulating synaptic physiology, neuronal excitability, and complex behavior (PMID:17566985)
• It was found that in the H263C and H341C variants, but not the F337A variant enzymes, the side chains of N75, M76, R164, H263, F337, H341, and E343 are oriented in a fashion similar to what is found in ferrochelatase with the bound porphyrin substrate (PMID:17567154)
• large deletions of the FECH gene are an important cause of erythropoietic protoporphyria (PMID:17597821)
• mutation associated with erythropoietic protoporphyria in Chinese family (PMID:17723290)
• show that in malignant tissue a transcriptional down-regulation of FECH occurs, which causes endogenous protoporphyrin-IX accumulation (PMID:17875605)
• most cases of EPP result from the coinheritance of IVS3-48C and a mutation in the FECH gene, and also document the existence of patients with mutations in homozygosity that may present a more severe form of the disease. (PMID:17875872)
• Data shows ferrochelatase undergoes significant changes in secondary structure during the catalytic cycle. (PMID:17884090)
• a ferrochelatase mutation in a Chinese family with erythropoietic protoporphyria. (PMID:18160121)
• Report ferrochelatase functional variants resulting in erythropoietic protoporphyria in an Ashkenazi Jewish family. (PMID:18758989)
• analysis of FECH mutations in patients with seasonal palmar keratoderma in erythropoietic protoporphyria (PMID:18787536)
• The mutation analysis in the FECH gene identified different genotypes with the t/t genotype, 7 with the t/M genotype, 14 with the c/t genotype and 10 with c/M genotype from different EPP families. (PMID:19656458)
• Sequencing of the ferrochelatase gene did not show a mutation in any of the patients studied. Furthermore, the hypomorphic allele IVS3-48C was absent in all individuals. (PMID:19656459)
• analysis of skin ferrochelatase and photosensitivity in mice and man (PMID:19657351)
• ferrochelatase localizes to both the mitochondrial outer and inner membranes, and the change in the equilibrium position of the forward and reverse activities may be regulated by the phosphorylation of ferrochelatase (PMID:19691493)
• The findings show that at least in the cases of Mn, Pb, Cd, and Hg, metal “inhibition” of ferrochelatase occurs after metal insertion and results from poor or diminished product release. (PMID:19703464)
• analysis of ion selectivity and substrate inhibition in the metal ion chelation catalyzed by human ferrochelatase (PMID:19767646)
• A novel splicing FECH mutation in a Chinese erythropoietic protoporphyria family is believed to be responsible for generating the phenotypic symptoms in this family. (PMID:19888946)
• the stability of newly formed ferrochelatase protein was dramatically decreased during iron deficiency (PMID:19965627)
• A novel homoallelic missense mutation (p.Ser318Tyr) was identified in the FECH gene in erythropoietic protoporphyria and palmar keratoderma (PMID:20337824)
• More than 96% of unrelated EPP patients have ferrochelatase deficiency (MIM 177000). Inheritance of a common hypomorphic IVS3-48C FECH allele trans to a deleterious FECH mutation reduces FECH activity below a critical threshold. Review. (PMID:20850938)
• analysis of the inhibitory metal ion-binding site in ferrochelatase (PMID:20966079)
• role of IVS3-48C allele in erythropoietic protoporphyria (PMID:21132468)
• Erythropoietic protoporphyria patients and their mother revealed heterozygosity for a novel mutation (c.1052delA) in FECH gene of both children, and heterozygosity for the hypomorphic allele IVS3-48T>C in all of them. (PMID:21659066)
• function of solvent-filled channels in human ferrochelatase (PMID:22712763)
• Loss-of-function FECH and gain-of-function erythroid-specific ALAS2 mutations causing erythropoietic protoporphyria and x-linked protoporphyria in North American patients reveal novel mutations and a high prevalence of X-linked protoporphyria. (PMID:23364466)
• Molecular dynamic simulations provided insight into the conformational movements and function of the active site residues of human ferrochelatase. (PMID:23446439)
• Sequence analysis of the FECH gene identified a novel missense mutation in exon 4 (c.418>A, G140R) of the FECH gene, as well as the common FECH IVS3-48 polymorphism in erythropoietic protoporphyria. (PMID:23600449)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	fech	ENSDARG00000003462
mus_musculus	Fech	ENSMUSG00000024588
rattus_norvegicus	Fech	ENSRNOG00000018053
drosophila_melanogaster	FeCH	FBGN0266268

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:95513) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 26 distinct phenotype terms.

Mouse phenotype (MP)	Records
skin photosensitivity	2
decreased hematocrit	1
abnormal erythropoiesis	1
jaundice	1
distended abdomen	1
decreased locomotor activity	1
abnormal circulating enzyme level	1
reduced fertility	1
abnormal erythrocyte morphology	1
reticulocytosis	1
anisocytosis	1
decreased hemoglobin content	1
decreased erythrocyte cell number	1
increased circulating alkaline phosphatase level	1
increased liver weight	1
increased porphyrin level	1
increased spleen weight	1
polychromatophilia	1
increased circulating bilirubin level	1
hypochromic anemia	1
decreased total body fat amount	1
increased red blood cell distribution width	1
leptocytosis	1
embryonic lethality, complete penetrance	1
increased erythrocyte protoporphyrin level	1

+1 more (showing top 25).

Additional cross-species homologs

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

Organism	UniProt	Identity	Method
Oryza sativa Indica Group	A2Y3Q5	100.0%	Diamond
Rickettsia bellii OSU 85-389	A8GYD7	100.0%	Diamond
Chlamydia trachomatis L2/434/Bu	B0B858	100.0%	Diamond
Chlamydia trachomatis L2b/UCH-1/proctitis	B0BCC3	100.0%	Diamond
Leptospira biflexa serovar Patoc strain ‘Patoc 1 (Ames)’	B0SF60	100.0%	Diamond
Leptospira biflexa serovar Patoc strain ‘Patoc 1 (Paris)’	B0SNJ9	100.0%	Diamond
Caulobacter vibrioides NA1000	B8GW40	100.0%	Diamond
Caulobacter vibrioides CB15	P57777	100.0%	Diamond
Oryza sativa Japonica Group	Q0DIV0	100.0%	Diamond
Rickettsia bellii RML369-C	Q1RGK5	100.0%	Diamond
Synechococcus elongatus PCC 7942 = FACHB-805	Q31S00	100.0%	Diamond
Synechococcus elongatus PCC 6301	Q5N2B2	100.0%	Diamond
Campylobacter jejuni subsp. jejuni 81-176	A1VYL5	99.7%	Diamond
Campylobacter jejuni subsp. jejuni 81116	A8FKS9	99.7%	Diamond
Wolbachia sp. wRi	C0R4L0	99.7%	Diamond
Chlamydia trachomatis D/UW-3/CX	O84492	99.7%	Diamond
Chlamydia trachomatis A/HAR-13	Q3KLL2	99.7%	Diamond
Wolbachia endosymbiont of Drosophila melanogaster	Q73FY6	99.7%	Diamond
Leptospira biflexa	Q8GCV0	99.7%	Diamond
Prochlorococcus marinus str. MIT 9303	A2C7Q7	99.5%	Diamond
Prochlorococcus marinus str. MIT 9313	Q7V6C6	99.5%	Diamond
Prochlorococcus marinus str. NATL1A	A2C0Y4	99.2%	Diamond
Prochlorococcus marinus str. NATL2A	Q46GQ1	99.2%	Diamond
Pan troglodytes	Q3YA36	99.1%	Diamond
Campylobacter jejuni RM1221	Q5HVR0	98.0%	Diamond
Campylobacter jejuni subsp. jejuni NCTC 11168 = ATCC 700819	Q9PI08	98.0%	Diamond
Citrifermentans bemidjiense Bem	B5EJ44	97.5%	Diamond
Geobacter sp. M21	C6E7U2	97.5%	Diamond
Trichormus variabilis ATCC 29413	Q3MCT9	97.4%	Diamond
Nostoc sp. PCC 7120 = FACHB-418	Q8YQR8	97.4%	Diamond
Helicobacter pylori G27	B5Z875	97.3%	Diamond
Helicobacter pylori P12	B6JMR9	97.3%	Diamond
Helicobacter pylori J99	Q9ZKD4	97.3%	Diamond
Prochlorococcus marinus str. AS9601	A2BQ06	97.2%	Diamond
Prochlorococcus marinus str. MIT 9301	A3PBP9	97.2%	Diamond
Prochlorococcus marinus str. MIT 9215	A8G3P0	97.2%	Diamond
Helicobacter pylori HPAG1	Q1CSI9	97.0%	Diamond
Helicobacter pylori Shi470	B2UUI4	96.7%	Diamond
Helicobacter pylori 26695	P56107	96.7%	Diamond
Prochlorococcus marinus str. MIT 9515	A2BVI7	96.2%	Diamond

Genomic neighbors (locus context)

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

Symbol	Type	Entrez
NARS1	protein-coding	4677
ATP8B1	protein-coding	5205
ST8SIA3	protein-coding	51046
ONECUT2	protein-coding	9480
ATP8B1-AS1	ncRNA	100505549
LINC02565	ncRNA	105372138

Protein

Protein identifiers

Ferrochelatase, mitochondrial — P22830 (reviewed: P22830)

Alternative names: Heme synthase, Protoheme ferro-lyase

All UniProt accessions (5): A0A499FJN5, P22830, K7EJM8, K7EJX5, K7ELX4

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the ferrous insertion into protoporphyrin IX and participates in the terminal step in the heme biosynthetic pathway.

Subunit / interactions. Homodimer. Homotetramer. Interacts with PGRMC1; the interaction results in decreased FECH activity. Interacts with ABCB10 and SLC25A37; this interaction forms an oligomeric complex. Forms a complex with ABCB7 and ABCB10, where a dimeric FECH bridges ABCB7 and ABCB10 homodimers; this complex may be required for cellular iron homeostasis, mitochondrial function and heme biosynthesis. Interacts with ABCB7 and ABCB10. Interacts with MIMS2 and PPOX to form an oligomeric iron transport complex required for heme synthesis.

Subcellular location. Mitochondrion inner membrane.

Disease relevance. Protoporphyria, erythropoietic, 1 (EPP1) [MIM:177000] An autosomal recessive form of porphyria with onset usually before age 10 years. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. Erythropoietic protoporphyria is marked by excessive protoporphyrin in erythrocytes, plasma, liver and feces, and by widely varying photosensitive skin changes ranging from a burning or pruritic sensation to erythema, edema and wheals. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by nitric oxide (NO). The 2Fe-2S cluster could act as a NO sensor.

Cofactor. Binds 1 [2Fe-2S] cluster.

Pathway. Porphyrin-containing compound metabolism; protoheme biosynthesis; protoheme from protoporphyrin-IX: step 1/1.

Similarity. Belongs to the ferrochelatase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P22830-1	1	yes
P22830-2	2

RefSeq proteins (5): NP_000131, NP_001012533, NP_001358023, NP_001358024, NP_001361707 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001015	Ferrochelatase	Family
IPR019772	Ferrochelatase_AS	Active_site
IPR033644	Ferrochelatase_C	Domain
IPR033659	Ferrochelatase_N	Domain

Pfam: PF00762

Enzyme classification (BRENDA)

• EC 4.98.1.1 — protoporphyrin ferrochelatase (BRENDA: 51 organisms, 115 substrates, 65 inhibitors, 196 Km, 68 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
FE2+	0.0005–0.166	61
PROTOPORPHYRIN IX	0.0002–0.72	34
MESOPORPHYRIN IX	0.0047–0.0302	24
ZN2+	0.0002–0.06	21
PROTOPORPHYRIN	0.002–0.05	13
MESOPORPHYRIN	0.004–0.1	11
CO2+	0.0052–0.56	6
DEUTEROPORPHYRIN IX	0.0026–0.054	5
CU2+	0.063–0.17	4
NI2+	0.0221–0.1037	4
PORPHYRIN	0.0121–0.0246	4
2,4-BISACETAL DEUTEROPORPHYRIN	0.056	1
2,4-DIACETYLDEUTEROPORPHYRIN	0.479	1
2,4-DISULFONIC DEUTEROPORPHYRIN	0.052	1
DEUTEROPORPHYRIN	0.0213	1

Catalyzed reactions (Rhea)

• heme b + 2 H(+) = protoporphyrin IX + Fe(2+) (RHEA:22584)

UniProt features (86 total): sequence variant 26, helix 19, strand 11, mutagenesis site 9, binding site 7, modified residue 4, turn 4, active site 2, transit peptide 1, chain 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

25 structures by resolution:

PDB	Title	Method	Resolution (Å)
3HCN	Hg and protoporphyrin bound Human Ferrochelatase	X-RAY DIFFRACTION	1.6
2HRC	1.7 angstrom structure of human ferrochelatase variant R115L	X-RAY DIFFRACTION	1.7
3AQI	H240A variant of human ferrochelatase	X-RAY DIFFRACTION	1.7
3HCO	Human ferrochelatase with Cd and protoporphyrin IX bound	X-RAY DIFFRACTION	1.8
4F4D	F337R variant of human ferrochelatase	X-RAY DIFFRACTION	1.8
1HRK	CRYSTAL STRUCTURE OF HUMAN FERROCHELATASE	X-RAY DIFFRACTION	2
2QD4	Wild type human ferrochelatase crystallized with MnCl2	X-RAY DIFFRACTION	2
3HCP	Human ferrochelatase with Mn and deuteroporphyrin bound	X-RAY DIFFRACTION	2
7CT7	FECH - inhibitor complex 2	X-RAY DIFFRACTION	2
7CTC	FECH - inhibitor complex 1	X-RAY DIFFRACTION	2
3W1W	Protein-drug complex	X-RAY DIFFRACTION	2.01
4KLR	E343Q variant of human ferrochelatase	X-RAY DIFFRACTION	2.18
2PO5	Crystal structure of human ferrochelatase mutant with His 263 replaced by Cys	X-RAY DIFFRACTION	2.2
2PO7	Crystal structure of human ferrochelatase mutant with His 341 replaced by Cys	X-RAY DIFFRACTION	2.2
2QD1	2.2 Angstrom Structure of the human ferrochelatase variant E343K with substrate bound	X-RAY DIFFRACTION	2.2
2QD2	F110A variant of human ferrochelatase with protoheme bound	X-RAY DIFFRACTION	2.2
2QD3	Wild type human ferrochelatase crystallized with ammonium sulfate	X-RAY DIFFRACTION	2.2
3HCR	Human Ferrochelatase with deuteroporphyrin and Ni Bound	X-RAY DIFFRACTION	2.2
2QD5	Structure of wild type human ferrochelatase in complex with a lead-porphyrin compound	X-RAY DIFFRACTION	2.3
2PNJ	Crystal structure of human ferrochelatase mutant with Phe 337 replaced by Ala	X-RAY DIFFRACTION	2.35
4KLC	E343D/F110A Double mutant of human ferrochelatase	X-RAY DIFFRACTION	2.4
2HRE	Structure of human ferrochelatase variant E343K with protoporphyrin IX bound	X-RAY DIFFRACTION	2.5
4MK4	S197C variant of human ferrochelatase.	X-RAY DIFFRACTION	2.5
4KLA	E343D variant of human ferrochelatase	X-RAY DIFFRACTION	2.6
4KMM	M76H variant of human ferrochelatase	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P22830-F1	87.37	0.81

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Lyases, Metabolic proteins, Predicted intracellular proteins, Disease related genes, Potential drug targets, Human disease related genes, Congenital disorders of metabolism, Congenital disorders of cofactor/vitamin metabolism, Essential proteins

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH approved

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 (2)

Position	Role
230
383

Ligand- & substrate-binding residues (7)

Position	Role
411	[2Fe-2S] cluster
115	protoporphyrin IX
123	protoporphyrin IX
130	protoporphyrin IX
196	[2Fe-2S] cluster
403	[2Fe-2S] cluster
406	[2Fe-2S] cluster

Post-translational modifications (4)

Type	Positions
N6-acetyllysine	57, 415
N6-succinyllysine	138, 415

Mutagenesis-validated functional residues (9)

Position	Phenotype
110	increases activity inhibition upon interaction with pgrmc1.
196	loss of activity.
360	no loss of activity.
395	no loss of activity.
403	loss of activity.
406	loss of activity.
411	loss of activity.
417	decreased activity.
417	greatly reduced activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 5; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

5 pathways:

ID	Pathway	Evidence
R-HSA-189451	Heme biosynthesis	curated
R-HSA-9837999	Mitochondrial protein degradation	curated
R-HSA-1430728	Metabolism	—
R-HSA-189445	Metabolism of porphyrins	—
R-HSA-392499	Metabolism of proteins	—

MSigDB gene sets: 250 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_HEMOGLOBIN_METABOLIC_PROCESS, HORIUCHI_WTAP_TARGETS_DN, GOBP_MYELOID_CELL_HOMEOSTASIS, REACTOME_METABOLISM_OF_PORPHYRINS, GOBP_ERYTHROCYTE_HOMEOSTASIS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, MODULE_335, GOBP_TETRAPYRROLE_BIOSYNTHETIC_PROCESS, GOBP_PROTEIN_LIPID_COMPLEX_ASSEMBLY, ADDYA_ERYTHROID_DIFFERENTIATION_BY_HEMIN, HUMMERICH_SKIN_CANCER_PROGRESSION_DN, GNF2_ANK1, GOBP_PORPHYRIN_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY

GO Biological Process (6): generation of precursor metabolites and energy (GO:0006091), heme biosynthetic process (GO:0006783), heme A biosynthetic process (GO:0006784), heme B biosynthetic process (GO:0006785), response to light stimulus (GO:0009416), porphyrin-containing compound biosynthetic process (GO:0006779)

GO Molecular Function (12): protoporphyrin ferrochelatase activity (GO:0004325), ferrous iron binding (GO:0008198), heme binding (GO:0020037), iron-responsive element binding (GO:0030350), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), 2 iron, 2 sulfur cluster binding (GO:0051537), iron ion binding (GO:0005506), protein binding (GO:0005515), lyase activity (GO:0016829), metal ion binding (GO:0046872), iron-sulfur cluster binding (GO:0051536)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759), mitochondrial membrane (GO:0031966)

Reactome top-level categories

3 top-level categories:

Category	Pathways
Metabolism of porphyrins	1
Metabolism of proteins	1
Metabolism	1

GO top-level categories

29 GO namespaces:

Category	Terms
heme biosynthetic process	2
mitochondrion	2
metabolic process	1
porphyrin-containing compound biosynthetic process	1
heme metabolic process	1
pigment biosynthetic process	1
response to radiation	1
porphyrin-containing compound metabolic process	1
tetrapyrrole biosynthetic process	1
lyase activity	1
iron ion binding	1
tetrapyrrole binding	1
mRNA binding	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
iron-sulfur cluster binding	1
transition metal ion binding	1
binding	1
catalytic activity	1
cation binding	1
metal cluster binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
intracellular organelle lumen	1
mitochondrial envelope	1
organelle membrane	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 7 of 23 annotations. The rest are phylogenetic / computational / electronic (IEA).

7 experimentally-supported GO terms:

GO term	NS	Evidence
heme B biosynthetic process	BP	direct assay
heme biosynthetic process	BP	direct assay
mitochondrial membrane	CC	direct assay
mitochondrion	CC	high-throughput
identical protein binding	MF	physical interaction
protein homodimerization activity	MF	direct assay
protoporphyrin ferrochelatase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,760 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FECH	ALAS2	P22557	957
FECH	CPOX	P36551	950
FECH	HMBS	P08396	943
FECH	ALAS1	P13196	889
FECH	FXN	Q16595	886
FECH	ALAD	P13716	868
FECH	UROS	P10746	866
FECH	PPOX	P50336	864
FECH	UROD	P06132	853
FECH	ACO2	Q99798	793
FECH	ISCU	Q9H1K1	790
FECH	ABCB7	O75027	785
FECH	NFS1	Q9Y697	780
FECH	SLC25A37	Q9NYZ2	773
FECH	ABCB6	Q9NP58	772

IntAct

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

18 partners by confidence:

Partner	Interaction type	MIscore	Records
ABCB7	association	0.710	9
PGRMC1	physical association	0.700	4
ABCB10	direct interaction	0.670	2
NELFCD	association	0.530	1
TIMP2	physical association	0.500	1
ATM	physical association	0.370	1
AMD1	association	0.350	2
C8orf76	association	0.350	1
CTTN	association	0.350	1
GAPDHS	association	0.350	1
GTPBP10	association	0.350	1
MINK1	association	0.350	1
POTEF	association	0.350	1
RCBTB2	association	0.350	1
TMOD4	association	0.350	1
TRIM74	association	0.350	1
UBL4B	association	0.350	1
CALM1	physical association	0.000	1

BioGRID (205 interactions; top human partners by supporting records): PPP2CB (Affinity Capture-MS; 6 records), PPP2R1A (Affinity Capture-MS; 6 records), ERCC8 (Affinity Capture-MS; 4 records), HSPD1 (Affinity Capture-MS; 4 records), PPP2CA (Affinity Capture-MS; 4 records), CALM1 (Affinity Capture-MS; 3 records), CLPP (Proximity Label-MS; 3 records), TIMP2 (Affinity Capture-MS; 3 records), ABCB7 (Reconstituted Complex; 2 records), ATPAF2 (Affinity Capture-MS; 2 records), C7orf55 (Affinity Capture-MS; 2 records), CLUH (Affinity Capture-MS; 2 records), CS (Proximity Label-MS; 2 records), CUL3 (Affinity Capture-MS; 2 records), CYP1A2 (Affinity Capture-MS; 2 records)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
NFE2L2	“up-regulates quantity by expression”	FECH	“transcriptional regulation”

Disease & clinical

Genetic variants

Variant evidence for FECH: 318 ClinVar records (79 pathogenic / likely pathogenic); 4 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	58
Likely pathogenic	21
Uncertain significance	91
Likely benign	68
Benign	43

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 79 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
560	NM_000140.5(FECH):c.580_584del (p.Tyr194fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
242756	NM_000140.5(FECH):c.1231T>G (p.Cys411Gly)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
1069596	NM_000140.5(FECH):c.901_902del (p.Trp301fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
1409435	NM_000140.5(FECH):c.1217G>A (p.Cys406Tyr)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
1508284	NM_000140.5(FECH):c.599-2A>G	Pathogenic	criteria provided, multiple submitters, no conflicts	3
631802	NM_000140.5(FECH):c.820G>A (p.Asp274Asn)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
803500	NM_000140.5(FECH):c.598+1G>T	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1012439	NM_000140.5(FECH):c.175C>T (p.Gln59Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1457371	NM_000140.5(FECH):c.463+1G>C	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1805745	NM_000140.5(FECH):c.40del (p.Ala14fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
2683631	NM_000140.5(FECH):c.215dup (p.Leu72fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
2727476	NM_000140.5(FECH):c.954dup (p.Ile319fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
2736734	NM_000140.5(FECH):c.930G>A (p.Trp310Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
3255565	NM_000140.5(FECH):c.205dup (p.Thr69fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
623168	NM_000140.5(FECH):c.913G>T (p.Val305Phe)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3

Per-variant reference — Sugi Variant

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

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 28 predictions of 1,010):

Position(s)	Effect	Δscore	Sites
18:57551382	acceptor_gain	1.0000
18:57554843–57554844	donor_loss	1.0000	5
18:57554953–57554954	acceptor_loss	1.0000	6
18:57562872–57562873	donor_loss	1.0000	5
18:57562981–57562982	acceptor_loss	1.0000	6
18:57566596	acceptor_gain	1.0000
18:57551384	acceptor_gain	0.9900
18:57554957	acceptor_gain	0.9900
18:57567744	donor_gain	0.9900
18:57571555	acceptor_gain	0.9900

AlphaMissense

1,067 missense substitutions predicted likely pathogenic (of 2,760 scored), across 256 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
F337	8	0.994	1.000
H263	8	0.992	0.998
D274	8	0.990	0.996
H341	8	0.987	0.996
D95	8	0.985	0.994
D340	8	0.971	0.996
F93	8	0.969	0.989
F260	8	0.963	0.996
F163	8	0.955	0.997
D349	8	0.941	0.989
F88	8	0.940	0.999
N372	8	0.934	0.994
D225	8	0.930	0.973
F377	8	0.929	0.994
F188	8	0.911	0.997
S201	8	0.907	0.997
D97	8	0.855	0.945
H157	8	0.854	0.983
H388	8	0.811	0.979
M288	8	0.773	0.908

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	4.69e-05
Kidney Renal Clear Cell Carcinoma (validation)	favorable	0.000476

Disease associations

OMIM: gene MIM:612386 | disease phenotypes: MIM:177000

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
protoporphyria, erythropoietic, 1	Definitive	Autosomal recessive	4
autosomal erythropoietic protoporphyria	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
protoporphyria, erythropoietic, 1	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (11 panels, 10 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

11 panels:

Panel	Rating
Cutaneous photosensitivity with a likely genetic cause	green
Erythropoietic protoporphyria, mild variant	green
Hypotonic infant	green
Leukodystrophy, childhood onset	green
Likely inborn error of metabolism	green
Non-acute porphyrias	green
Paediatric disorders	green
Undiagnosed metabolic disorders	green
Unexplained death in infancy and sudden unexplained death in childhood	green
Vascular skin disorders	green
Iron metabolism disorders - NOT common HFE mutations	amber

Mondo (2): protoporphyria, erythropoietic, 1 (MONDO:0008319), autosomal erythropoietic protoporphyria (MONDO:0019263)

Orphanet (1): Autosomal erythropoietic protoporphyria (Orphanet:79278)

HPO phenotypes

16 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000964	Eczematoid dermatitis
HP:0000969	Edema
HP:0000989	Pruritus
HP:0000992	Cutaneous photosensitivity
HP:0001081	Cholelithiasis
HP:0001394	Cirrhosis
HP:0001399	Hepatic failure
HP:0001410	Decreased liver function
HP:0001878	Hemolytic anemia
HP:0001935	Microcytic anemia
HP:0002155	Hypertriglyceridemia
HP:0010472	Abnormal circulating porphyrin concentration
HP:0010783	Erythema
HP:0011463	Childhood onset
HP:6000697	Low tissue ferrochelatase activity

GWAS associations

4 associations:

Study	Trait	p-value
GCST90002404_295	Red cell distribution width	2e-12
GCST005993_10	Mean corpuscular hemoglobin	7e-12
GCST006011_33	Mean corpuscular volume	6e-9
GCST003986_25	Migraine	6e-8

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0004527	mean corpuscular hemoglobin
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3879831 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 362,493 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

34 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL1289926	AXITINIB	4	16,510
CHEMBL2105717	CABOZANTINIB	4	11,799
CHEMBL553	ERLOTINIB	4	109,860
CHEMBL939	GEFITINIB	4	119,425
CHEMBL1289601	LENVATINIB	4	9,224
CHEMBL180022	NERATINIB	4	9,891
CHEMBL255863	NILOTINIB	4	39,362
CHEMBL2035187	PACRITINIB	4	3,544
CHEMBL3545110	RIBOCICLIB	4	8,501
CHEMBL3989868	TUCATINIB	4	3,355
CHEMBL1229517	VEMURAFENIB	4	16,487
CHEMBL2105728	CRENOLANIB	3	2,278
CHEMBL1091644	LINSITINIB	3	1,520
CHEMBL1241855	RIGOSERTIB	3	1,641
CHEMBL3218578	BGT-226 FREE BASE	2	3,018
CHEMBL513909	BI-2536	2	932
CHEMBL1614713	CC-401	2	396
CHEMBL483321	CP-724714	2	909
CHEMBL1079175	MK-2206	2	3,133
CHEMBL1822792	MK-2461	2	708
CHEMBL3120215	OSI-027	2
CHEMBL607707	PELITINIB	2
CHEMBL475251	R-406	2
CHEMBL3039517	RABUSERTIB	2
CHEMBL2103842	VARLITINIB	2
CHEMBL1944698	ZOTIRACICLIB	2
CHEMBL551064	AEW-541	1
CHEMBL1801204	AZD-8055	1
CHEMBL598797	CUDC-101	1
CHEMBL482967	CYC-116	1
CHEMBL1090479	GSK-1070916	1
CHEMBL494089	GSK-690693	1
CHEMBL3109738	JNJ-26483327	1
CHEMBL2323775	MK-8033	1

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

1 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs536560	ethambutol, isoniazid / pyrazinamide / rifampin	Toxicity	Genotype CC is associated with increased likelihood of Drug-induced liver injury when treated with ethambutol null isoniazid / pyrazinamide / rifampin in people with Tuberculosis as compared to genotypes CT + TT.	PMID:40582371

Binding affinities (BindingDB)

54 measured of 83 human assays (84 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
7-(4-(3-Ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide	IC50	2.4 nM
Momelotinib	IC50	8 nM	US-9469613: (N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide
2-amino-4-methyl-1,3-thiazol-5-yl)-N-[4-(morpholin-4-yl)phenyl]pyrimidin-2-amine, 5	IC50	9.2 nM
1-[2-[5-[(3-methyloxetan-3-yl)methoxy]benzimidazol-1-yl]quinolin-8-yl]piperidin-4-amine	IC50	10 nM
CHEBI:72317	IC50	14 nM
4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)-N-(4-(methylsulfonyl)phenyl)pyrimidin-2-amine	IC50	16 nM
PLX-4032	IC50	19 nM
2-[(3-chloro-4-fluoroanilino)methyl]-5-propyl-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	33.6 nM	US-12161642: Ferrochelatase inhibitors and methods of use
(Z)-but-2-enedioic acid;8-(6-methoxypyridin-3-yl)-3-methyl-1-[4-piperazin-1-yl-3-(trifluoromethyl)phenyl]imidazo[4,5-c]quinolin-2-one	IC50	41.9 nM	US-9284315: Three-ring PI3K and/or mTOR inhibitor
2-[(3,4-difluoroanilino)methyl]-5-propyl-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	42.9 nM	US-12161642: Ferrochelatase inhibitors and methods of use
GSK-1070916	IC50	59 nM
6-[(4-chlorophenyl)methyl]-2-[(4-methoxyanilino)methyl]-5-methyl-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	61.4 nM	US-12161642: Ferrochelatase inhibitors and methods of use
2-[(4-chloroanilino)methyl]-5-propyl-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	91.6 nM	US-12161642: Ferrochelatase inhibitors and methods of use
2-(4-tert-butylphenyl)-5-[(5-chloro-2-methylanilino)methyl]-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	98.1 nM	US-12161642: Ferrochelatase inhibitors and methods of use
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	KD	120 nM	US-9145414: 1,2,4-triazine-6-carboxamide derivative
2-(4-tert-butylphenyl)-5-[(quinolin-2-ylamino)methyl]-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	178 nM	US-12161642: Ferrochelatase inhibitors and methods of use
11-[(3-chloro-4-methylanilino)methyl]-1,8,10,12-tetrazatricyclo[7.3.0.03,7]dodeca-3(7),8,10-trien-2-one	IC50	227 nM	US-12161642: Ferrochelatase inhibitors and methods of use
BIBF-1120	EC50	276 nM
2-[(4-methylanilino)methyl]-5-propyl-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	293 nM	US-12161642: Ferrochelatase inhibitors and methods of use
5-[(5-chloro-2-methylanilino)methyl]-2-(2-methylphenyl)-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	346 nM	US-12161642: Ferrochelatase inhibitors and methods of use
2-[(3-chloroanilino)methyl]-5-propyl-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	346 nM	US-12161642: Ferrochelatase inhibitors and methods of use
2-(4-tert-butylphenyl)-5-[(3-methoxyanilino)methyl]-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	491 nM	US-12161642: Ferrochelatase inhibitors and methods of use
2-[(3-methylanilino)methyl]-5-propyl-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	508 nM	US-12161642: Ferrochelatase inhibitors and methods of use
2-(4-tert-butylphenyl)-5-[(3-chloroanilino)methyl]-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	511 nM	US-12161642: Ferrochelatase inhibitors and methods of use
2-[(4-fluoroanilino)methyl]-5-propyl-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	525 nM	US-12161642: Ferrochelatase inhibitors and methods of use
2-[(3-chloro-4-methylanilino)methyl]-5-propyl-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	570 nM	US-12161642: Ferrochelatase inhibitors and methods of use
2-[(3-chloro-2-methylanilino)methyl]-5-propan-2-yl-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	751 nM	US-12161642: Ferrochelatase inhibitors and methods of use
2-(4-tert-butylphenyl)-5-[(5-chloro-2-methoxyanilino)methyl]-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	808 nM	US-12161642: Ferrochelatase inhibitors and methods of use
2-[(4-chloroanilino)methyl]-5-propyl-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	829 nM	US-12161642: Ferrochelatase inhibitors and methods of use
2-[(3-chloro-4-methylanilino)methyl]-5-propan-2-yl-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	1020 nM	US-12161642: Ferrochelatase inhibitors and methods of use
11-[(4-chloroanilino)methyl]-1,8,10,12-tetrazatricyclo[7.3.0.03,7]dodeca-3(7),8,10-trien-2-one	IC50	1050 nM	US-12161642: Ferrochelatase inhibitors and methods of use
6-[(4-chlorophenyl)methyl]-2-[(2-ethylanilino)methyl]-5-methyl-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	1250 nM	US-12161642: Ferrochelatase inhibitors and methods of use
2-(4-tert-butylphenyl)-5-[(2,6-dimethylanilino)methyl]-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	1390 nM	US-12161642: Ferrochelatase inhibitors and methods of use
CHEMBL5653589	KD	1440 nM
11-[(3-chloroanilino)methyl]-1,8,10,12-tetrazatricyclo[7.3.0.03,7]dodeca-3(7),8,10-trien-2-one	IC50	1570 nM	US-12161642: Ferrochelatase inhibitors and methods of use
2-[(3-chloro-2-methylanilino)methyl]-5-propyl-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	2150 nM	US-12161642: Ferrochelatase inhibitors and methods of use
2-[(3-methoxyanilino)methyl]-5-propyl-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	2860 nM	US-12161642: Ferrochelatase inhibitors and methods of use
ethyl 3-[2-[(3-chloro-4-methylanilino)methyl]-5-methyl-7-oxo-1H-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]propanoate	IC50	2990 nM	US-12161642: Ferrochelatase inhibitors and methods of use
11-[(4-methylanilino)methyl]-1,8,10,12-tetrazatricyclo[7.3.0.03,7]dodeca-3(7),8,10-trien-2-one	IC50	3620 nM	US-12161642: Ferrochelatase inhibitors and methods of use
11-[(3-methoxyanilino)methyl]-1,8,10,12-tetrazatricyclo[7.3.0.03,7]dodeca-3(7),8,10-trien-2-one	IC50	3750 nM	US-12161642: Ferrochelatase inhibitors and methods of use
5-propyl-2-[[3-(trifluoromethyl)anilino]methyl]-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	4390 nM	US-12161642: Ferrochelatase inhibitors and methods of use
11-[(3-methylanilino)methyl]-1,8,10,12-tetrazatricyclo[7.3.0.03,7]dodeca-3(7),8,10-trien-2-one	IC50	9340 nM	US-12161642: Ferrochelatase inhibitors and methods of use
2-[(4-ethylanilino)methyl]-5-propyl-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	10600 nM	US-12161642: Ferrochelatase inhibitors and methods of use
MK-8033	IC50	14700 nM
2-[(4-methylanilino)methyl]-5-propan-2-yl-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	16800 nM	US-12161642: Ferrochelatase inhibitors and methods of use
2-[(2-methylanilino)methyl]-5-propan-2-yl-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	17900 nM	US-12161642: Ferrochelatase inhibitors and methods of use
5-methyl-2-[(3-methylanilino)methyl]-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	18700 nM	US-12161642: Ferrochelatase inhibitors and methods of use
5-methyl-2-[(4-methylanilino)methyl]-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	22500 nM	US-12161642: Ferrochelatase inhibitors and methods of use
2-[(2-phenylanilino)methyl]-5-propyl-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	27300 nM	US-12161642: Ferrochelatase inhibitors and methods of use
2-[(3-methylanilino)methyl]-5-propan-2-yl-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one	IC50	28100 nM	US-12161642: Ferrochelatase inhibitors and methods of use

ChEMBL bioactivities

34 potent at pChembl≥5 of 42 total, top 34 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.61	Kd	243	nM	ZOTIRACICLIB
6.11	Kd	783	nM	CYC-116
5.97	Kd	1069	nM	MK-2206
5.96	Kd	1089	nM	CHEMBL3688339
5.85	Kd	1419	nM	VEMURAFENIB
5.62	Kd	2415	nM	GSK-1070916
5.58	Kd	2628	nM	CABOZANTINIB
5.57	Kd	2701	nM	GSK-690693
5.55	Kd	2806	nM	LENVATINIB
5.54	Kd	2867	nM	CUDC-101
5.54	Kd	2884	nM	CHEMBL3752910
5.54	Kd	2905	nM	CHEMBL3752910
5.54	ED50	2920	nM	CHEMBL3752910
5.51	Kd	3108	nM	BGT-226 FREE BASE
5.51	Kd	3080	nM	R-406
5.47	Kd	3418	nM	MK-2461
5.46	Kd	3481	nM	CHEMBL3699142
5.42	Kd	3824	nM	RABUSERTIB
5.42	Kd	3801	nM	BI-2536
5.41	Kd	3912	nM	TUCATINIB
5.40	Kd	3974	nM	JNJ-26483327
5.38	Kd	4213	nM	LINSITINIB
5.38	Kd	4138	nM	NILOTINIB
5.30	EC50	5012	nM	VEMURAFENIB
5.25	Kd	5577	nM	RIGOSERTIB
5.22	Kd	6029	nM	NERATINIB
5.19	Kd	6501	nM	AEW-541
5.17	Kd	6682	nM	GEFITINIB
5.17	Kd	6840	nM	AXITINIB
5.16	Kd	6896	nM	AZD-8055
5.16	Kd	6905	nM	ERLOTINIB
5.13	Kd	7354	nM	CRENOLANIB
5.09	Kd	8143	nM	CHEMBL5653589
5.09	ED50	8184	nM	CHEMBL5653589

PubChem BioAssay actives

64 with measured affinity, of 277 total; 43 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(16E)-14-methyl-20-oxa-5,7,14,27-tetrazatetracyclo[19.3.1.12,6.18,12]heptacosa-1(25),2(27),3,5,8,10,12(26),16,21,23-decaene	1425001: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.2430	uM
4-methyl-5-[2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]-1,3-thiazol-2-amine	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	0.7000	uM
Gefitinib	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	1.0000	uM
8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-one	1425001: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	1.0690	uM
1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-[[4-[(dimethylamino)methyl]cyclohexyl]amino]-1,5-naphthyridin-3-yl]ethanone	1425001: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	1.0890	uM
Vemurafenib	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	1.3000	uM
3-[4-[4-[2-[3-[(dimethylamino)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethylpyrazol-3-yl]phenyl]-1,1-dimethylurea	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	1.7000	uM
Nilotinib	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	1.7000	uM
14-[[[(2R)-1,4-dioxan-2-yl]methyl-methylsulfamoyl]amino]-5-(1-methylpyrazol-4-yl)-2-oxo-7-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,9,12,14-heptaene	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	2.1000	uM
3-[8-amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclobutan-1-ol	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	2.2000	uM
4-(2-methyl-3-propan-2-ylimidazol-4-yl)-N-(4-methylsulfonylphenyl)pyrimidin-2-amine	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	2.6000	uM
Cabozantinib	1425001: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	2.6280	uM
4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-[[(3S)-piperidin-3-yl]methoxy]imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	2.7000	uM
Lenvatinib	1425001: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	2.8060	uM
7-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]oxy-N-hydroxyheptanamide	1425001: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	2.8670	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148380: Binding affinity to human FECH incubated for 45 mins by Kinobead based pull down assay	kd	2.8840	uM
(3R,4R)-4-amino-1-[[4-(3-methoxyanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	3.0000	uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	1425001: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	3.0800	uM
Axitinib	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	3.1000	uM
8-(6-methoxy-3-pyridinyl)-3-methyl-1-[4-piperazin-1-yl-3-(trifluoromethyl)phenyl]imidazo[4,5-c]quinolin-2-one	1425001: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	3.1080	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	3.2000	uM
Momelotinib	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	3.4000	uM
3-[2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-N-methylbenzamide	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	3.4000	uM
3-[3-[N-[4-[(dimethylamino)methyl]phenyl]-C-phenylcarbonimidoyl]-2-hydroxy-1H-indol-6-yl]-N-ethylprop-2-ynamide	1425001: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	3.4810	uM
1-[2-[5-[(3-methyloxetan-3-yl)methoxy]benzimidazol-1-yl]quinolin-8-yl]piperidin-4-amine	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	3.8000	uM
4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide	1425001: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	3.8010	uM
1-[5-bromo-4-methyl-2-[[(2S)-morpholin-2-yl]methoxy]phenyl]-3-(5-methylpyrazin-2-yl)urea	1425001: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	3.8240	uM
Tucatinib	1425001: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	3.9120	uM
5-bromo-18-methoxy-10-methyl-16-oxa-2,10,21,23-tetrazatetracyclo[15.6.2.03,8.020,24]pentacosa-1(23),3(8),4,6,17,19,21,24-octaene	1425001: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	3.9740	uM
7-[3-(azetidin-1-ylmethyl)cyclobutyl]-5-(3-phenylmethoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-amine	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	4.4000	uM
4-[4-amino-5-(7-methoxy-1H-indol-2-yl)imidazo[5,1-f][1,2,4]triazin-7-yl]cyclohexane-1-carboxylic acid	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	4.5000	uM
Neratinib	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	5.1000	uM
2-[2-methoxy-5-[[(E)-2-(2,4,6-trimethoxyphenyl)ethenyl]sulfonylmethyl]anilino]acetic acid	1425001: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	5.5770	uM
[5-[2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-2-methoxyphenyl]methanol	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	6.2000	uM
6-[5-[(2-methylsulfonylethylamino)methyl]furan-2-yl]-N-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl]quinazolin-4-amine	1801713: Competition Binding Assays from Article 10.1021/acschembio.5b01063: “Chemical Proteomics Reveals Ferrochelatase as a Common Off-target of Kinase Inhibitors.”	kd	6.4000	uM
7-[3-(azetidin-1-yl)cyclobutyl]-5-(3-phenylmethoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-amine	1425001: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	6.5010	uM
Erlotinib	1425001: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	6.9050	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148380: Binding affinity to human FECH incubated for 45 mins by Kinobead based pull down assay	kd	8.1427	uM
(E)-N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide	1425001: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	10.5450	uM
2-methoxy-N-[(E)-3-[4-[3-methyl-4-[(6-methyl-3-pyridinyl)oxy]anilino]quinazolin-6-yl]prop-2-enyl]acetamide	1425001: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	28.5700	uM
3-[3-(2-piperidin-1-ylethoxy)phenyl]-5-(1H-1,2,4-triazol-5-yl)-1H-indazole	1425001: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	32.3840	uM
1-[5-(1-methylpyrazol-4-yl)-2-oxo-7-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,9,12,14-heptaen-14-yl]-N-(pyridin-2-ylmethyl)methanesulfonamide	1425001: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	32.6400	uM
Pacritinib	1425001: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	67.9140	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects cotreatment, decreases reaction, increases expression, affects methylation	4
Valproic Acid	affects expression, increases expression	4
bisphenol A	affects cotreatment, decreases methylation, decreases expression, increases expression	3
Particulate Matter	decreases expression, increases abundance, increases expression	3
mercuric bromide	increases expression, affects cotreatment	2
zinc mesoporphyrin	increases chemical synthesis, increases reaction	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Cisplatin	decreases expression, affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Cadmium Chloride	decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
bisphenol F	increases expression	1
chloroacetaldehyde	affects expression	1
tributyltin	decreases activity	1
beta-lapachone	increases expression	1
sulforaphane	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
cinnamyl alcohol	increases expression	1
pyridoxal isonicotinoyl hydrazone	decreases expression, decreases reaction, decreases abundance	1
ferric chloride	decreases expression, decreases reaction, increases expression	1
tobacco tar	increases expression	1
ochratoxin A	decreases expression	1
n-hexane	increases expression	1
4-hydroxy-2-nonenal	decreases expression	1
nickel sulfate	increases expression	1
methyl salicylate	increases expression	1
isoeugenol	increases expression	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1

ChEMBL screening assays

9 unique, capped per target: 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3877219	Binding	Stabilization of FECH in human K562 cells after 1 hr by thermal shift assay	Non-kinase targets of protein kinase inhibitors. — *Nat Rev Drug Discov*

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1MI	Abcam K-562 FECH KO	Cancer cell line	Female
CVCL_D2J3	Abcam Raji FECH KO	Cancer cell line	Male
CVCL_GS68	GM05008	Finite cell line	Female
CVCL_UQ50	Abcam Jurkat FECH KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

29 trials:

NCT	Phase	Status	Title
NCT00004940	Phase 3	COMPLETED	Phase III Study of L-Cysteine in Patients With Erythropoietic Protoporphyria
NCT00979745	Phase 3	COMPLETED	Phase III Confirmatory Study in Erythropoietic Protoporphyria (EPP)
NCT01605136	Phase 3	COMPLETED	Phase III Confirmatory Study in Erythropoietic Protoporphyria
NCT04053270	Phase 3	COMPLETED	Multicentre Phase III Erythropoietic Protoporphyria Study
NCT04402489	Phase 3	COMPLETED	Study to Evaluate Efficacy, Safety, and Tolerability of MT-7117 in Subjects With Erythropoietic Protoporphyria or X-Linked Protoporphyria
NCT04578496	Phase 3	COMPLETED	A Safety Extension Study in Patients With Erythropoietic Protoporphyria (EPP)
NCT05005975	Phase 3	ACTIVE_NOT_RECRUITING	Extension Study to Evaluate Safety and Tolerability of Oral Dersimelagon (MT-7117) in Subjects With Erythropoietic Protoporphyria (EPP) or X-Linked Protoporphyria (XLP)
NCT06144840	Phase 3	COMPLETED	INcreased Sun Exposure Without Pain In Research Participants With EPP or XLP
NCT06910358	Phase 3	ACTIVE_NOT_RECRUITING	Study of Bitopertin in Participants With EPP or XLP (APOLLO)
NCT01097044	Phase 2	COMPLETED	Phase II Confirmatory Study in Erythropoietic Protoporphyria (EPP)
NCT03520036	Phase 2	COMPLETED	Study to Evaluate Efficacy, Safety, and Tolerability of MT-7117 in Subjects With Erythropoietic Protoporphyria
NCT05020184	Phase 2	COMPLETED	Effect of Oral Cimetidine in the Protoporphyrias
NCT05308472	Phase 2	COMPLETED	Study of Bitopertin to Evaluate the Safety, Tolerability, Efficacy, and PPIX Concentrations in Participants With EPP
NCT06971900	Phase 2	COMPLETED	GATEWAY: A Phase 2a Study of PORT-77 in Adults With Erythropoietic Protoporphyria
NCT01422915	Phase 2/3	COMPLETED	Sorbent Therapy of the Cutaneous Porphyrias
NCT05883748	Phase 2/3	ENROLLING_BY_INVITATION	HELIOS: Open-Label, Long-Term Extension Study to Investigate the Safety, Tolerability, and Efficacy of DISC-1459 (Bitopertin) in Participants With EPP or XLP
NCT07820085	Phase 2/3	RECRUITING	A Study to Investigate PORT-77 Oral Dosing Compared With Placebo in Participants With Erythropoietic Protoporphyria (EPP) or X-linked Protoporphyria (XLP)
NCT06388642	Phase 1/2	COMPLETED	Pharmacokinetics of Afamelanotide in Erythropoietic Protoporphyria Patients
NCT00004831	Not specified	COMPLETED	Study of Cysteine Hydrochloride for Erythropoietic Protoporphyria
NCT00206869	Not specified	UNKNOWN	Does Exercise and Heat Increase the Lightsensibility in Patients With Erythropoietic Protoporphyria
NCT01550705	Not specified	TERMINATED	Effect of Isoniazid on Protoporphyrin Levels in Erythropoietic Protoporphyria
NCT01688895	Not specified	COMPLETED	Erythropoietic Protoporphyrias: Studies of the Natural History, Genotype-Phenotype Correlations, and Psychosocial Impact
NCT01880983	Not specified	COMPLETED	Mitoferrin-1 Expression in Erythropoietic Protoporphyria (Porphyria Rare Disease Clinical Research Consortium (RDCRC))
NCT02979249	Not specified	COMPLETED	Oral Iron for Erythropoietic Protoporphyrias
NCT03682731	Not specified	COMPLETED	Light Exposure Patterns and Symptoms Among Patients With Erythropoietic Protoporphyria
NCT05572125	Not specified	COMPLETED	Iron Therapy in Erythropoietic Protoporphyria
NCT05780840	Not specified	UNKNOWN	Protection Against Visible Light by Dihydroxyacetone in Erythropoietic Protoporphyria
NCT07567131	Not specified	RECRUITING	Observational Study of Adults and Adolescents With Erythropoietic Protoporphyria (EPP) and X-linked Porphyria (XLP)
NCT07603401	Not specified	AVAILABLE	Expanded Access Program of Bitopertin For Participants With EPP or XLP

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for FECH across ~30M SureChEMBL compounds — explore on Sugi Predict.