CYP4F22

Summary

CYP4F22 (cytochrome P450 family 4 subfamily F member 22, HGNC:26820) is a protein-coding gene on chromosome 19p13.12, encoding Ultra-long-chain fatty acid omega-hydroxylase (Q6NT55). A cytochrome P450 monooxygenase involved in epidermal ceramide biosynthesis.

This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This gene is part of a cluster of cytochrome P450 genes on chromosome 19 and encodes an enzyme thought to play a role in the 12(R)-lipoxygenase pathway. Mutations in this gene are the cause of ichthyosis lamellar type 3.

Source: NCBI Gene 126410 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive congenital ichthyosis 5 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 314 total — 40 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 31
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_173483

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26820
Approved symbol	CYP4F22
Name	cytochrome P450 family 4 subfamily F member 22
Location	19p13.12
Locus type	gene with protein product
Status	Approved
Aliases	FLJ39501
Ensembl gene	ENSG00000171954
Ensembl biotype	protein_coding
OMIM	611495
Entrez	126410

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000269703, ENST00000601005, ENST00000894419, ENST00000894420, ENST00000894421

RefSeq mRNA: 1 — MANE Select: NM_173483 NM_173483

CCDS: CCDS12331

Canonical transcript exons

ENST00000269703 — 14 exons

Exon	Start	End
ENSE00000899761	15537535	15537662
ENSE00000951052	15544150	15544279
ENSE00000951126	15537361	15537414
ENSE00001056065	15537872	15537993
ENSE00001056084	15548108	15548241
ENSE00001056098	15540450	15540717
ENSE00001135242	15550674	15550756
ENSE00001135253	15549138	15549202
ENSE00001135703	15529709	15529853
ENSE00001691009	15543971	15544037
ENSE00002986172	15523693	15523799
ENSE00003089838	15508525	15508583
ENSE00003216302	15525336	15525558
ENSE00003710402	15551294	15552317

Expression profiles

Bgee: expression breadth ubiquitous, 103 present calls, max score 95.66.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.7900 / max 261.3279, expressed in 128 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
174314	0.7205	114
174313	0.0695	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	95.66	gold quality
upper arm skin	UBERON:0004263	92.88	gold quality
skin of leg	UBERON:0001511	91.59	gold quality
skin of abdomen	UBERON:0001416	90.51	gold quality
mammalian vulva	UBERON:0000997	89.75	gold quality
zone of skin	UBERON:0000014	89.29	gold quality
penis	UBERON:0000989	80.95	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.24	gold quality
esophagus mucosa	UBERON:0002469	79.36	gold quality
upper leg skin	UBERON:0004262	78.72	gold quality
gingiva	UBERON:0001828	76.70	gold quality
granulocyte	CL:0000094	76.08	gold quality
buccal mucosa cell	CL:0002336	75.48	silver quality
gingival epithelium	UBERON:0001949	75.04	silver quality
vagina	UBERON:0000996	73.94	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.09	silver quality
right lobe of liver	UBERON:0001114	72.54	gold quality
nipple	UBERON:0002030	71.29	gold quality
oral cavity	UBERON:0000167	68.86	gold quality
liver	UBERON:0002107	68.28	gold quality
esophagus squamous epithelium	UBERON:0006920	68.01	silver quality
leukocyte	CL:0000738	67.69	gold quality
monocyte	CL:0000576	67.26	gold quality
urinary bladder	UBERON:0001255	64.90	gold quality
ectocervix	UBERON:0012249	64.53	gold quality
tendon of biceps brachii	UBERON:0008188	63.63	gold quality
pancreatic ductal cell	CL:0002079	63.48	silver quality
esophagus	UBERON:0001043	60.21	gold quality
prostate gland	UBERON:0002367	59.47	gold quality
skin of hip	UBERON:0001554	59.04	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	14.76

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1I2

miRNA regulators (miRDB)

40 targeting CYP4F22, 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-4682	100.00	68.89	1258
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-3064-5P	99.26	66.13	1497
HSA-MIR-3085-3P	99.26	66.16	1490
HSA-MIR-6504-5P	99.26	65.95	1487
HSA-MIR-6803-5P	99.19	63.90	1026
HSA-MIR-7109-5P	99.18	66.13	1057
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-3196	98.96	63.91	326
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-423-5P	98.69	67.48	1522
HSA-MIR-3184-5P	98.56	67.13	1491
HSA-MIR-6816-5P	98.46	64.35	364
HSA-MIR-3180	98.46	64.68	348
HSA-MIR-3180-3P	98.46	64.68	348
HSA-MIR-4665-5P	97.91	67.69	1536

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 9)

• REVIEW: genetic analyses have identified a wide spectrum of mutations in the CYP4V2gene from patients suffering from Bietti’s crystalline corneoretinal dystrophy, and mutations in theCYP4F22 gene have been linked to lamellar ichthyosis (PMID:21540472)
• Letter: CYP4F22 is highly expressed at the site and timing of onset of keratinization during skin development. (PMID:22209317)
• description of CYP4F22 mutations from a Japanese collodion baby with lamellar ichthyosis [case report] (PMID:23871423)
• We report two cases of Congenital Ichthyosiform Erythroderma showing homozygous mutations in the gene CYP4F22. (PMID:26646773)
• patients carrying one or two truncating CYP4F22 mutations affecting the SBRs tend to develop collodion membrane at birth (PMID:27735052)
• we provide an up-to-date overview of all published and novel CYP4F22 mutations and point out possible mutation hot spots. We discuss the molecular and clinical findings, the genotype-phenotype correlations and consequences on genetic testing. (PMID:30011118)
• Study reports a consanguineous family from Southern Tunisia including three members affected with congenital ichthyosis likely due to a novel missense mutation c.728G>T (p.Arg243Leu) in exon 8 of CYP4F2. (PMID:31020658)
• The present study reports five CYP4F22 mutations, two of them novel, increasing the number of CYP4F22 mutations currently listed. Additionally, our results suggest that the recurrent c.1303C>T change has a founder effect in Spanish population and c.1303C>T carrier families originated from a single ancestor with probable African ancestry. (PMID:32069299)
• Impaired production of the skin barrier lipid acylceramide by CYP4F22 ichthyosis mutations. (PMID:33067036)

Cross-species orthologs

30 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cyp4f39	ENSMUSG00000061126
rattus_norvegicus	Cyp4f39	ENSRNOG00000075541
drosophila_melanogaster	Cyp4d1	FBGN0005670
drosophila_melanogaster	Cyp4d2	FBGN0011576
drosophila_melanogaster	Cyp4e2	FBGN0014469
drosophila_melanogaster	Cyp4c3	FBGN0015032
drosophila_melanogaster	Cyp4d8	FBGN0015033
drosophila_melanogaster	Cyp4e1	FBGN0015034
drosophila_melanogaster	Cyp4e3	FBGN0015035
drosophila_melanogaster	Cyp4ae1	FBGN0015036
drosophila_melanogaster	Cyp4p1	FBGN0015037
drosophila_melanogaster	Cyp4d14	FBGN0023541
drosophila_melanogaster	Cyp4s3	FBGN0030615
drosophila_melanogaster	Cyp4ac1	FBGN0031693
drosophila_melanogaster	Cyp4ac2	FBGN0031694
drosophila_melanogaster	Cyp4ac3	FBGN0031695
drosophila_melanogaster	Cyp4d21	FBGN0031925
drosophila_melanogaster	Cyp4ad1	FBGN0033292
drosophila_melanogaster	Cyp4p2	FBGN0033395
drosophila_melanogaster	Cyp4p3	FBGN0033397
drosophila_melanogaster	Cyp4aa1	FBGN0034053
drosophila_melanogaster	Cyp4d20	FBGN0035344
drosophila_melanogaster	Cyp312a1	FBGN0036778
caenorhabditis_elegans		WBGENE00007140
caenorhabditis_elegans		WBGENE00009226
caenorhabditis_elegans		WBGENE00010354
caenorhabditis_elegans		WBGENE00013381
caenorhabditis_elegans		WBGENE00016147
caenorhabditis_elegans		WBGENE00021200
caenorhabditis_elegans		WBGENE00021412

Paralogs (12): CYP19A1 (ENSG00000137869), CYP4B1 (ENSG00000142973), CYP4V2 (ENSG00000145476), CYP4A22 (ENSG00000162365), CYP4F11 (ENSG00000171903), CYP4F2 (ENSG00000186115), CYP4Z1 (ENSG00000186160), CYP4F12 (ENSG00000186204), CYP4X1 (ENSG00000186377), CYP4F8 (ENSG00000186526), CYP4F3 (ENSG00000186529), CYP4A11 (ENSG00000187048)

Protein

Protein identifiers

Ultra-long-chain fatty acid omega-hydroxylase — Q6NT55 (reviewed: Q6NT55)

Alternative names: Cytochrome P450 4F22

All UniProt accessions (1): Q6NT55

UniProt curated annotations — full annotation on UniProt →

Function. A cytochrome P450 monooxygenase involved in epidermal ceramide biosynthesis. Hydroxylates the terminal carbon (omega-hydroxylation) of ultra-long-chain fatty acyls (C28-C36) prior to ceramide synthesis. Contributes to the synthesis of three classes of omega-hydroxy-ultra-long chain fatty acylceramides having sphingosine, 6-hydroxysphingosine and phytosphingosine bases, all major lipid components that underlie the permeability barrier of the stratum corneum. Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase).

Subcellular location. Endoplasmic reticulum membrane. Microsome membrane.

Disease relevance. Ichthyosis, congenital, autosomal recessive 5 (ARCI5) [MIM:604777] A form of autosomal recessive congenital ichthyosis, a disorder of keratinization with abnormal differentiation and desquamation of the epidermis, resulting in abnormal skin scaling over the whole body. The main skin phenotypes are lamellar ichthyosis (LI) and non-bullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur. Lamellar ichthyosis is a condition often associated with an embedment in a collodion-like membrane at birth; skin scales later develop, covering the entire body surface. Non-bullous congenital ichthyosiform erythroderma characterized by fine whitish scaling on an erythrodermal background; larger brownish scales are present on the buttocks, neck and legs. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the cytochrome P450 family.

RefSeq proteins (1): NP_775754* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001128	Cyt_P450	Family
IPR002401	Cyt_P450_E_grp-I	Family
IPR017972	Cyt_P450_CS	Conserved_site
IPR036396	Cyt_P450_sf	Homologous_superfamily
IPR050196	Cytochrome_P450_Monoox	Family

Pfam: PF00067

Enzyme classification (BRENDA):

• EC 1.14.14.177 — ultra-long-chain fatty acid omega-hydroxylase (BRENDA: 1 organisms, 2 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 2 shown:

• triacontanoate + reduced [NADPH–hemoprotein reductase] + O2 = omega-hydroxy-triacontanoate + oxidized [NADPH–hemoprotein reductase] + H2O + H(+) (RHEA:50336)
• an omega-methyl-ultra-long-chain fatty acid + reduced [NADPH–hemoprotein reductase] + O2 = an omega-hydroxy-ultra-long-chain fatty acid + oxidized [NADPH–hemoprotein reductase] + H2O + H(+) (RHEA:63376)

UniProt features (15 total): sequence variant 7, topological domain 2, sequence conflict 2, binding site 2, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6NT55-F1	93.59	0.78

Functional residue map

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

Ligand- & substrate-binding residues (2): 335 (covalent); 475 (axial binding residue)

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-211935	Fatty acids
R-HSA-211958	Miscellaneous substrates
R-HSA-211979	Eicosanoids
R-HSA-2142691	Synthesis of Leukotrienes (LT) and Eoxins (EX)
R-HSA-5579005	Defective CYP4F22 causes ARCI5

MSigDB gene sets: 137 (showing top): REACTOME_BIOLOGICAL_OXIDATIONS, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_CERAMIDE_BIOSYNTHETIC_PROCESS, GOBP_SPHINGOLIPID_METABOLIC_PROCESS, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_AMIDE_BIOSYNTHETIC_PROCESS, GOBP_LIPID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOBP_LIPID_BIOSYNTHETIC_PROCESS, GOBP_CERAMIDE_METABOLIC_PROCESS, GOBP_SPHINGOLIPID_BIOSYNTHETIC_PROCESS, GOBP_MEMBRANE_LIPID_METABOLIC_PROCESS, RIGGI_EWING_SARCOMA_PROGENITOR_UP, GOBP_MEMBRANE_LIPID_BIOSYNTHETIC_PROCESS, GOCC_NUCLEAR_OUTER_MEMBRANE_ENDOPLASMIC_RETICULUM_MEMBRANE_NETWORK

GO Biological Process (3): icosanoid metabolic process (GO:0006690), ceramide biosynthetic process (GO:0046513), lipid metabolic process (GO:0006629)

GO Molecular Function (7): monooxygenase activity (GO:0004497), iron ion binding (GO:0005506), oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen (GO:0016705), heme binding (GO:0020037), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872)

GO Cellular Component (3): endoplasmic reticulum membrane (GO:0005789), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Cytochrome P450 - arranged by substrate type	3
Arachidonate metabolism	1
Metabolic disorders of biological oxidation enzymes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
oxidoreductase activity	2
carboxylic acid metabolic process	1
ceramide metabolic process	1
sphingolipid biosynthetic process	1
primary metabolic process	1
transition metal ion binding	1
tetrapyrrole binding	1
binding	1
catalytic activity	1
cation binding	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1424 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CYP4F22	NIPAL4	Q0D2K0	986
CYP4F22	ABCA12	Q86UK0	977
CYP4F22	TGM1	P22735	916
CYP4F22	PNPLA1	Q8N8W4	885
CYP4F22	LIPN	Q5VXI9	863
CYP4F22	ALOXE3	Q9BYJ1	860
CYP4F22	ALOX12B	O75342	830
CYP4F22	CERS3	Q8IU89	796
CYP4F22	SDR9C7	Q8NEX9	702
CYP4F22	SULT2B1	O00204	611
CYP4F22	SLC27A4	Q6P1M0	580
CYP4F22	ELOVL4	Q9GZR5	575
CYP4F22	ABHD5	Q8WTS1	561
CYP4F22	CASP14	P31944	485
CYP4F22	SPINK5	Q9NQ38	464

IntAct

24 interactions, top by confidence:

A	B	Type	Score
CYP4F22	TLCD4	psi-mi:“MI:0915”(physical association)	0.560
AQP6	CYP4F22	psi-mi:“MI:0915”(physical association)	0.560
MSMO1	CYP4F22	psi-mi:“MI:0915”(physical association)	0.560
CYP4F22	REEP2	psi-mi:“MI:0915”(physical association)	0.560
ST6GALNAC6	A2ML1	psi-mi:“MI:0914”(association)	0.350
OR2A4	A2ML1	psi-mi:“MI:0914”(association)	0.350
CCR1	UBA6	psi-mi:“MI:0914”(association)	0.350
PCDHB3	ESYT2	psi-mi:“MI:0914”(association)	0.350
SSUH2	IGLC7	psi-mi:“MI:0914”(association)	0.350
PIGH	ILVBL	psi-mi:“MI:0914”(association)	0.350
TTMP	NBAS	psi-mi:“MI:0914”(association)	0.350
C18orf21	A2ML1	psi-mi:“MI:0914”(association)	0.350
MBNL1	A2ML1	psi-mi:“MI:0914”(association)	0.350
ATP2A3	UBXN8	psi-mi:“MI:0914”(association)	0.350
SMPD2	A2ML1	psi-mi:“MI:0914”(association)	0.350
CYP4F22	AQP6	psi-mi:“MI:0915”(physical association)	0.000
CYP4F22	MSMO1	psi-mi:“MI:0915”(physical association)	0.000
CYP4F22	TLCD4	psi-mi:“MI:0915”(physical association)	0.000
CYP4F22	REEP2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (14): CYP4F22 (Two-hybrid), CYP4F22 (Two-hybrid), CYP4F22 (Two-hybrid), CYP4F22 (Two-hybrid), CYP4F22 (Affinity Capture-MS), CYP4F22 (Affinity Capture-MS), CYP4F22 (Affinity Capture-MS), CYP4F22 (Affinity Capture-MS), CYP4F22 (Affinity Capture-MS), CYP4F22 (Affinity Capture-MS), CYP4F22 (Affinity Capture-MS), CYP4F22 (Affinity Capture-MS), CYP4F22 (Affinity Capture-MS), CYP4F22 (Affinity Capture-MS)

ESM2 similar proteins: A2A974, F1Q8C3, H1A988, O18993, O35728, O88833, P00186, P04799, P08516, P08684, P13584, P14579, P14581, P15128, P15129, P20815, P20816, P20817, P24453, P24462, P24463, P24464, P33268, P33274, P51869, P51871, P78329, P79102, P79401, P98187, Q00557, Q08477, Q29496, Q3MID2, Q64391, Q64462, Q64464, Q6A152, Q6NT55, Q86W10

Diamond homologs: A0A017SFB8, A0A075TMP8, A0A075TRL5, A0A0U5CJM3, A0A1D6F9Y9, A0A1D6HSP4, A0A1L9WN31, A0A1L9WN72, A0A1U9YHZ8, A0A1V6NWJ0, A0A2B7YEY0, A0A2H3CNS9, A0A2H3CZX2, A0A2P1DP94, A0A6S6QPY4, A1CFL5, A1CFL6, A2A974, A2RRT9, A8NCK4, A8NCK6, C8VJR0, F1SY52, F1SY62, F1SY66, F1SY73, F1SY82, F1SY91, F1SY96, F1SYF1, F1SYI7, F2ZAF9, G1UB11, G1XU03, G3Y416, G9N4A8, H1A981, I3DZK9, O49394, O49396

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	40
Likely pathogenic	15
Uncertain significance	110
Likely benign	59
Benign	55

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1392931	NM_173483.4(CYP4F22):c.1395T>A (p.Tyr465Ter)	Pathogenic
1398773	NM_173483.4(CYP4F22):c.1483C>T (p.Arg495Cys)	Pathogenic
1459651	NC_000019.9:g.(?15636148)(15662282_?)del	Pathogenic
1526150	NM_173483.4(CYP4F22):c.296G>A (p.Trp99Ter)	Pathogenic
279799	NM_173483.4(CYP4F22):c.59dup (p.Ile21fs)	Pathogenic
3242731	NC_000019.9:g.(?15661465)(15662282_?)del	Pathogenic
328433	NM_173483.4(CYP4F22):c.667C>T (p.Gln223Ter)	Pathogenic
3682574	NM_173483.4(CYP4F22):c.641_654dup (p.Asn219fs)	Pathogenic
3692531	NM_173483.4(CYP4F22):c.136del (p.Cys46fs)	Pathogenic
379536	NM_173483.4(CYP4F22):c.1084C>T (p.Arg362Ter)	Pathogenic
3896071	NM_173483.4(CYP4F22):c.1207_1208del (p.Thr403fs)	Pathogenic
420584	NM_173483.4(CYP4F22):c.976C>T (p.Arg326Ter)	Pathogenic
430019	NM_173483.4(CYP4F22):c.1007-2A>G	Pathogenic
560306	NM_173483.4(CYP4F22):c.242G>A (p.Gly81Asp)	Pathogenic
560307	NM_173483.4(CYP4F22):c.493_499delinsCTTGATT (p.Phe165_Ile167delinsLeuAspPhe)	Pathogenic
560308	NM_173483.4(CYP4F22):c.550-2A>T	Pathogenic
560309	NM_173483.4(CYP4F22):c.592G>T (p.Asp198Tyr)	Pathogenic
560310	NM_173483.4(CYP4F22):c.643_644del (p.Val215fs)	Pathogenic
560311	NM_173483.4(CYP4F22):c.847C>T (p.Arg283Trp)	Pathogenic
560312	NM_173483.4(CYP4F22):c.917T>C (p.Ile306Thr)	Pathogenic
560315	NM_173483.4(CYP4F22):c.1532A>G (p.Glu511Gly)	Pathogenic
560316	NM_173483.4(CYP4F22):c.720_723del (p.Val241fs)	Pathogenic
560317	NM_173483.4(CYP4F22):c.1352G>C (p.Arg451Pro)	Pathogenic
560319	NM_173483.4(CYP4F22):c.421+1G>A	Pathogenic
560320	NM_173483.4(CYP4F22):c.467G>A (p.Arg156His)	Pathogenic
560321	NM_173483.4(CYP4F22):c.697A>C (p.Ile233Leu)	Pathogenic
560322	NM_173483.4(CYP4F22):c.1163C>A (p.Thr388Lys)	Pathogenic
560324	NM_173483.4(CYP4F22):c.1137-18_1137-4del	Pathogenic
560325	NM_173483.4(CYP4F22):c.1084C>G (p.Arg362Gly)	Pathogenic
560327	NM_173483.4(CYP4F22):c.981del (p.Glu328fs)	Pathogenic

SpliceAI

1928 predictions. Top by Δscore:

Variant	Effect	Δscore
19:15525334:A:AG	acceptor_gain	1.0000
19:15525334:AG:A	acceptor_gain	1.0000
19:15525335:G:GG	acceptor_gain	1.0000
19:15525335:GG:G	acceptor_gain	1.0000
19:15525335:GGAT:G	acceptor_gain	1.0000
19:15525554:GCATG:G	donor_gain	1.0000
19:15525555:CATG:C	donor_gain	1.0000
19:15525555:CATGG:C	donor_loss	1.0000
19:15525556:ATG:A	donor_gain	1.0000
19:15525557:TG:T	donor_gain	1.0000
19:15525557:TGG:T	donor_loss	1.0000
19:15525558:GG:G	donor_gain	1.0000
19:15525558:GGTA:G	donor_loss	1.0000
19:15525559:G:A	donor_loss	1.0000
19:15525559:G:GG	donor_gain	1.0000
19:15525560:T:G	donor_loss	1.0000
19:15529707:A:AG	acceptor_gain	1.0000
19:15529708:G:GG	acceptor_gain	1.0000
19:15537531:CCA:C	acceptor_loss	1.0000
19:15537532:CAG:C	acceptor_loss	1.0000
19:15537533:A:AG	acceptor_gain	1.0000
19:15537533:A:AT	acceptor_loss	1.0000
19:15537533:AG:A	acceptor_gain	1.0000
19:15537533:AGG:A	acceptor_gain	1.0000
19:15537533:AGGG:A	acceptor_gain	1.0000
19:15537534:G:GG	acceptor_gain	1.0000
19:15537534:GG:G	acceptor_gain	1.0000
19:15537534:GGG:G	acceptor_gain	1.0000
19:15537534:GGGG:G	acceptor_gain	1.0000
19:15537534:GGGGA:G	acceptor_gain	1.0000

AlphaMissense

3475 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:15537600:T:C	F163L	0.998
19:15537602:C:A	F163L	0.998
19:15537602:C:G	F163L	0.998
19:15550740:T:C	F468L	0.998
19:15550742:C:A	F468L	0.998
19:15550742:C:G	F468L	0.998
19:15537579:C:A	R156S	0.997
19:15548154:A:C	S395R	0.997
19:15548156:C:A	S395R	0.997
19:15548156:C:G	S395R	0.997
19:15548160:C:A	R397S	0.997
19:15537580:G:C	R156P	0.996
19:15550692:T:C	F452L	0.996
19:15550694:T:A	F452L	0.996
19:15550694:T:G	F452L	0.996
19:15550756:G:T	R473M	0.996
19:15551305:G:A	G477E	0.996
19:15537567:T:A	W152R	0.995
19:15537567:T:C	W152R	0.995
19:15537878:T:A	W186R	0.995
19:15537878:T:C	W186R	0.995
19:15544031:T:C	F334L	0.995
19:15544033:T:A	F334L	0.995
19:15544033:T:G	F334L	0.995
19:15548152:A:T	E394V	0.995
19:15548161:G:C	R397P	0.995
19:15550750:G:A	G471E	0.995
19:15551300:C:G	C475W	0.995
19:15537377:G:C	K128N	0.994
19:15537377:G:T	K128N	0.994

dbSNP variants (sampled 300 via entrez): RS1000103284 (19:15535817 T>C), RS1000120510 (19:15534175 G>A), RS1000127939 (19:15550501 C>A,T), RS1000205173 (19:15511714 G>C,T), RS1000250200 (19:15521649 A>G,T), RS1000335722 (19:15515504 C>T), RS1000366881 (19:15513765 A>G), RS1000492540 (19:15534498 G>A), RS1000493687 (19:15551688 T>C), RS1000537684 (19:15513038 A>G), RS1000678486 (19:15508456 A>G,T), RS1000898484 (19:15509949 T>C), RS1001003632 (19:15552424 G>A), RS1001095837 (19:15546959 C>A), RS1001124836 (19:15546032 T>C)

Disease associations

OMIM: gene MIM:611495 | disease phenotypes: MIM:604777, MIM:600057, MIM:603165

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive congenital ichthyosis 5	Strong	Autosomal recessive
lamellar ichthyosis	Supportive	Autosomal recessive

Mondo (5): autosomal recessive congenital ichthyosis 5 (MONDO:0011485), lamellar ichthyosis (MONDO:0017778), bladder exstrophy-epispadias-cloacal exstrophy complex (MONDO:0700039), atopic eczema (MONDO:0004980), ichthyosis (MONDO:0019269)

Orphanet (3): Lamellar ichthyosis (Orphanet:313), Classic bladder exstrophy (Orphanet:93930), Ichthyosis (Orphanet:79354)

HPO phenotypes

31 total (30 of 31 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000164	Abnormality of the dentition
HP:0000232	Everted lower lip vermilion
HP:0000389	Chronic otitis media
HP:0000656	Ectropion
HP:0000958	Dry skin
HP:0000962	Hyperkeratosis
HP:0000982	Palmoplantar keratoderma
HP:0000989	Pruritus
HP:0001019	Erythroderma
HP:0001036	Parakeratosis
HP:0001597	Abnormal nail morphology
HP:0001927	Acanthocytosis
HP:0001944	Dehydration
HP:0002205	Recurrent respiratory infections
HP:0003577	Congenital onset
HP:0004322	Short stature
HP:0007479	Congenital nonbullous ichthyosiform erythroderma
HP:0008064	Ichthyosis
HP:0008070	Sparse hair
HP:0011039	Abnormal helix morphology
HP:0025092	Epidermal acanthosis
HP:0033252	Palmar hyperlinearity
HP:0040162	Orthokeratosis
HP:0040190	White scaling skin
HP:0100543	Cognitive impairment
HP:0100679	Lack of skin elasticity
HP:0100758	Gangrene
HP:0100806	Sepsis

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002388_46	Lymphocyte count	1.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004587	lymphocyte count

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D003876	Dermatitis, Atopic	C16.320.850.210; C17.800.174.193; C17.800.815.193; C17.800.827.210; C20.543.480.343
D007057	Ichthyosis	C16.131.831.512; C16.614.492; C17.800.428.333; C17.800.804.512
C537265	Lamellar ichthyosis, type 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — CYP4 family

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	affects expression, increases expression	2
Cyclosporine	decreases expression	2
beauvericin	affects cotreatment, decreases expression	1
sodium arsenate	decreases expression, increases abundance	1
ethyl-p-hydroxybenzoate	decreases expression	1
afimoxifene	decreases reaction, increases expression	1
sodium arsenite	decreases expression, affects splicing	1
butyraldehyde	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
pentanal	increases expression	1
di-n-butylphosphoric acid	affects expression	1
fipronil	increases expression, affects cotreatment	1
enniatins	affects cotreatment, decreases expression	1
obeticholic acid	decreases expression	1
bisphenol S	affects cotreatment, decreases methylation	1
Decitabine	affects expression	1
Fulvestrant	decreases methylation, affects cotreatment	1
Acetaminophen	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Calcitriol	increases expression	1
Cisplatin	affects expression	1
DEET	affects cotreatment, increases expression	1
Estradiol	increases expression	1
Estrogens	decreases reaction, increases expression	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment, decreases expression	1
Aflatoxin B1	decreases expression	1
Cadmium Chloride	increases expression	1
Okadaic Acid	decreases expression	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00106496	PHASE4	COMPLETED	A Multi-Center Study of Short and Long-term Use of Protopic Ointment in Patients With Atopic Dermatitis
NCT00117377	PHASE4	COMPLETED	Effects of Pimecrolimus Cream 1% on the Molecular and Cellular Profile of Adult Male Patients With Atopic Dermatitis
NCT00119158	PHASE4	COMPLETED	Combination Therapy for Atopic Dermatitis
NCT00120302	PHASE4	COMPLETED	Quality of Life Study in Adults With Facial Eczema
NCT00121316	PHASE4	COMPLETED	Safety and Efficacy of Pimecrolimus Cream 1% in Mild to Moderate Head and Neck Atopic Dermatitis (AD) Patients
NCT00121381	PHASE4	COMPLETED	Pimecrolimus Cream 1% Plus Topical Corticosteroid in Patients (2-17 Years of Age) With Severe Atopic Dermatitis
NCT00124709	PHASE4	TERMINATED	Safety and Efficacy of Pimecrolimus Cream 1% in Atopic Disease Modification
NCT00130364	PHASE4	COMPLETED	Efficacy and Safety of Pimecrolimus Cream 1% in Patients (2 to 11 Years Old) With Mild to Moderate Facial Atopic Dermatitis
NCT00139581	PHASE4	COMPLETED	Comparison of Pimecrolimus Cream 1% Twice-Daily to Once-Daily Dosing in the Management of Atopic Dermatitis in Pediatric Subjects
NCT00150059	PHASE4	COMPLETED	Efficacy and Safety of Pimecrolimus Cream 1% in Patients ≥ 3 Months of Age With Mild or Moderate Atopic Dermatitis
NCT00179959	PHASE4	COMPLETED	The Impact of Treating Staphylococcus Aureus Infection and Colonization on the Clinical Severity of Atopic Dermatitis
NCT00180141	PHASE4	COMPLETED	Elidel-Study: Elidel in Patients With Atopic Dermatitis
NCT00185510	PHASE4	COMPLETED	Efficacy and Safety Study of Advantan for Maintenance Treatment of Atopic Dermatitis
NCT00236106	PHASE4	COMPLETED	Short Term Growth in Children With Atopic Dermatitis
NCT00367016	PHASE4	COMPLETED	Immunologic Basis of Anti-IgE Therapy (Study II: On Patients With Asthma)
NCT00367393	PHASE4	COMPLETED	Reconstitution With Pimecrolimus Cream 1% of Steroid-damaged Skin in Adults With Atopic Dermatitis
NCT00368719	PHASE4	WITHDRAWN	Evaluation to Assess the Long Term Safety of Tacrolimus Ointment for Atopic Dermatitis
NCT00445081	PHASE4	COMPLETED	Prednisolone vs. Ciclosporine in Severe Atopic Eczema
NCT00460083	PHASE4	COMPLETED	Epiceram Versus Elidel for Treatment of Mild to Moderate Atopic Dermatitis
NCT00484003	PHASE4	COMPLETED	A Quality of Life and Safety Study With Pimecrolimus Cream, 1% in Children (Age 2-12 Years) With Atopic Dermatitis
NCT00509990	PHASE4	COMPLETED	Open Label Study of Long Term Treatment of Pediatric Treatment of Atopic Dermatitis With Pimecrolimus Cream 1% Within a Usual Clinical Setting
NCT00510003	PHASE4	COMPLETED	Assessment of Pruritus Improvement With Pimecrolimus Treatment on the Areas Affected by Mild-to-moderate AD, in Patients 2- to 11- Year-old
NCT00546000	PHASE4	COMPLETED	Cutivate Lotion HPA Axis Pediatric Study
NCT00557284	PHASE4	COMPLETED	Efficacy Study of Montelukast in Atopic Dermatitis Induced by Food Allergens
NCT00559546	PHASE4	COMPLETED	Montelukast as a Controller of Atopic Syndrome
NCT00616538	PHASE4	COMPLETED	Epiceram™ Device Versus Mid-Strength Topical Steroid (Fluticasone Propionate 0.05%) for Treatment of Atopic Dermatitis
NCT00654355	PHASE4	COMPLETED	Measuring Adherence to Topical Therapy in Children With Atopic Dermatitis and the Impact of a Return Visit
NCT00666159	PHASE4	COMPLETED	Comparison Study Between Protopic (Tacrolimus Ointment) and Elidel (Pimecrolimus Cream) in Treating Pediatric Patients With Atopic Dermatitis
NCT00666302	PHASE4	COMPLETED	A Comparison Study Between Protopic (Tacrolimus) Ointment and Elidel (Pimecrolimus) Cream in Treating Subjects With Atopic Dermatitis
NCT00667160	PHASE4	COMPLETED	Comparison Study Between Protopic (Tacrolimus Ointment) and Elidel (Pimecrolimus Cream) in Pediatric Patients With Mild Atopic Dermatitis
NCT00671528	PHASE4	TERMINATED	Safety and Efficacy of Quadriderme® in the Treatment of Impetiginous Eczema (Study P05134AM4)
NCT00673725	PHASE4	COMPLETED	Locobase® REPAIR Used as an Adjunctive to Standard Therapy in Children With Moderate to Severe Atopic Dermatitis
NCT00689832	PHASE4	COMPLETED	Protopic Ointment in Children Atopic Eczema
NCT00690105	PHASE4	COMPLETED	Protopic Ointment in Adult Atopic Eczema of the Face
NCT00690833	PHASE4	COMPLETED	Efficacy of Desonide (Desonatetm) Gel 0.05% in Younger and Older Subjects With Atopic Dermatitis
NCT00693693	PHASE4	COMPLETED	Adherence to Topical Hydrocortisone 17-butyrate 0.1% (Locoid®) Using Different Vehicles in Adults With Atopic Dermatitis
NCT00771121	PHASE4	UNKNOWN	Effect of Moisturizing Creams on Skin Barrier Function
NCT00810862	PHASE4	TERMINATED	Study of Pimecrolimus Treatment for Atopic Dermatitis of African American Children
NCT00819507	PHASE4	COMPLETED	VANOS Cream and Skin Barrier Function
NCT00822783	PHASE4	COMPLETED	Study to Determine the Effect of an Anti-IgE Agent on Inflammatory Cells in the Skin of Atopic Dermatitis Patients