Familial porphyria cutanea tarda

Summary

Familial porphyria cutanea tarda (MONDO:0008296) is a disease caused by UROD (GenCC Strong), with 3 cohort genes and 1 clinical trial.

At a glance

• Causal gene: UROD (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 62
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	familial porphyria cutanea tarda
Mondo ID	MONDO:0008296
EFO	EFO:0009043
OMIM	176100
Orphanet	443062
ICD-11	1318287619
SNOMED CT	59229005
UMLS	C0268323
MedGen	75669
GARD	0017750
Is cancer (heuristic)	no

Also known as: hereditary porphyria cutanea tarda · PCT · porphyria cutanea tarda type II · porphyria cutanea tarda, susceptibility to

Data availability: 62 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › dermatitis › porphyria cutanea tarda › familial porphyria cutanea tarda

Related subtypes (2): sporadic porphyria cutanea tarda, hepatoerythropoietic porphyria

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

62 retrieved; paginated sample, class counts are floors:

23 uncertain significance, 10 conflicting classifications of pathogenicity, 9 likely pathogenic, 8 pathogenic, 7 pathogenic/likely pathogenic, 2 benign/likely benign, 1 conflicting classifications of pathogenicity; other, 1 benign, 1 conflicting classifications of pathogenicity; other; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
1065637	NM_000410.4(HFE):c.1006+1G>A	HFE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
407079	NM_000410.4(HFE):c.546_547del (p.Leu183fs)	HFE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1325337	NM_000374.5(UROD):c.138T>A (p.Phe46Leu)	UROD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1436524	NM_000374.5(UROD):c.424C>T (p.Arg142Ter)	UROD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457336	NM_000374.5(UROD):c.616C>T (p.Gln206Ter)	UROD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3370430	NM_000374.5(UROD):c.186dup (p.Glu63Ter)	UROD	Pathogenic	criteria provided, single submitter
64679	NM_000374.5(UROD):c.346C>T (p.Gln116Ter)	UROD	Pathogenic	criteria provided, multiple submitters, no conflicts
65	NM_000374.5(UROD):c.842G>T (p.Gly281Val)	UROD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
66	NM_000374.5(UROD):c.842G>A (p.Gly281Glu)	UROD	Pathogenic	criteria provided, single submitter
67	NM_000374.5(UROD):c.636+1G>C	UROD	Pathogenic	criteria provided, multiple submitters, no conflicts
73	NM_000374.5(UROD):c.494T>G (p.Met165Arg)	UROD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
74	NM_000374.5(UROD):c.583C>T (p.Leu195Phe)	UROD	Pathogenic	no assertion criteria provided
75	NM_000374.5(UROD):c.912C>A (p.Asn304Lys)	UROD	Pathogenic	criteria provided, single submitter
801474	NM_000374.5(UROD):c.904C>T (p.Gln302Ter)	UROD	Pathogenic	criteria provided, single submitter
915319	NM_000374.5(UROD):c.21-1G>C	UROD	Pathogenic	criteria provided, single submitter
1298341	NM_000374.5(UROD):c.583_611del (p.Leu195fs)	UROD	Likely pathogenic	criteria provided, single submitter
254172	NM_000374.5(UROD):c.578G>C (p.Arg193Pro)	UROD	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2575049	NM_000374.5(UROD):c.101G>A (p.Trp34Ter)	UROD	Likely pathogenic	no assertion criteria provided
2664811	NM_000374.5(UROD):c.725del (p.Lys242fs)	UROD	Likely pathogenic	criteria provided, single submitter
2690773	NM_000374.5(UROD):c.758dup (p.Ala254fs)	UROD	Likely pathogenic	criteria provided, single submitter
3892821	NM_000374.5(UROD):c.943-14_944del	UROD	Likely pathogenic	criteria provided, single submitter
4077731	NM_000374.5(UROD):c.775-2del	UROD	Likely pathogenic	criteria provided, single submitter
4280626	NM_000374.5(UROD):c.133+2_133+4del	UROD	Likely pathogenic	criteria provided, single submitter
72	NM_000374.5(UROD):c.942G>A (p.Glu314=)	UROD	Likely pathogenic	criteria provided, multiple submitters, no conflicts
10	NM_000410.4(HFE):c.187C>G (p.His63Asp)	HFE	Conflicting classifications of pathogenicity; other	criteria provided, conflicting classifications
11	NM_000410.4(HFE):c.193A>T (p.Ser65Cys)	HFE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
9	NM_000410.4(HFE):c.845G>A (p.Cys282Tyr)	HFE	Conflicting classifications of pathogenicity; other; risk factor	criteria provided, conflicting classifications
297460	NM_000374.5(UROD):c.474+15G>C	UROD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297462	NM_000374.5(UROD):c.738C>T (p.Ala246=)	UROD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297463	NM_000374.5(UROD):c.758T>A (p.Leu253Gln)	UROD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
UROD	Definitive	Semidominant	UROD-related inherited porphyria	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
UROD	Orphanet:443062	Familial porphyria cutanea tarda
UROD	Orphanet:95159	Hepatoerythropoietic porphyria
HFE	Orphanet:443057	Sporadic porphyria cutanea tarda
HFE	Orphanet:443062	Familial porphyria cutanea tarda
HFE	Orphanet:465508	Symptomatic form of HFE-related hemochromatosis
HFE	Orphanet:586	Cystic fibrosis
HFE	Orphanet:648581	Digenic hemochromatosis

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
UROD	HGNC:12591	ENSG00000126088	P06132	Uroporphyrinogen decarboxylase	gencc,clinvar
HFE	HGNC:4886	ENSG00000010704	Q30201	Hereditary hemochromatosis protein	clinvar
HFE-AS1	HGNC:55168			HFE antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
UROD	Uroporphyrinogen decarboxylase	Catalyzes the sequential decarboxylation of the four acetate side chains of uroporphyrinogen to form coproporphyrinogen and participates in the fifth step in the heme biosynthetic pathway.
HFE	Hereditary hemochromatosis protein	Binds to transferrin receptor (TFR) and reduces its affinity for iron-loaded transferrin.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	1	9.7×	0.298
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
UROD	Enzyme (other)	yes	4.1.1.37	Uroporphyrinogen_deCOase, Uroporphyrinogen_deCO2ase_HemE, UROD/MetE-like_sf
HFE	Antibody/Immunoglobulin	yes		MHC_I_a_a1/a2, Ig/MHC_CS, Ig_C1-set
HFE-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 1.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	1

Top tissues across cohort

Tissue	Cohort genes
parotid gland	1
right adrenal gland	1
trabecular bone tissue	1
olfactory bulb	1
stromal cell of endometrium	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
UROD	298	ubiquitous	marker	trabecular bone tissue, parotid gland, right adrenal gland
HFE	238	ubiquitous	marker	type B pancreatic cell, olfactory bulb, stromal cell of endometrium
HFE-AS1

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
UROD	1,910
HFE	1,569
HFE-AS1	0

Intra-cohort edges

A	B	Sources
HFE	UROD	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
UROD	P06132	19
HFE	Q30201	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 3 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Heme biosynthesis	1	380.7×	0.005	UROD
Transferrin endocytosis and recycling	1	184.2×	0.005	HFE

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
porphyrin-containing compound catabolic process	1	8426.0×	0.002	UROD
negative regulation of antigen processing and presentation of endogenous peptide antigen via MHC class I	1	8426.0×	0.002	HFE
regulation of iron ion transport	1	4213.0×	0.002	HFE
response to iron ion starvation	1	2808.7×	0.002	HFE
porphyrin-containing compound metabolic process	1	2106.5×	0.002	UROD
negative regulation of CD8-positive, alpha-beta T cell activation	1	2106.5×	0.002	HFE
negative regulation of T cell cytokine production	1	1203.7×	0.003	HFE
cellular response to iron ion	1	1203.7×	0.003	HFE
obsolete protoporphyrinogen IX biosynthetic process	1	842.6×	0.003	UROD
heme B biosynthetic process	1	842.6×	0.003	UROD
regulation of protein localization to cell surface	1	842.6×	0.003	HFE
heme A biosynthetic process	1	766.0×	0.003	UROD
transferrin transport	1	766.0×	0.003	HFE
urate metabolic process	1	766.0×	0.003	HFE
positive regulation of peptide hormone secretion	1	766.0×	0.003	HFE
hormone biosynthetic process	1	702.2×	0.003	HFE
response to iron ion	1	468.1×	0.004	HFE
negative regulation of ubiquitin-dependent protein catabolic process	1	421.3×	0.004	HFE
positive regulation of receptor-mediated endocytosis	1	401.2×	0.004	HFE
heme biosynthetic process	1	300.9×	0.005	UROD
multicellular organismal-level iron ion homeostasis	1	290.6×	0.005	HFE
negative regulation of proteasomal ubiquitin-dependent protein catabolic process	1	200.6×	0.007	HFE
positive regulation of SMAD protein signal transduction	1	191.5×	0.007	HFE
intracellular iron ion homeostasis	1	122.1×	0.010	HFE
receptor-mediated endocytosis	1	110.9×	0.011	HFE
BMP signaling pathway	1	100.3×	0.011	HFE
protein-containing complex assembly	1	56.9×	0.019	HFE
gene expression	1	39.9×	0.027	HFE
cell surface receptor signaling pathway	1	32.0×	0.032	HFE
positive regulation of gene expression	1	19.4×	0.051	HFE

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
UROD	0	0
HFE	0	0
HFE-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
UROD	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
UROD	4.1.1.37	uroporphyrinogen decarboxylase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	UROD, HFE
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	HFE-AS1

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
UROD	2	—
HFE	0	—
HFE-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03388944	Not specified	COMPLETED	PCT Guided Stopping of Antibiotic Therapy in Children With Sepsis