UROS

Summary

UROS (uroporphyrinogen III synthase, HGNC:12592) is a protein-coding gene on chromosome 10q26.2, encoding Uroporphyrinogen-III synthase (P10746). Catalyzes cyclization of the linear tetrapyrrole, hydroxymethylbilane, to the macrocyclic uroporphyrinogen III, the branch point for the various sub-pathways leading to the wide diversity of porphyrins. It is a selective cancer dependency (DepMap: 11.3% of cell lines).

The protein encoded by this gene catalyzes the fourth step of porphyrin biosynthesis in the heme biosynthetic pathway. Defects in this gene cause congenital erythropoietic porphyria (Gunther’s disease).

Source: NCBI Gene 7390 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cutaneous porphyria (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 166 total — 27 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 71
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 11.3% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_000375

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12592
Approved symbol	UROS
Name	uroporphyrinogen III synthase
Location	10q26.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000188690
Ensembl biotype	protein_coding
OMIM	606938
Entrez	7390

Gene structure

Transcript identifiers

Ensembl transcripts: 48 — 37 protein_coding, 7 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000368774, ENST00000368778, ENST00000368786, ENST00000368797, ENST00000420761, ENST00000462490, ENST00000464267, ENST00000465577, ENST00000470483, ENST00000484541, ENST00000616800, ENST00000622016, ENST00000648119, ENST00000648427, ENST00000649275, ENST00000649450, ENST00000649536, ENST00000650185, ENST00000650472, ENST00000650524, ENST00000650587, ENST00000713579, ENST00000879942, ENST00000879943, ENST00000879944, ENST00000879945, ENST00000879946, ENST00000879947, ENST00000879948, ENST00000879949, ENST00000879950, ENST00000879951, ENST00000879952, ENST00000879953, ENST00000879954, ENST00000879955, ENST00000879956, ENST00000879957, ENST00000879958, ENST00000879959, ENST00000940865, ENST00000940866, ENST00000940867, ENST00000940868, ENST00000940869, ENST00000961000, ENST00000961001, ENST00000961002

RefSeq mRNA: 5 — MANE Select: NM_000375 NM_000375, NM_001324036, NM_001324037, NM_001324038, NM_001324039

CCDS: CCDS7648, CCDS81522, CCDS91371, CCDS91372

Canonical transcript exons

ENST00000368797 — 10 exons

Exon	Start	End
ENSE00001372447	125816437	125816525
ENSE00001384033	125816177	125816260
ENSE00003570772	125798065	125798145
ENSE00003625193	125815034	125815130
ENSE00003653296	125796103	125796188
ENSE00003662875	125812214	125812288
ENSE00003665235	125807413	125807487
ENSE00003669362	125794880	125794978
ENSE00003835309	125823029	125823258
ENSE00003841182	125788586	125789005

Expression profiles

Bgee: expression breadth ubiquitous, 277 present calls, max score 97.50.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 49.6357 / max 470.7266, expressed in 1823 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
111904	41.0933	1817
111903	3.8225	1557
111905	3.1672	1554
111901	0.9248	76
111896	0.2490	83
111897	0.1844	66
111899	0.0655	21
111898	0.0621	14
111902	0.0462	15
111900	0.0208	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
nucleus accumbens	UBERON:0001882	97.50	gold quality
caudate nucleus	UBERON:0001873	97.39	gold quality
putamen	UBERON:0001874	97.15	gold quality
amygdala	UBERON:0001876	97.15	gold quality
right frontal lobe	UBERON:0002810	97.15	gold quality
cingulate cortex	UBERON:0003027	97.08	gold quality
anterior cingulate cortex	UBERON:0009835	97.07	gold quality
apex of heart	UBERON:0002098	96.79	gold quality
prefrontal cortex	UBERON:0000451	96.76	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	95.93	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.89	gold quality
Brodmann (1909) area 10	UBERON:0013541	95.73	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.60	gold quality
right atrium auricular region	UBERON:0006631	95.60	gold quality
frontal cortex	UBERON:0001870	95.42	gold quality
heart left ventricle	UBERON:0002084	95.34	gold quality
neocortex	UBERON:0001950	95.20	gold quality
gastrocnemius	UBERON:0001388	95.14	gold quality
cardiac ventricle	UBERON:0002082	95.08	gold quality
telencephalon	UBERON:0001893	95.01	gold quality
cardiac atrium	UBERON:0002081	94.98	gold quality
middle frontal gyrus	UBERON:0002702	94.97	gold quality
muscle of leg	UBERON:0001383	94.92	gold quality
frontal pole	UBERON:0002795	94.86	gold quality
lateral nuclear group of thalamus	UBERON:0002736	94.71	gold quality
forebrain	UBERON:0001890	94.60	gold quality
cerebral cortex	UBERON:0000956	94.49	gold quality
Ammon’s horn	UBERON:0001954	94.44	gold quality
heart	UBERON:0000948	94.43	gold quality
right lobe of liver	UBERON:0001114	94.41	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	142.06
E-CURD-112	yes	46.81
E-MTAB-10042	yes	25.91
E-ANND-3	yes	10.64
E-MTAB-9388	yes	9.04
E-MTAB-9801	no	2.76

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PPARA

miRNA regulators (miRDB)

4 targeting UROS, 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-4697-3P	99.89	67.09	1123
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-6767-3P	93.99	66.01	204

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 11.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 10)

• two novel misense mutations in the UROS gene. (PMID:17298225)
• NMR analyses of URO-synthase titrated with competitive inhibitors N(D)-methyl-1-formylbilane or URO’gen III, revealed resonance perturbations of specific residues lining the cleft between 2 major domains of URO synthase that mapped enzyme’s active site. (PMID:18004775)
• The decrease in the expression of ubiquitous HMBS and UROS mRNAs under hypoxia is associated with accumulation of hypoxia-inducible factor 1alpha protein. (PMID:19021769)
• UROS mutations related to erythropoietic porphyria identify a key helix for protein stability. (PMID:19099412)
• Data show that branchpoint sequence (BPS)mutation reduced the wild-type transcript and UROS enzyme activity in CEP lymphoblasts to approximately 10% and 15% of normal, respectively. (PMID:19965637)
• Intracellular rescue of the uroporphyrinogen III synthase activity in enzymes carrying the hotspot mutation C73R. (PMID:21343304)
• REVIEW: Structural, thermodynamic, and mechanistical studies in uroporphyrinogen III synthase and molecular basis of congenital erythropoietic porphyria (PMID:21570665)
• A, T to C change at nucleotide 34313, leading to a substitution of Leucine by Proline at codon 237, was observed in the homozygous state in a family with congenital erythropoietic porphyria. (PMID:22350154)
• we show evidence that abnormal protein homeostasis is a prevalent mechanism responsible for UROS deficiency and that modulators of UROS proteolysis such as proteasome inhibitors or chemical chaperones may represent an attractive therapeutic option to reduce porphyrin accumulation and prevent skin photosensitivity in Congenital erythropoietic porphyria (CEP)patients when the genotype includes a missense variant. (PMID:28334762)
• These results expand the molecular heterogeneity of the erythropoietic porphyrias by adding a total of 7 novel mutations in uroporphyrinogen III synthase. (PMID:30454868)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	uros	ENSDARG00000027491
mus_musculus	Uros	ENSMUSG00000030979
rattus_norvegicus	Uros	ENSRNOG00000017810
drosophila_melanogaster	Uros1	FBGN0030066
drosophila_melanogaster	Uros2	FBGN0038361

Protein

Protein identifiers

Uroporphyrinogen-III synthase — P10746 (reviewed: P10746)

Alternative names: Hydroxymethylbilane hydrolyase [cyclizing], Uroporphyrinogen-III cosynthase

All UniProt accessions (17): A0A087WUV7, A0A087WZB7, A0A087X021, A0A0S2Z4T8, A0A0S2Z5C5, A0A3B3IS33, A0A3B3IS76, A0A3B3ISL9, A0A3B3ISM6, A0A3B3ISX6, A0A3B3ITJ2, A0A3B3IU75, A0A3B3IUC8, P10746, Q5T3L7, Q5T3L8, Q5T3L9

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes cyclization of the linear tetrapyrrole, hydroxymethylbilane, to the macrocyclic uroporphyrinogen III, the branch point for the various sub-pathways leading to the wide diversity of porphyrins. Porphyrins act as cofactors for a multitude of enzymes that perform a variety of processes within the cell such as methionine synthesis (vitamin B12) or oxygen transport (heme).

Subunit / interactions. Monomer.

Subcellular location. Cytoplasm. Cytosol.

Tissue specificity. Ubiquitous.

Disease relevance. Congenital erythropoietic porphyria (CEP) [MIM:263700] 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. The manifestations of CEP are heterogeneous, ranging from nonimmune hydrops fetalis due to severe hemolytic anemia in utero to milder, later onset forms, which have only skin lesions due to cutaneous photosensitivity in adult life. The deficiency in UROS activity results in the non-enzymatic conversion of hydroxymethylbilane (HMB) into the uroporphyrinogen-I isomer. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Porphyrin-containing compound metabolism; protoporphyrin-IX biosynthesis; coproporphyrinogen-III from 5-aminolevulinate: step 3/4.

Similarity. Belongs to the uroporphyrinogen-III synthase family.

RefSeq proteins (5): NP_000366, NP_001310965, NP_001310966, NP_001310967, NP_001310968 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003754	4pyrrol_synth_uPrphyn_synth	Domain
IPR036108	4pyrrol_syn_uPrphyn_synt_sf	Homologous_superfamily
IPR039793	UROS/Hem4	Family

Pfam: PF02602

Enzyme classification (BRENDA):

• EC 4.2.1.75 — uroporphyrinogen-III synthase (BRENDA: 19 organisms, 20 substrates, 29 inhibitors, 14 Km, 8 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
HYDROXYMETHYLBILANE	0.0001–10	8

Catalyzed reactions (Rhea), 1 shown:

• hydroxymethylbilane = uroporphyrinogen III + H2O (RHEA:18965)

UniProt features (63 total): sequence variant 24, helix 15, strand 12, mutagenesis site 9, turn 2, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1JR2	X-RAY DIFFRACTION	1.84

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P10746-F1	93.18	0.83

Functional residue map

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

Mutagenesis-validated functional residues (9):

Position	Phenotype
63	does not affect enzymatic activity.
65	slightly affects enzymatic activity.
103	slightly affects enzymatic activity.
127	does not affect enzymatic activity.
168	impairs enzymatic activity.
197	does not affect enzymatic activity.
220	does not affect enzymatic activity.
227	does not affect enzymatic activity.
228	impairs enzymatic activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-189451	Heme biosynthesis

MSigDB gene sets: 373 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_RESPONSE_TO_AMINE, REACTOME_METABOLISM_OF_PORPHYRINS, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, GOBP_TETRAPYRROLE_BIOSYNTHETIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_RESPONSE_TO_METAL_ION, GOBP_PORPHYRIN_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, MODULE_285, GOBP_CELLULAR_RESPONSE_TO_ARSENIC_CONTAINING_SUBSTANCE, GOBP_TETRAPYRROLE_METABOLIC_PROCESS, GOBP_PIGMENT_METABOLIC_PROCESS

GO Biological Process (10): uroporphyrinogen III biosynthetic process (GO:0006780), obsolete protoporphyrinogen IX biosynthetic process (GO:0006782), heme biosynthetic process (GO:0006783), heme A biosynthetic process (GO:0006784), heme B biosynthetic process (GO:0006785), response to platinum ion (GO:0070541), cellular response to arsenic-containing substance (GO:0071243), cellular response to amine stimulus (GO:0071418), porphyrin-containing compound biosynthetic process (GO:0006779), tetrapyrrole biosynthetic process (GO:0033014)

GO Molecular Function (3): uroporphyrinogen-III synthase activity (GO:0004852), folic acid binding (GO:0005542), lyase activity (GO:0016829)

GO Cellular Component (3): mitochondrion (GO:0005739), cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of porphyrins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
porphyrin-containing compound biosynthetic process	2
heme biosynthetic process	2
cytoplasm	2
cellular anatomical structure	2
carboxylic acid biosynthetic process	1
uroporphyrinogen III metabolic process	1
heme metabolic process	1
pigment biosynthetic process	1
response to metal ion	1
response to arsenic-containing substance	1
cellular response to chemical stimulus	1
response to amine	1
cellular response to nitrogen compound	1
porphyrin-containing compound metabolic process	1
tetrapyrrole biosynthetic process	1
biosynthetic process	1
tetrapyrrole metabolic process	1
hydro-lyase activity	1
vitamin binding	1
carboxylic acid binding	1
modified amino acid binding	1
heterocyclic compound binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1114 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UROS	HMBS	P08396	946
UROS	BCCIP	Q9P287	929
UROS	UROD	P06132	918
UROS	CPOX	P36551	913
UROS	ALAD	P13716	893
UROS	DHX32	Q7L7V1	886
UROS	FECH	P22830	872
UROS	PPOX	P50336	859
UROS	ALAS2	P22557	796
UROS	ALAS1	P13196	771
UROS	GATA1	P15976	693
UROS	SLC25A38	Q96DW6	664
UROS	ABCB6	Q9NP58	629
UROS	SLC25A37	Q9NYZ2	512
UROS	ABCB7	O75027	502

IntAct

9 interactions, top by confidence:

A	B	Type	Score
Mgu	GCLM	psi-mi:“MI:0914”(association)	0.530
CCN5	ICAM1	psi-mi:“MI:0914”(association)	0.530
Mgu	EED	psi-mi:“MI:0915”(physical association)	0.400
PA	Mgu	psi-mi:“MI:0915”(physical association)	0.370
COPS5	FBLL1	psi-mi:“MI:0914”(association)	0.350
PNPLA4	Mgu	psi-mi:“MI:0914”(association)	0.350
UBQLN4	Mgu	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (32): MOCS1 (Affinity Capture-MS), TCEAL1 (Affinity Capture-MS), GCLM (Affinity Capture-MS), CTU2 (Affinity Capture-MS), EED (Affinity Capture-MS), CTU1 (Affinity Capture-MS), ATG7 (Affinity Capture-MS), BOLA1 (Affinity Capture-MS), UROS (Co-fractionation), MOCS1 (Affinity Capture-MS), BOLA1 (Affinity Capture-MS), GCLM (Affinity Capture-MS), TCEAL1 (Affinity Capture-MS), UROS (Affinity Capture-RNA), UROS (Negative Genetic)

ESM2 similar proteins: A3GGU3, A5DNX8, A5DUX4, A7TJ85, B5VSC3, E7NMM0, O14353, O74742, O94634, P06174, P10746, P23060, P24521, P25616, P32452, P32460, P35202, P38773, P38796, P40506, P43636, P48445, P49958, P51163, P53095, P53110, P53178, P87214, P87241, Q03786, Q04066, Q08282, Q09839, Q10170, Q12181, Q59LF2, Q59ZV4, Q5A931, Q6BS98, Q6BVA4

Diamond homologs: P10746, P51163

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	27
Likely pathogenic	5
Uncertain significance	52
Likely benign	40
Benign	26

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1002289	NM_000375.3(UROS):c.693_749del (p.Ala234_Ala252del)	Pathogenic
1427883	NM_000375.3(UROS):c.223G>T (p.Glu75Ter)	Pathogenic
1452604	NM_000375.3(UROS):c.710T>C (p.Leu237Pro)	Pathogenic
1452606	NM_000375.3(UROS):c.633dup (p.Ser212fs)	Pathogenic
1456823	NM_000375.3(UROS):c.296T>C (p.Val99Ala)	Pathogenic
1458139	NM_000375.3(UROS):c.395-2A>C	Pathogenic
2136940	NM_000375.3(UROS):c.634T>C (p.Ser212Pro)	Pathogenic
3244935	NC_000010.10:g.(?127483429)(127483567_?)del	Pathogenic
3696149	NM_000375.3(UROS):c.556C>T (p.Gln186Ter)	Pathogenic
3750	NM_000375.3(UROS):c.217T>C (p.Cys73Arg)	Pathogenic
3751	NM_000375.3(UROS):c.158C>T (p.Pro53Leu)	Pathogenic
3752	NM_000375.3(UROS):c.197C>T (p.Ala66Val)	Pathogenic
3753	NM_000375.3(UROS):c.184A>G (p.Thr62Ala)	Pathogenic
3755	NM_000375.3(UROS):c.10C>T (p.Leu4Phe)	Pathogenic
3756	NC_000010.11:g.125815036_125815132del	Pathogenic
3757	UROS, 80-BP INS	Pathogenic
3759	NM_000375.3(UROS):c.562G>A (p.Gly188Arg)	Pathogenic
3760	NM_000375.3(UROS):c.243A>T (p.Glu81Asp)	Pathogenic
3761	NM_000375.3(UROS):c.562G>T (p.Gly188Trp)	Pathogenic
3762	NM_000375.3(UROS):c.-203T>C	Pathogenic
3763	NM_000375.3(UROS):c.-26-183G>A	Pathogenic
3764	NM_000375.3(UROS):c.-26-193C>A	Pathogenic
3765	NM_000375.3(UROS):c.-26-197C>A	Pathogenic
3766	NM_000375.3(UROS):c.673G>A (p.Gly225Ser)	Pathogenic
3768	NM_000375.3(UROS):c.395-1dup	Pathogenic
3769	NM_000375.3(UROS):c.743C>A (p.Pro248Gln)	Pathogenic
694740	NM_000375.3(UROS):c.56A>G (p.Tyr19Cys)	Pathogenic
1066786	NM_000375.3(UROS):c.7G>T (p.Val3Phe)	Likely pathogenic
30626	NM_000375.3(UROS):c.661-31T>G	Likely pathogenic
3780780	NM_000375.3(UROS):c.320-1G>C	Likely pathogenic

SpliceAI

2647 predictions. Top by Δscore:

Variant	Effect	Δscore
10:125794875:CTTA:C	donor_loss	1.0000
10:125794876:TTACC:T	donor_loss	1.0000
10:125794877:TACCT:T	donor_loss	1.0000
10:125794878:A:AC	donor_gain	1.0000
10:125794878:A:T	donor_loss	1.0000
10:125794879:C:CC	donor_gain	1.0000
10:125794879:C:CG	donor_loss	1.0000
10:125794975:CCCC:C	acceptor_gain	1.0000
10:125794976:CCCC:C	acceptor_gain	1.0000
10:125812289:C:CC	acceptor_gain	1.0000
10:125815139:C:CT	acceptor_gain	1.0000
10:125816430:CACTT:C	donor_loss	1.0000
10:125816431:ACTTA:A	donor_loss	1.0000
10:125816432:CTTA:C	donor_loss	1.0000
10:125816433:TTACC:T	donor_loss	1.0000
10:125816434:T:TG	donor_loss	1.0000
10:125816435:A:AC	donor_gain	1.0000
10:125816435:AC:A	donor_gain	1.0000
10:125816435:ACCCT:A	donor_loss	1.0000
10:125816436:C:CC	donor_gain	1.0000
10:125816436:CC:C	donor_gain	1.0000
10:125816521:GGGCA:G	acceptor_gain	1.0000
10:125816522:GGCA:G	acceptor_gain	1.0000
10:125816523:GCA:G	acceptor_gain	1.0000
10:125816524:CA:C	acceptor_gain	1.0000
10:125816524:CAC:C	acceptor_gain	1.0000
10:125816525:AC:A	acceptor_loss	1.0000
10:125816526:C:CA	acceptor_loss	1.0000
10:125816526:C:CC	acceptor_gain	1.0000
10:125816532:C:CT	acceptor_gain	1.0000

AlphaMissense

1716 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:125794949:A:C	S197R	0.997
10:125794949:A:T	S197R	0.997
10:125794951:T:G	S197R	0.997
10:125812262:A:G	W91R	0.997
10:125812262:A:T	W91R	0.997
10:125815089:G:C	S63R	0.997
10:125815089:G:T	S63R	0.997
10:125815091:T:G	S63R	0.997
10:125816210:A:C	F38L	0.995
10:125816210:A:T	F38L	0.995
10:125816212:A:G	F38L	0.995
10:125788992:C:T	G225D	0.993
10:125794952:A:C	F196L	0.993
10:125794952:A:T	F196L	0.993
10:125794954:A:G	F196L	0.993
10:125794950:C:T	S197N	0.992
10:125812260:C:A	W91C	0.991
10:125812260:C:G	W91C	0.991
10:125815073:C:G	A69P	0.990
10:125816479:C:A	K7N	0.990
10:125816479:C:G	K7N	0.990
10:125796162:A:G	Y168H	0.989
10:125812234:C:T	G100E	0.989
10:125788998:G:T	A223D	0.988
10:125794928:A:C	S204R	0.988
10:125794928:A:T	S204R	0.988
10:125794930:T:G	S204R	0.988
10:125794964:G:C	S192R	0.988
10:125794964:G:T	S192R	0.988
10:125794966:T:G	S192R	0.988

dbSNP variants (sampled 300 via entrez): RS1000095543 (10:125799404 T>C,G), RS1000114050 (10:125808531 G>C), RS1000284045 (10:125804969 T>A), RS1000390607 (10:125804475 C>A), RS1000414358 (10:125810088 C>G), RS1000462753 (10:125820023 A>G), RS1000497067 (10:125820279 T>G), RS1000611595 (10:125805148 C>T), RS1000620194 (10:125814501 A>T), RS1000673266 (10:125810147 A>G), RS1000823625 (10:125808740 G>C), RS1000871714 (10:125793426 C>G), RS1001001224 (10:125787516 C>A), RS1001027732 (10:125821901 TA>T), RS1001073961 (10:125787945 A>G)

Disease associations

OMIM: gene MIM:606938 | disease phenotypes: MIM:263700

GenCC curated gene-disease

Disease	Classification	Inheritance
cutaneous porphyria	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
cutaneous porphyria	Definitive	AR

Mondo (1): cutaneous porphyria (MONDO:0009902)

Orphanet (1): Congenital erythropoietic porphyria (Orphanet:79277)

HPO phenotypes

71 total (30 of 71 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000509	Conjunctivitis
HP:0000559	Corneal scarring
HP:0000618	Blindness
HP:0000656	Ectropion
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0000952	Jaundice
HP:0000953	Hyperpigmentation of the skin
HP:0000969	Edema
HP:0000987	Atypical scarring of skin
HP:0000989	Pruritus
HP:0000992	Cutaneous photosensitivity
HP:0000998	Hypertrichosis
HP:0001010	Hypopigmentation of the skin
HP:0001030	Fragile skin
HP:0001072	Thickened skin
HP:0001081	Cholelithiasis
HP:0001096	Keratoconjunctivitis
HP:0001560	Abnormality of the amniotic fluid
HP:0001596	Alopecia
HP:0001744	Splenomegaly
HP:0001790	Nonimmune hydrops fetalis
HP:0001873	Thrombocytopenia
HP:0001878	Hemolytic anemia
HP:0001882	Decreased total leukocyte count
HP:0001892	Abnormal bleeding
HP:0001923	Reticulocytosis
HP:0002219	Facial hypertrichosis
HP:0002223	Absent eyebrow

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006585_962	Blood protein levels	4.000000e-27

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D017092	Porphyria, Erythropoietic	C16.320.850.738; C17.800.827.738; C18.452.811.250

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4433 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression	5
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
cobaltous chloride	decreases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Cyclosporine	decreases expression	2
GSK-J4	decreases expression	1
methylmercuric chloride	decreases expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
tamibarotene	affects expression	1
CGP 52608	affects binding, increases reaction	1
ICG 001	increases expression	1
jinfukang	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Atrazine	decreases expression	1
Carbamazepine	affects expression	1
Cisplatin	increases expression	1
Gasoline	affects cotreatment, decreases expression, increases abundance	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, decreases expression, increases abundance	1
Silicon Dioxide	decreases expression	1
Thiram	decreases expression	1
Tretinoin	increases expression	1
Copper Sulfate	decreases expression	1
Particulate Matter	increases abundance, affects cotreatment, decreases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL815496	Binding	Compound was tested for its activity as substrate of Uroporphyrinogen III synthase; No	Studies On uro’gen III synthase with modified bilanes — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07024316	PHASE1/PHASE2	RECRUITING	A Study to Investigate the Improvement of Photosensitivity in Terms of Skin Lesions Associated With CEP Following Administration of Oral ATL-001 (Ciclopirox Oral Solution) in Participants Aged >18 Years of Age With CEP
NCT01561157	Not specified	RECRUITING	Longitudinal Study of the Porphyrias