PNPLA1

Summary

PNPLA1 (patatin like domain 1, omega-hydroxyceramide transacylase , HGNC:21246) is a protein-coding gene on chromosome 6p21.31, encoding Omega-hydroxyceramide transacylase (Q8N8W4). Omega-hydroxyceramide transacylase involved in the synthesis of omega-O-acylceramides (esterified omega-hydroxyacyl-sphingosine; EOS), which are extremely hydrophobic lipids involved in skin barrier formation.

The protein encoded by this gene belongs to the patatin-like phospholipase (PNPLA) family, which is characterized by the presence of a highly conserved patatin domain. PNPLA family members have diverse lipolytic and acyltransferase activities, and are key elements in lipid metabolism. While other members of this family have been well characterized, the function of this gene remained an enigma. However, recent studies show that this gene is expressed in the skin epidermal keratinocytes, and has a role in glycerophospholipid metabolism in the cutaneous barrier. Consistent with these observations, mutations in this gene are associated with ichthyosis in human (autosomal recessive congenital ichthyoses, ARCI) and dog. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 285848 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive congenital ichthyosis 10 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 277 total — 20 pathogenic, 22 likely-pathogenic
• Phenotypes (HPO): 20
• MANE Select transcript: NM_001374623

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21246
Approved symbol	PNPLA1
Name	patatin like domain 1, omega-hydroxyceramide transacylase
Location	6p21.31
Locus type	gene with protein product
Status	Approved
Aliases	FLJ38755, dJ50J22.1
Ensembl gene	ENSG00000180316
Ensembl biotype	protein_coding
OMIM	612121
Entrez	285848

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000312917, ENST00000388715, ENST00000394571, ENST00000457797, ENST00000636260

RefSeq mRNA: 4 — MANE Select: NM_001374623 NM_001145716, NM_001145717, NM_001374623, NM_173676

CCDS: CCDS34438, CCDS47416, CCDS54997, CCDS93903

Canonical transcript exons

ENST00000636260 — 9 exons

Exon	Start	End
ENSE00001250619	36306292	36306376
ENSE00001250629	36301861	36302469
ENSE00001250638	36295364	36295424
ENSE00001503727	36294190	36294399
ENSE00001503728	36293061	36293126
ENSE00003664360	36291320	36291552
ENSE00003793489	36311763	36313955
ENSE00003798689	36307587	36307712
ENSE00003915538	36270060	36270664

Expression profiles

Bgee: expression breadth ubiquitous, 104 present calls, max score 84.99.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0053 / max 1.7684, expressed in 4 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
67501	0.0053	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skin of abdomen	UBERON:0001416	84.99	gold quality
skin of leg	UBERON:0001511	84.66	gold quality
zone of skin	UBERON:0000014	81.38	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	74.70	gold quality
monocyte	CL:0000576	72.52	gold quality
leukocyte	CL:0000738	72.34	gold quality
blood	UBERON:0000178	66.83	gold quality
granulocyte	CL:0000094	65.32	gold quality
bone marrow cell	CL:0002092	64.79	silver quality
upper leg skin	UBERON:0004262	61.00	gold quality
body of stomach	UBERON:0001161	60.42	gold quality
adult mammalian kidney	UBERON:0000082	57.98	gold quality
stomach	UBERON:0000945	57.50	gold quality
vermiform appendix	UBERON:0001154	56.95	gold quality
bone marrow	UBERON:0002371	55.07	gold quality
buccal mucosa cell	CL:0002336	54.79	gold quality
caecum	UBERON:0001153	54.48	gold quality
fundus of stomach	UBERON:0001160	53.88	gold quality
spleen	UBERON:0002106	53.40	gold quality
kidney	UBERON:0002113	53.36	gold quality
mucosa of transverse colon	UBERON:0004991	51.47	gold quality
small intestine Peyer’s patch	UBERON:0003454	50.31	gold quality
small intestine	UBERON:0002108	49.91	gold quality
duodenum	UBERON:0002114	48.63	gold quality
prefrontal cortex	UBERON:0000451	48.41	gold quality
smooth muscle tissue	UBERON:0001135	48.26	gold quality
gall bladder	UBERON:0002110	47.52	gold quality
ganglionic eminence	UBERON:0004023	47.49	gold quality
right adrenal gland cortex	UBERON:0035827	47.32	gold quality
cortex of kidney	UBERON:0001225	46.96	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.58
E-MTAB-6075	no	91.62

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

47 targeting PNPLA1, 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-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-20A-3P	99.44	69.10	1575
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-7158-5P	99.25	67.95	796
HSA-MIR-4477B	99.23	70.49	1733
HSA-MIR-196A-3P	99.19	67.34	1204
HSA-MIR-6504-3P	99.17	69.31	2891
HSA-MIR-146A-3P	99.13	68.99	1881
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-3149	98.77	67.13	1639
HSA-MIR-6731-3P	98.61	67.86	749

Literature-anchored findings (GeneRIF, showing 24)

• PNPLA1 exhibited a modest effect on obesity (PMID:19390624)
• One missense and one nonsense mutation in the catalytic domain of human PNPLA1 were found in six individuals with autosomal recessive congenital ichthyoses from two families. (PMID:22246504)
• These results identified hPNPLA1 and a mutant in HeLa cells. (PMID:24057234)
• Results show that PNPLA1 missense mutations observed in this European family affect the patanin-like domain (PMID:24344921)
• the variant identified will expand the spectrum of mutations in the PNPLA1 gene, provides more evidence for lack of genotype-phenotype correlation and clinical variability in PNPLA1 and underscores its role in causing autosomal recessive congenital ichthyosis (PMID:26691440)
• Letter: novel missense PNPLA1 variant causing autosomal recessive congenital ichthyosis in a Pakistani family. (PMID:26778108)
• an essential role of PNPLA1 in the synthesis of omega-O-AcylCers in human and murine skin. (PMID:27751867)
• analysis of distinct and previously unreported mutations in the PNPLA1 gene in nine extended consanguineous families with autosomal recessive congenital ichthyosis (PMID:27884779)
• The results show potential phenotypic variation in a small percentage of patients with PNPLA1 mutations. The variability of the clinical manifestations and the lack of typical clinical features are specific for patients with PNPLA1 mutations. (PMID:28093717)
• PNPLA1 catalyses the omega-O-esterification with linoleic acid to form acylceramides. (PMID:28248300)
• PNPLA1 is directly involved in acylceramide synthesis as a transacylase. (PMID:28248318)
• Data support that PNPLA1/Pnpla1 is a key player in the formation of omega-O-acylceramide, a crucial process for the epidermal permeability barrier function. (PMID:28369476)
• The PNPLA1 mutations reportedhere show PNPLA1 to be an important, if relatively rare, cause of ARCI. (PMID:28403545)
• 16 PNPLA1 mutations are known in autosomal recessive congenital ichthyosis. (PMID:28958709)
• Prospective observation of additional patients will allow to confirm that a cyclic scaling course is a distinctive manifestation in a subset of PNPLA1-associated autosomal recessive congenital ichthyosis (PMID:28983987)
• The results here report on three patients with mutations in the ichthyosis-related gene, PNPLA1, involved in lipid metabolism, presenting with erythrokeratoderma. (PMID:29023646)
• We report two novel PNPLA1 mutations including one novel missense mutation c.335C > A (p.Ser112Tyr) and one novel deletion mutation c.733_735delTAC (p.Tyr245del) in Turkish autosomal recessive congenital ichthyosis patients from unrelated consanguineous families. (PMID:29624231)
• Study results suggest that ABHD5 functions to retain triglyceride, the substrate of PNPLA1, in the endoplasmic reticulum, the site of acylceramide production, and to present TG to PNPLA1. These findings reveal the molecular mechanism by which ABHD5 mutations cause ichthyosis symptoms in Chanarin-Dorfman syndrome. (PMID:30527376)
• PNPLA1 mutations caused disturbances in both autophagosome formation and fusion of autophagosomes with lysosomes. Results indicate a possible role for PNPLA1 protein in lipid droplets regulation via lipophagy-mediated degradation. (PMID:30655104)
• PNPLA1 c.417_418delinsTC mutation has founder effects in the Spanish patients with autosomal recessive congenital ichthyosis. (PMID:31120544)
• Targeted regions sequencing identified four novel PNPLA1 mutations in two Chinese families with autosomal recessive congenital ichthyosis. (PMID:31833240)
• Homozygous variant p.Ser427Pro in PNPLA1 is a preventive factor from atopic dermatitis. (PMID:31864761)
• Impaired production of skin barrier lipid acylceramides and abnormal localization of PNPLA1 due to ichthyosis-causing mutations in PNPLA1. (PMID:35970721)
• Expanding the molecular and clinical spectrum of autosomal recessive congenital ichthyosis caused by pathogenic variants in NIPAL4 and PNPLA1 and evaluation of novel therapeutic interventions. (PMID:37458571)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Pnpla1	ENSMUSG00000043286
rattus_norvegicus	Pnpla1	ENSRNOG00000028622

Paralogs (4): PNPLA4 (ENSG00000006757), PNPLA5 (ENSG00000100341), PNPLA3 (ENSG00000100344), PNPLA2 (ENSG00000177666)

Protein

Protein identifiers

Omega-hydroxyceramide transacylase — Q8N8W4 (reviewed: Q8N8W4)

Alternative names: Patatin-like phospholipase domain-containing protein 1

All UniProt accessions (4): Q8N8W4, A0A0C4DG24, A0A1B0GW56, B8XXQ3

UniProt curated annotations — full annotation on UniProt →

Function. Omega-hydroxyceramide transacylase involved in the synthesis of omega-O-acylceramides (esterified omega-hydroxyacyl-sphingosine; EOS), which are extremely hydrophobic lipids involved in skin barrier formation. Catalyzes the last step of the synthesis of omega-O-acylceramides by transferring linoleic acid from triglycerides to an omega-hydroxyceramide. Omega-O-acylceramides, are required for the biogenesis of lipid lamellae in the stratum corneum and the formation of the cornified lipid envelope which are essential for the epidermis barrier function. These lipids also play a role in keratinocyte differentiation. May also act on omega-hydroxylated ultra-long chain fatty acids (omega-OH ULCFA) and acylglucosylceramides (GlcEOS).

Subcellular location. Cytoplasm.

Tissue specificity. Expressed in the digestive system. Expressed in the epidermis of skin keratinocytes. Strongly expressed in the granular layer. Expressed in the upper epidermis and eccrine sweat glands of the dermis and in the region of keratin filament bundles, which is more pronounced in upper epidermal layers and in the lower cornified layers.

Disease relevance. Ichthyosis, congenital, autosomal recessive 10 (ARCI10) [MIM:615024] 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.

Induction. Up-regulated upon induced differentiation of keratinocytes.

Miscellaneous. Inactive. Inactive.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8N8W4-1	1	yes
Q8N8W4-2	2
Q8N8W4-3	3

RefSeq proteins (4): NP_001139188, NP_001139189, NP_001361552, NP_775947 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002641	PNPLA_dom	Domain
IPR016035	Acyl_Trfase/lysoPLipase	Homologous_superfamily
IPR033562	PLPL	Family
IPR039180	PNPLA1	Family

Pfam: PF01734

Enzyme classification (BRENDA):

• EC 2.3.1.296 — omega-hydroxyceramide transacylase (BRENDA: 3 organisms, 21 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 11 shown:

• N-(30-hydroxytriacontanoyl)-sphing-4-enine + 1,2,3-tri-(9Z,12Z)-octadecadienoylglycerol = N-[30-(9Z,12Z-octadecadienoyloxy)-triacontanoyl]-sphing-4-enine + di-(9Z,12Z)-octadecadienoylglycerol (RHEA:55264)
• an N-(omega-hydroxy-ultra-long chain fatty acyl)-sphingoid base + a (9Z,12Z)-octadecadienoyl-containing triacyl-sn-glycerol = an N-[omega-(9Z,12Z-octadecadienoyloxy)-O-ultra-long chain fatty acyl]-sphingoid base + a diacylglycerol (RHEA:61528)
• N-(28-hydroxyoctacosanoyl)-sphing-4-enine + a (9Z,12Z)-octadecadienoyl-containing triacyl-sn-glycerol = N-(28-(9Z,12Z-octadecadienoyloxy)-octacosanoyl)-sphing-4-enine + a diacylglycerol (RHEA:65648)
• N-(32-hydroxydotriacontanoyl)-sphing-4-enine + a (9Z,12Z)-octadecadienoyl-containing triacyl-sn-glycerol = N-(32-(9Z,12Z-octadecadienoyloxy)-dotricontanoyl)-sphing-4-enine + a diacylglycerol (RHEA:65652)
• N-(32-hydroxydotriacontenoyl)-sphing-4-enine + a (9Z,12Z)-octadecadienoyl-containing triacyl-sn-glycerol = an N-(32-(9Z,12Z-octadecadienoyloxy)-dotriacontenoyl)-sphing-4-enine + a diacylglycerol (RHEA:65668)
• an N-(34-hydroxytetratriacontenoyl)-sphing-4-enine + a (9Z,12Z)-octadecadienoyl-containing triacyl-sn-glycerol = an N-(34-(9Z,12Z-octadecadienoyloxy)-tetratriacontenoyl)-sphing-4-enine + a diacylglycerol (RHEA:65672)
• an N-(34-hydroxytetratriacontadienoyl)-sphing-4-enine + a (9Z,12Z)-octadecadienoyl-containing triacyl-sn-glycerol = an N-(34-(9Z,12Z-octadecadienoyloxy)-tetratriacontadienoyl)-sphing-4-enine + a diacylglycerol (RHEA:65676)
• an N-(36-hydroxyhexatriacontenoyl)-sphing-4-enine + a (9Z,12Z)-octadecadienoyl-containing triacyl-sn-glycerol = an N-(36-(9Z,12Z-octadecadienoyloxy)-hexatriacontenoyl)-sphing-4-enine + a diacylglycerol (RHEA:65680)
• an N-(36-hydroxyhexatriacontadienoyl)-sphing-4-enine + a (9Z,12Z)-octadecadienoyl-containing triacyl-sn-glycerol = an N-(36-(9Z,12Z-octadecadienoyloxy)-hexatriacontadienoyl)-sphing-4-enine + a diacylglycerol (RHEA:65684)
• an N-(38-hydroxyoctatriacontenoyl)-sphing-4-enine + a (9Z,12Z)-octadecadienoyl-containing triacyl-sn-glycerol = an N-(38-(9Z,12Z-octadecadienoyloxy)-octatriacontenoyl)-sphing-4-enine + a diacylglycerol (RHEA:65688)
• an N-(omega-hydroxy-ultra-long chain fatty acyl)-sphing-4-enine + a (9Z,12Z)-octadecadienoyl-containing triacyl-sn-glycerol = an N-(omega-(9Z,12Z-octadecadienoyloxy)-ultra-long chain fatty acyl)-sphing-4-enine + a diacylglycerol (RHEA:65692)

UniProt features (21 total): sequence variant 6, compositionally biased region 4, active site 2, splice variant 2, region of interest 2, short sequence motif 2, chain 1, domain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N8W4-F1	64.54	0.33

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): 53 (nucleophile); 172 (proton acceptor)

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 130 (showing top): GOBP_CERAMIDE_BIOSYNTHETIC_PROCESS, GOBP_LIPID_HOMEOSTASIS, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GOBP_SPHINGOLIPID_METABOLIC_PROCESS, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_AMIDE_BIOSYNTHETIC_PROCESS, GOBP_NEUTRAL_LIPID_CATABOLIC_PROCESS, GOBP_LIPID_METABOLIC_PROCESS, GOBP_TRIGLYCERIDE_CATABOLIC_PROCESS, GOBP_NEUTRAL_LIPID_METABOLIC_PROCESS, GOBP_LIPID_BIOSYNTHETIC_PROCESS, GOBP_CERAMIDE_METABOLIC_PROCESS, GOBP_SPHINGOLIPID_BIOSYNTHETIC_PROCESS, GOBP_GLYCEROLIPID_CATABOLIC_PROCESS, GOBP_LIPID_CATABOLIC_PROCESS

GO Biological Process (8): triglyceride catabolic process (GO:0019433), ceramide biosynthetic process (GO:0046513), lipid homeostasis (GO:0055088), omega-hydroxyceramide biosynthetic process (GO:0106342), lipid metabolic process (GO:0006629), lipid catabolic process (GO:0016042), keratinocyte differentiation (GO:0030216), establishment of skin barrier (GO:0061436)

GO Molecular Function (6): triacylglycerol lipase activity (GO:0004806), acyltransferase activity, transferring groups other than amino-acyl groups (GO:0016747), structural constituent of skin epidermis (GO:0030280), omega-hydroxyceramide transacylase activity (GO:0106341), transferase activity (GO:0016740), hydrolase activity (GO:0016787)

GO Cellular Component (3): cytoplasm (GO:0005737), lipid droplet (GO:0005811), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
catalytic activity	2
cellular anatomical structure	2
triglyceride metabolic process	1
acylglycerol catabolic process	1
ceramide metabolic process	1
sphingolipid biosynthetic process	1
chemical homeostasis	1
ceramide biosynthetic process	1
primary metabolic process	1
lipid metabolic process	1
catabolic process	1
epidermal cell differentiation	1
skin development	1
skin epidermis development	1
lipase activity	1
carboxylic ester hydrolase activity	1
acyltransferase activity	1
structural molecule activity	1
acyltransferase activity, transferring groups other than amino-acyl groups	1
intracellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

548 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PNPLA1	CYP4F22	Q6NT55	885
PNPLA1	NIPAL4	Q0D2K0	859
PNPLA1	ABHD5	Q8WTS1	836
PNPLA1	CERS3	Q8IU89	807
PNPLA1	ALOXE3	Q9BYJ1	797
PNPLA1	ALOX12B	O75342	788
PNPLA1	ABCA12	Q86UK0	784
PNPLA1	LIPN	Q5VXI9	775
PNPLA1	TGM1	P22735	764
PNPLA1	SDR9C7	Q8NEX9	724
PNPLA1	PNPLA8	Q9NP80	666
PNPLA1	SLC27A4	Q6P1M0	663
PNPLA1	SULT2B1	O00204	625
PNPLA1	ELOVL4	Q9GZR5	581
PNPLA1	PNPLA6	Q8IY17	575

IntAct

3 interactions, top by confidence:

A	B	Type	Score
PNPLA1	TCP1	psi-mi:“MI:0914”(association)	0.350
PNPLA1	METTL15	psi-mi:“MI:0914”(association)	0.350

BioGRID (33): UBR4 (Affinity Capture-MS), NIF3L1 (Affinity Capture-MS), CCT6B (Affinity Capture-MS), TMEM160 (Affinity Capture-MS), CCT3 (Affinity Capture-MS), UBAC1 (Affinity Capture-MS), RNF123 (Affinity Capture-MS), TXNDC9 (Affinity Capture-MS), PDCL (Affinity Capture-MS), HBB (Affinity Capture-MS), UBAC1 (Affinity Capture-MS), NIF3L1 (Affinity Capture-MS), RNF123 (Affinity Capture-MS), TXNDC9 (Affinity Capture-MS), UBR4 (Affinity Capture-MS)

ESM2 similar proteins: A2ARP1, A7Z050, D3YWQ0, D3ZEY4, F1MAB7, F1S5L4, O08560, O75912, P0C548, P0C644, P16386, P49898, P54310, P97564, Q11186, Q13574, Q2KI18, Q2NKY8, Q32LZ8, Q3MJ16, Q3TRM4, Q3TZX8, Q3U1Y4, Q50L41, Q50L42, Q50L43, Q5GJ77, Q5RDF1, Q5XIL6, Q5ZI74, Q61586, Q68DD2, Q68J42, Q6IWH7, Q6NZR5, Q6P5E8, Q7Z6Z6, Q80UP3, Q80YU0, Q8BJ56

Diamond homologs: P0C548, P41247, Q11186, Q2KI18, Q32LZ8, Q3V1D5, Q7Z6Z6, Q8BJ56, Q8N8W4, Q91WW7, Q96AD5, Q9NST1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	20
Likely pathogenic	22
Uncertain significance	113
Likely benign	41
Benign	38

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
2136383	NM_001374623.1(PNPLA1):c.275del (p.Pro92fs)	Pathogenic
2782330	NM_001374623.1(PNPLA1):c.439-2A>G	Pathogenic
3246149	NC_000006.11:g.(?36259077)(36262196_?)del	Pathogenic
3335972	NM_001374623.1(PNPLA1):c.417_418delinsTC (p.Ser140Pro)	Pathogenic
3374967	NM_001374623.1(PNPLA1):c.301A>G (p.Arg101Gly)	Pathogenic
3900745	NM_001374623.1(PNPLA1):c.536A>G (p.Gln179Arg)	Pathogenic
39561	NM_001374623.1(PNPLA1):c.391G>T (p.Glu131Ter)	Pathogenic
39562	NM_001374623.1(PNPLA1):c.176C>T (p.Ala59Val)	Pathogenic
4281245	NM_001374623.1(PNPLA1):c.56C>T (p.Ser19Leu)	Pathogenic
4693753	NM_001374623.1(PNPLA1):c.1318C>T (p.Arg440Ter)	Pathogenic
4847788	NM_001374623.1(PNPLA1):c.1143del (p.Ser382fs)	Pathogenic
545920	NM_001374623.1(PNPLA1):c.878_881dup (p.Pro295fs)	Pathogenic
633818	NM_001374623.1(PNPLA1):c.727TAC[2] (p.Tyr245del)	Pathogenic
684637	NM_001374623.1(PNPLA1):c.92C>A (p.Ala31Asp)	Pathogenic
684638	NM_001374623.1(PNPLA1):c.514G>A (p.Asp172Asn)	Pathogenic
684639	NM_001374623.1(PNPLA1):c.448T>C (p.Cys150Arg)	Pathogenic
684640	NM_001374623.1(PNPLA1):c.1300del (p.Ala434fs)	Pathogenic
684641	NM_001374623.1(PNPLA1):c.362A>C (p.His121Pro)	Pathogenic
684645	NM_001374623.1(PNPLA1):c.421A>G (p.Lys141Glu)	Pathogenic
684646	NM_001374623.1(PNPLA1):c.157T>C (p.Ser53Pro)	Pathogenic
1180808	NM_001374623.1(PNPLA1):c.670A>G (p.Asn224Asp)	Likely pathogenic
2445879	NM_001374623.1(PNPLA1):c.736C>T (p.Arg246Ter)	Likely pathogenic
3336275	NM_001374623.1(PNPLA1):c.158C>T (p.Ser53Leu)	Likely pathogenic
3382149	NM_001374623.1(PNPLA1):c.88G>A (p.Gly30Arg)	Likely pathogenic
3391281	NM_001374623.1(PNPLA1):c.121del (p.Arg41fs)	Likely pathogenic
3392516	NM_001374623.1(PNPLA1):c.715-2A>C	Likely pathogenic
3593567	NM_001374623.1(PNPLA1):c.206-1G>A	Likely pathogenic
3593568	NM_001374623.1(PNPLA1):c.1136_1152del (p.Lys379fs)	Likely pathogenic
3593569	NM_001374623.1(PNPLA1):c.1289C>G (p.Ser430Ter)	Likely pathogenic
3593570	NM_001374623.1(PNPLA1):c.1384+2T>C	Likely pathogenic

SpliceAI

2441 predictions. Top by Δscore:

Variant	Effect	Δscore
6:36271359:GCCTA:G	donor_gain	1.0000
6:36291316:GCAG:G	acceptor_loss	1.0000
6:36291318:A:AC	acceptor_loss	1.0000
6:36291318:A:AG	acceptor_gain	1.0000
6:36291318:AGAT:A	acceptor_gain	1.0000
6:36291319:G:GT	acceptor_gain	1.0000
6:36291319:GA:G	acceptor_gain	1.0000
6:36291319:GAT:G	acceptor_gain	1.0000
6:36291319:GATG:G	acceptor_gain	1.0000
6:36291319:GATGA:G	acceptor_gain	1.0000
6:36291468:G:GT	donor_gain	1.0000
6:36291468:G:T	donor_gain	1.0000
6:36291516:G:GA	donor_gain	1.0000
6:36291538:G:GT	donor_gain	1.0000
6:36294185:CACA:C	acceptor_loss	1.0000
6:36294188:A:AG	acceptor_gain	1.0000
6:36294188:A:C	acceptor_loss	1.0000
6:36294188:AGAG:A	acceptor_gain	1.0000
6:36294189:G:GC	acceptor_gain	1.0000
6:36294189:GAGG:G	acceptor_gain	1.0000
6:36294189:GAGGT:G	acceptor_gain	1.0000
6:36294366:G:GT	donor_gain	1.0000
6:36294397:GTG:G	donor_gain	1.0000
6:36295425:G:GG	donor_gain	1.0000
6:36243258:TAAG:T	donor_loss	0.9900
6:36243259:AAG:A	donor_loss	0.9900
6:36243261:GGTA:G	donor_loss	0.9900
6:36243262:GTAG:G	donor_loss	0.9900
6:36243263:T:G	donor_loss	0.9900
6:36271364:G:GG	donor_gain	0.9900

AlphaMissense

3670 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:36270526:T:C	F23L	0.999
6:36270528:C:A	F23L	0.999
6:36270528:C:G	F23L	0.999
6:36293079:T:C	F153L	0.999
6:36293081:C:A	F153L	0.999
6:36293081:C:G	F153L	0.999
6:36294200:A:T	D172V	0.999
6:36294357:C:A	N224K	0.999
6:36294357:C:G	N224K	0.999
6:36270512:T:C	F18S	0.998
6:36270520:A:C	S21R	0.998
6:36270522:T:A	S21R	0.998
6:36270522:T:G	S21R	0.998
6:36270547:G:T	G30W	0.998
6:36270610:G:T	G51W	0.998
6:36291485:T:C	L124P	0.998
6:36291545:T:C	L144P	0.998
6:36293072:C:G	C150W	0.998
6:36293073:A:C	S151R	0.998
6:36293075:C:A	S151R	0.998
6:36293075:C:G	S151R	0.998
6:36293091:T:G	Y157D	0.998
6:36293115:T:G	Y165D	0.998
6:36294193:T:G	Y170D	0.998
6:36294202:G:T	G173W	0.998
6:36294203:G:A	G173E	0.998
6:36295388:G:T	G247W	0.998
6:36270524:G:A	G22E	0.997
6:36270527:T:C	F23S	0.997
6:36270548:G:A	G30E	0.997

dbSNP variants (sampled 300 via entrez): RS1000021864 (6:36248867 T>A,C), RS1000053623 (6:36298655 G>A), RS1000084485 (6:36300864 T>C), RS1000122335 (6:36253766 A>G,T), RS1000128739 (6:36255789 T>C,G), RS1000187303 (6:36257071 G>A), RS1000205254 (6:36313699 C>CT), RS1000214704 (6:36295687 G>A), RS1000226362 (6:36272630 G>A), RS1000261594 (6:36243566 T>C), RS1000281022 (6:36312676 G>A), RS1000283526 (6:36250594 T>C), RS1000335384 (6:36250943 C>A), RS1000382747 (6:36269931 A>C), RS1000472450 (6:36258795 T>A,C)

Disease associations

OMIM: gene MIM:612121 | disease phenotypes: MIM:615024, MIM:242300

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive congenital ichthyosis 10	Strong	Autosomal recessive
congenital non-bullous ichthyosiform erythroderma	Supportive	Autosomal recessive

Mondo (5): autosomal recessive congenital ichthyosis 10 (MONDO:0014011), lamellar ichthyosis (MONDO:0017778), autosomal recessive congenital ichthyosis (MONDO:0017265), ichthyosis (MONDO:0019269), congenital non-bullous ichthyosiform erythroderma (MONDO:0019306)

Orphanet (4): Congenital ichthyosiform erythroderma (Orphanet:79394), Lamellar ichthyosis (Orphanet:313), Autosomal recessive congenital ichthyosis (Orphanet:281097), Ichthyosis (Orphanet:79354)

HPO phenotypes

20 total (20 of 20 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000491	Keratitis
HP:0000656	Ectropion
HP:0000962	Hyperkeratosis
HP:0000966	Hypohidrosis
HP:0000982	Palmoplantar keratoderma
HP:0000989	Pruritus
HP:0001019	Erythroderma
HP:0001508	Failure to thrive
HP:0001596	Alopecia
HP:0001597	Abnormal nail morphology
HP:0003577	Congenital onset
HP:0004322	Short stature
HP:0007479	Congenital nonbullous ichthyosiform erythroderma
HP:0007503	Generalized ichthyosis
HP:0008064	Ichthyosis
HP:0025080	Orthokeratotic hyperkeratosis
HP:0025114	Hypergranulosis
HP:0200020	Corneal erosion

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST011494_27	Daytime nap	1.000000e-07
GCST90002383_410	Hematocrit	7.000000e-12
GCST90002384_89	Hemoglobin	3.000000e-13
GCST90002403_394	Red blood cell count	8.000000e-18

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007828	daytime rest measurement
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0004305	erythrocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D007057	Ichthyosis	C16.131.831.512; C16.614.492; C17.800.428.333; C17.800.804.512

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
triphenyl phosphate	affects expression	1
sodium arsenite	increases expression	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
clothianidin	increases expression	1
Lipopolysaccharides	affects cotreatment, increases expression	1
Thiram	increases expression	1
Tretinoin	increases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	increases methylation	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04996485	PHASE4	UNKNOWN	Scientific Substantiation and Assessment of the Effectiveness of Pathogenetic Methods of Therapy for Congenital Ichthyosis in Children
NCT01222000	PHASE3	UNKNOWN	Treatment of the Recessive Nonbullous Congenital Ichthyosis by the Epigallocatechine Cutaneous
NCT00004690	PHASE3	COMPLETED	Phase III Study of Monolaurin Cream Therapy for Patients With Congenital Ichthyosis
NCT05295732	PHASE3	COMPLETED	The ASCEND Study: Evaluating TMB-001 in the Treatment of RXLI or ARCI Ichthyosis
NCT03041038	PHASE2	COMPLETED	The Efficacy and Safety of Secukinumab in Patients With Ichthyoses
NCT03738800	PHASE2	TERMINATED	A Safety, Efficacy and Systemic Exposure Study of CD5789 Cream in Adults and Adolescents With Lamellar Ichthyosis
NCT02864082	PHASE2	COMPLETED	A Safety and Tolerability Study of Topical PAT-001 in Congenital Ichthyosis
NCT04154293	PHASE2	COMPLETED	A Vehicle Controlled Study to Evaluate Safety and Efficacy of Topical TMB-001 for Treatment of Congenital Ichthyosis
NCT04697056	PHASE2	TERMINATED	A Study to Evaluate the Efficacy and Safety of Imsidolimab (ANB019) in the Treatment of Participants With Ichthyosis
NCT06136403	PHASE2	RECRUITING	A 44-week Monocentric Open Study Assessing the Efficacy and Safety of Deucravacitinib in Adults With Inflammatory Genodermatoses
NCT06362447	PHASE2	NOT_YET_RECRUITING	Efficacy of Injectable Gentamicin in Hereditary Ichthyosis
NCT00001292	Not specified	COMPLETED	Study of Scaling Disorders and Other Inherited Skin Diseases
NCT05312073	Not specified	COMPLETED	Study of in Vivo and in Vitro Transcriptomic and Proteomic Signatures in Unhereditary Ichtyosis
NCT04549792	EARLY_PHASE1	COMPLETED	An Open-Label and Long-Term Extension Study to Evaluate the Efficacy and Safety of Ustekinumab in the Treatment of Patients With Ichthyoses
NCT07050810	EARLY_PHASE1	ENROLLING_BY_INVITATION	Thera-Clean® Microbubbles System in Patients With Skin Diseases
NCT00074685	Not specified	COMPLETED	National Registry for Ichthyosis and Related Disorders
NCT02655861	Not specified	TERMINATED	A Multi-center, Prospective Evaluation of Infants and Children With Congenital Ichthyosis
NCT03051347	Not specified	COMPLETED	Asthma and Atopic Dermatitis Validation of PROMIS Pediatric Instruments
NCT03417856	Not specified	ENROLLING_BY_INVITATION	Defining the Skin and Blood Biomarkers of Ichthyosis
NCT03464994	Not specified	COMPLETED	Ophthalmological Abnormalities in Hereditary Ichthyosis (ICHTYO-KERATO)
NCT03641261	Not specified	COMPLETED	Therapeutic Education Using an Internet Application in Hereditary Ichthyosis
NCT03796052	Not specified	COMPLETED	Study Determining Safety and Efficacy of Avena Sativa (Oat) Skincare Products for Treating Skin Dryness and Itching in Cancer Patients
NCT05610306	Not specified	COMPLETED	Quality of Life in Middle-aged and Older Patients With Congenital Ichthyosis
NCT05954416	Not specified	RECRUITING	FARD (RaDiCo Cohort) (RaDiCo-FARD)
NCT06123091	Not specified	UNKNOWN	Exploring Patient Reported Outcomes in Inherited Ichthyosis
NCT06330324	Not specified	ENROLLING_BY_INVITATION	Reproductive Options in Inherited Skin Diseases
NCT06330350	Not specified	RECRUITING	Qualitative Study in Patients With Genodermatoses and Healthcare Professionals on Reproductive Counselling
NCT07066150	Not specified	COMPLETED	A Clinical Evaluation of Marula-Derived Ceramide Cream on Skin Barrier Function Enhancement