NIPAL4

Summary

NIPAL4 (NIPA like domain containing 4, HGNC:28018) is a protein-coding gene on chromosome 5q33.3, encoding Magnesium transporter NIPA4 (Q0D2K0). Acts as a Mg(2+) transporter.

This gene likely encodes a membrane receptor. Mutations in this gene have been associated with autosomal recessive congenital ichthyosis.

Source: NCBI Gene 348938 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive congenital ichthyosis 6 (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 238 total — 27 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 36
• MANE Select transcript: NM_001099287

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28018
Approved symbol	NIPAL4
Name	NIPA like domain containing 4
Location	5q33.3
Locus type	gene with protein product
Status	Approved
Aliases	ICHYN, SLC57A6, NIPA4
Ensembl gene	ENSG00000172548
Ensembl biotype	protein_coding
OMIM	609383
Entrez	348938

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 2 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000311946, ENST00000435489, ENST00000519150, ENST00000519946, ENST00000521390

RefSeq mRNA: 2 — MANE Select: NM_001099287 NM_001099287, NM_001172292

CCDS: CCDS47328

Canonical transcript exons

ENST00000311946 — 6 exons

Exon	Start	End
ENSE00001211164	157472332	157474722
ENSE00001238402	157460213	157460357
ENSE00003492950	157471657	157471817
ENSE00003620724	157467049	157467105
ENSE00003635297	157463094	157463333
ENSE00003638589	157468722	157468812

Expression profiles

Bgee: expression breadth ubiquitous, 165 present calls, max score 95.10.

FANTOM5 (CAGE): breadth broad, TPM avg 6.2614 / max 188.5908, expressed in 512 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
59822	3.9645	451
59823	1.8771	335
59821	0.4198	202

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper arm skin	UBERON:0004263	95.10	gold quality
skin of abdomen	UBERON:0001416	92.90	gold quality
skin of leg	UBERON:0001511	92.62	gold quality
zone of skin	UBERON:0000014	91.57	gold quality
gingival epithelium	UBERON:0001949	91.48	gold quality
gingiva	UBERON:0001828	89.28	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.56	gold quality
upper leg skin	UBERON:0004262	87.85	gold quality
mammalian vulva	UBERON:0000997	86.89	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	85.45	gold quality
spinal cord	UBERON:0002240	84.63	gold quality
lower esophagus mucosa	UBERON:0035834	84.14	gold quality
penis	UBERON:0000989	83.77	gold quality
esophagus mucosa	UBERON:0002469	82.65	gold quality
nipple	UBERON:0002030	80.43	gold quality
esophagus squamous epithelium	UBERON:0006920	79.96	gold quality
inferior vagus X ganglion	UBERON:0005363	79.54	gold quality
kidney epithelium	UBERON:0004819	79.43	gold quality
cardiac muscle of right atrium	UBERON:0003379	79.30	gold quality
urinary bladder	UBERON:0001255	79.27	gold quality
left ventricle myocardium	UBERON:0006566	79.16	gold quality
skin of hip	UBERON:0001554	79.15	gold quality
subthalamic nucleus	UBERON:0001906	77.56	silver quality
vagina	UBERON:0000996	76.61	gold quality
corpus callosum	UBERON:0002336	75.80	gold quality
vena cava	UBERON:0004087	75.73	gold quality
myocardium	UBERON:0002349	75.47	gold quality
substantia nigra	UBERON:0002038	75.14	gold quality
midbrain	UBERON:0001891	75.10	gold quality
dorsal plus ventral thalamus	UBERON:0001897	75.09	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.86

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

127 targeting NIPAL4, 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-4262	100.00	73.26	3931
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-4267	99.96	66.53	2368

Literature-anchored findings (GeneRIF, showing 16)

• Six homozygous mutations including one nonsense and five missense mutations were identified in a new gene, ichthyin, on chromosome 5q33 in patients with autosomal recessive congenital ichthyosis (ichthyin). (PMID:15317751)
• mutations in ichthyin are associated with specific structural abnormalities in the granular layer of epidermis (PMID:17557927)
• The results suggest that liarozole exerts a therapeutic effect in lamellar ichthyosis by mildly affecting the expression of retinoid- regulated genes in epidermis. (PMID:19197536)
• A recurrent missense mutation, p.A176D, was identified in individuals with autosomal recessive ichthyosis. (PMID:20016120)
• diffuse yellowish keratoderma may be indicative of mutations in NIPAL4, providing an easily assessable genotype-phenotype correlation (PMID:22098531)
• combined findings indicate that ichthyin is associated with keratins and desmosomes in epidermis and is involved in lipid metabolism, possibly through processing of lamellar bodies (PMID:22258272)
• Autosomal recessive congenital ichthyosis patients with NIPAL4 mutations and abnormal ichthyin expression showed increased 12R-LOX and eLOX-3 staining and a colocalization signal of these lipoxygenases that was three times the normal intensity. (PMID:22622417)
• FATP4, ichthyin and TGM1 interact in lipid processing essential for maintaining the epidermal barrier function (PMID:23290633)
• We have identified a novel NIPAL4 mutation in two patients from Romania with autosomal recessive congenital ichthyosis. (PMID:26456858)
• Case Report: novel NIPAL4 mutation in Japanese female with ichthyosiform erythroderma. (PMID:27868142)
• NIPAL4 mutations are associated with Ichthyotic Phenotype. (PMID:29548991)
• Results identified 16 novel mutations in NIPAL4 in a large cohort of families with autosomal recessive congenital ichthyosis (ARCI) and increase the total number of pathogenic mutations to 34. (PMID:31347739)
• Identification of a novel missense mutation in NIPAL4 gene: First 3D model construction predicted its pathogenicity. (PMID:31876100)
• Variants in NIPAL4 and ALOXE3 cause autosomal recessive congenital ichthyosis in Pakistani families. (PMID:31883158)
• Expanding the clinical phenotype associated with NIPAL4 mutation: Study of a Tunisian consanguineous family with erythrokeratodermia variabilis-Like Autosomal Recessive Congenital Ichthyosis. (PMID:34669720)
• 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

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	nipal4	ENSDARG00000059365
mus_musculus	Nipal4	ENSMUSG00000020411
rattus_norvegicus	Nipal4	ENSRNOG00000006255
drosophila_melanogaster	spict	FBGN0032451
caenorhabditis_elegans		WBGENE00021820

Paralogs (5): NIPAL3 (ENSG00000001461), NIPAL2 (ENSG00000104361), NIPA2 (ENSG00000140157), NIPAL1 (ENSG00000163293), NIPA1 (ENSG00000170113)

Protein

Protein identifiers

Magnesium transporter NIPA4 — Q0D2K0 (reviewed: Q0D2K0)

Alternative names: Ichthyin, NIPA-like protein 4, Non-imprinted in Prader-Willi/Angelman syndrome region protein 4

All UniProt accessions (2): Q0D2K0, H0YC31

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a Mg(2+) transporter. Can also transport other divalent cations such as Ba(2+), Sr(2+) and Fe(2+) but to a much less extent than Mg(2+). May be a receptor for ligands (trioxilins A3 and B3) from the hepoxilin pathway.

Subcellular location. Cell membrane.

Tissue specificity. Highly expressed in brain, lung, stomach, keratinocytes and leukocytes, and in all other tissues tested except liver, thyroid and fetal brain.

Disease relevance. Ichthyosis, congenital, autosomal recessive 6 (ARCI6) [MIM:612281] 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 NIPA family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q0D2K0-1	1	yes
Q0D2K0-2	2

RefSeq proteins (2): NP_001092757, NP_001165763 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008521	Mg_trans_NIPA	Family
IPR037185	EmrE-like	Homologous_superfamily

Pfam: PF05653

Catalyzed reactions (Rhea), 1 shown:

• Mg(2+)(in) = Mg(2+)(out) (RHEA:29827)

UniProt features (32 total): topological domain 10, transmembrane region 9, sequence variant 7, glycosylation site 3, chain 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q0D2K0-F1	78.91	0.47

Functional residue map

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

Glycosylation sites (3): 7, 12, 40

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5223345	Miscellaneous transport and binding events

MSigDB gene sets: 159 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GAUSSMANN_MLL_AF4_FUSION_TARGETS_E_UP, GOBP_MAGNESIUM_ION_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, GOBP_TRANSMEMBRANE_TRANSPORT, GOMF_METAL_ION_TRANSMEMBRANE_TRANSPORTER_ACTIVITY, GOMF_MONOATOMIC_CATION_TRANSMEMBRANE_TRANSPORTER_ACTIVITY, ZHOU_INFLAMMATORY_RESPONSE_LIVE_UP, GOMF_TRANSPORTER_ACTIVITY, MEISSNER_NPC_HCP_WITH_H3_UNMETHYLATED, MEISSNER_BRAIN_HCP_WITH_H3K4ME3_AND_H3K27ME3, GOMF_MONOATOMIC_ION_TRANSMEMBRANE_TRANSPORTER_ACTIVITY, GOMF_MAGNESIUM_ION_TRANSMEMBRANE_TRANSPORTER_ACTIVITY, REACTOME_TRANSPORT_OF_SMALL_MOLECULES

GO Biological Process (3): magnesium ion transport (GO:0015693), monoatomic ion transport (GO:0006811), magnesium ion transmembrane transport (GO:1903830)

GO Molecular Function (2): magnesium ion transmembrane transporter activity (GO:0015095), protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
metal ion transport	1
transport	1
magnesium ion transport	1
monoatomic cation transmembrane transport	1
metal ion transmembrane transporter activity	1
magnesium ion transmembrane transport	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

448 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NIPAL4	CYP4F22	Q6NT55	986
NIPAL4	TGM1	P22735	958
NIPAL4	ALOXE3	Q9BYJ1	923
NIPAL4	ABCA12	Q86UK0	920
NIPAL4	ALOX12B	O75342	917
NIPAL4	PNPLA1	Q8N8W4	859
NIPAL4	ABHD5	Q8WTS1	770
NIPAL4	LIPN	Q5VXI9	763
NIPAL4	CERS3	Q8IU89	742
NIPAL4	MAGT1	Q9H0U3	733
NIPAL4	SDR9C7	Q8NEX9	685
NIPAL4	SLC27A4	Q6P1M0	681
NIPAL4	SULT2B1	O00204	616
NIPAL4	CYP4F3	Q08477	611
NIPAL4	PTP4A2	Q12974	610

IntAct

49 interactions, top by confidence:

A	B	Type	Score
NIPAL4	LHFPL5	psi-mi:“MI:0915”(physical association)	0.560
NIPAL4	COMT	psi-mi:“MI:0915”(physical association)	0.560
NIPAL4	RNF185	psi-mi:“MI:0915”(physical association)	0.560
NIPAL4	CMTM2	psi-mi:“MI:0915”(physical association)	0.560
NIPAL4	HHLA2	psi-mi:“MI:0915”(physical association)	0.560
NIPAL4	TM4SF18	psi-mi:“MI:0915”(physical association)	0.560
NIPAL4	IL10RA	psi-mi:“MI:0915”(physical association)	0.560
NIPAL4	SSMEM1	psi-mi:“MI:0915”(physical association)	0.560
NIPAL4	GPR152	psi-mi:“MI:0915”(physical association)	0.560
CLDN7	NIPAL4	psi-mi:“MI:0915”(physical association)	0.560
TRHR	NIPAL4	psi-mi:“MI:0915”(physical association)	0.560
ACKR2	NIPAL4	psi-mi:“MI:0915”(physical association)	0.560
FFAR2	NIPAL4	psi-mi:“MI:0915”(physical association)	0.560
COMT	NIPAL4	psi-mi:“MI:0915”(physical association)	0.560
GJB1	NIPAL4	psi-mi:“MI:0915”(physical association)	0.560
NIPAL4	RNF19B	psi-mi:“MI:0915”(physical association)	0.560
M		psi-mi:“MI:0914”(association)	0.350
NIPAL4	PGRMC2	psi-mi:“MI:0914”(association)	0.350
SLC27A4	NIPAL4	psi-mi:“MI:2364”(proximity)	0.270
NIPAL4	RNF185	psi-mi:“MI:0915”(physical association)	0.000
NIPAL4	CMTM2	psi-mi:“MI:0915”(physical association)	0.000
NIPAL4	HHLA2	psi-mi:“MI:0915”(physical association)	0.000
NIPAL4	TM4SF18	psi-mi:“MI:0915”(physical association)	0.000
NIPAL4	IL10RA	psi-mi:“MI:0915”(physical association)	0.000
NIPAL4	SSMEM1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (43): NIPAL4 (Affinity Capture-MS), NIPAL4 (Positive Genetic), NIPAL4 (Two-hybrid), NIPAL4 (Two-hybrid), NIPAL4 (Two-hybrid), NIPAL4 (Two-hybrid), NIPAL4 (Two-hybrid), NIPAL4 (Two-hybrid), NIPAL4 (Two-hybrid), NIPAL4 (Two-hybrid), NIPAL4 (Two-hybrid), NIPAL4 (Two-hybrid), NIPAL4 (Two-hybrid), TRHR (Two-hybrid), GPR152 (Two-hybrid)

ESM2 similar proteins: A0NGI1, A7YW81, O74750, O94654, P40004, Q00974, Q02334, Q03730, Q04083, Q09875, Q0D2K0, Q0V9U2, Q10000, Q29Q28, Q3E6T0, Q3SWX0, Q54V96, Q54ZG7, Q550W6, Q55FV8, Q5R7Q3, Q5T1Q4, Q6CR04, Q6FSF8, Q7RTP0, Q7TML3, Q8BGK5, Q8BHK1, Q8BLX4, Q8BMW7, Q8BZF2, Q8IXU6, Q8MXJ9, Q8N8Q9, Q8R1E7, Q8WY98, Q94EI9, Q968A5, Q9C8M1, Q9JJC8

Diamond homologs: B3LFA3, F4JKQ7, Q0D2K0, Q3SWX0, Q5A5P7, Q5R7Q3, Q5RDB8, Q6NVV3, Q7RTP0, Q8BHK1, Q8BMW7, Q8BZF2, Q8GWX2, Q8GYS1, Q8N8Q9, Q94AH3, Q9H841, Q9JJC8, Q9LIR9, Q9LNK7, Q91WC7, Q5RD30, Q6P499, Q8BGN5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	27
Likely pathogenic	8
Uncertain significance	113
Likely benign	39
Benign	29

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1445008	NM_001099287.2(NIPAL4):c.318G>A (p.Trp106Ter)	Pathogenic
1729	NM_001099287.2(NIPAL4):c.247C>T (p.Arg83Ter)	Pathogenic
1730	A114N	Pathogenic
1732	NM_001099287.2(NIPAL4):c.586+1G>A	Pathogenic
2423698	NC_000005.9:g.(?156887143)(156899968_?)del	Pathogenic
2693241	NM_001099287.2(NIPAL4):c.139C>T (p.Gln47Ter)	Pathogenic
3698669	NM_001099287.2(NIPAL4):c.703G>C (p.Gly235Arg)	Pathogenic
372383	NM_001099287.2(NIPAL4):c.502G>A (p.Gly168Arg)	Pathogenic
3775110	NM_001099287.2(NIPAL4):c.586G>A (p.Gly196Arg)	Pathogenic
633804	NM_001099287.2(NIPAL4):c.897C>A (p.Tyr299Ter)	Pathogenic
633805	NM_001099287.2(NIPAL4):c.520_526del (p.Ile174fs)	Pathogenic
638534	NM_001099287.2(NIPAL4):c.37+5G>C	Pathogenic
638535	NM_001099287.2(NIPAL4):c.97del (p.Leu33fs)	Pathogenic
638537	NM_001099287.2(NIPAL4):c.239G>T (p.Gly80Val)	Pathogenic
638539	NM_001099287.2(NIPAL4):c.284G>A (p.Gly95Glu)	Pathogenic
638540	NM_001099287.2(NIPAL4):c.348A>C (p.Glu116Asp)	Pathogenic
638541	NM_001099287.2(NIPAL4):c.369C>G (p.Tyr123Ter)	Pathogenic
638542	NM_001099287.2(NIPAL4):c.425+1G>A	Pathogenic
638543	NM_001099287.2(NIPAL4):c.426-3del	Pathogenic
638544	NM_001099287.2(NIPAL4):c.437C>T (p.Ser146Phe)	Pathogenic
638545	NM_001099287.2(NIPAL4):c.509C>G (p.Thr170Arg)	Pathogenic
638547	NM_001099287.2(NIPAL4):c.523del (p.His175fs)	Pathogenic
638548	NM_001099287.2(NIPAL4):c.650C>T (p.Pro217Leu)	Pathogenic
638550	NM_001099287.2(NIPAL4):c.703G>A (p.Gly235Arg)	Pathogenic
638551	NM_001099287.2(NIPAL4):c.753C>G (p.Asn251Lys)	Pathogenic
638552	NM_001099287.2(NIPAL4):c.828C>A (p.Ser276Arg)	Pathogenic
638553	NM_001099287.2(NIPAL4):c.1082del (p.Asn361fs)	Pathogenic
1175309	NM_001099287.2(NIPAL4):c.649C>G (p.Pro217Ala)	Likely pathogenic
1722366	NM_001099287.2(NIPAL4):c.4G>T (p.Glu2Ter)	Likely pathogenic
1804711	NM_001099287.2(NIPAL4):c.587-2A>G	Likely pathogenic

SpliceAI

1173 predictions. Top by Δscore:

Variant	Effect	Δscore
5:157463089:TCCA:T	acceptor_loss	1.0000
5:157463091:CA:C	acceptor_loss	1.0000
5:157463092:AGGT:A	acceptor_loss	1.0000
5:157463330:GCTG:G	donor_gain	1.0000
5:157463332:TGGTA:T	donor_loss	1.0000
5:157463333:GGT:G	donor_loss	1.0000
5:157463334:G:C	donor_loss	1.0000
5:157463335:T:A	donor_loss	1.0000
5:157467047:A:AG	acceptor_gain	1.0000
5:157467048:G:GG	acceptor_gain	1.0000
5:157467106:G:GG	donor_gain	1.0000
5:157468796:C:G	donor_gain	1.0000
5:157471650:C:CA	acceptor_gain	1.0000
5:157471650:C:G	acceptor_gain	1.0000
5:157471655:A:AG	acceptor_gain	1.0000
5:157471656:G:GA	acceptor_gain	1.0000
5:157471656:GT:G	acceptor_gain	1.0000
5:157471656:GTGCC:G	acceptor_gain	1.0000
5:157472327:CAAA:C	acceptor_loss	1.0000
5:157472328:A:AG	acceptor_gain	1.0000
5:157472328:AAAG:A	acceptor_gain	1.0000
5:157472328:AAAGG:A	acceptor_gain	1.0000
5:157472329:AAG:A	acceptor_gain	1.0000
5:157472330:A:G	acceptor_gain	1.0000
5:157472330:AG:A	acceptor_gain	1.0000
5:157472330:AGGGT:A	acceptor_loss	1.0000
5:157472331:G:A	acceptor_gain	1.0000
5:157472331:G:GG	acceptor_gain	1.0000
5:157460353:GAACG:G	donor_gain	0.9900
5:157460355:ACGG:A	donor_loss	0.9900

AlphaMissense

3024 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:157472610:T:C	F351L	0.998
5:157472612:C:A	F351L	0.998
5:157472612:C:G	F351L	0.998
5:157463273:A:C	S135R	0.997
5:157463275:C:A	S135R	0.997
5:157463275:C:G	S135R	0.997
5:157471736:A:C	S231R	0.997
5:157471738:C:A	S231R	0.997
5:157471738:C:G	S231R	0.997
5:157467084:T:A	W167R	0.995
5:157467084:T:C	W167R	0.995
5:157467094:G:A	G170E	0.995
5:157472590:T:C	L344P	0.995
5:157472598:G:C	A347P	0.995
5:157468799:A:C	S200R	0.994
5:157468801:T:A	S200R	0.994
5:157468801:T:G	S200R	0.994
5:157463274:G:T	S135I	0.993
5:157467093:G:A	G170R	0.993
5:157467093:G:C	G170R	0.993
5:157463287:G:C	K139N	0.992
5:157463287:G:T	K139N	0.992
5:157472438:C:G	C293W	0.992
5:157472610:T:A	F351I	0.992
5:157463298:T:C	L143P	0.991
5:157467086:G:C	W167C	0.991
5:157467086:G:T	W167C	0.991
5:157467087:T:A	W168R	0.991
5:157467087:T:C	W168R	0.991
5:157468731:G:A	G177E	0.991

dbSNP variants (sampled 300 via entrez): RS1000449061 (5:157469844 G>T), RS1001011675 (5:157465296 G>A), RS1001427182 (5:157458734 G>C), RS1001895690 (5:157461450 C>A), RS1002234861 (5:157466256 G>C), RS1002268351 (5:157467376 G>A,T), RS1002378246 (5:157467637 T>A), RS1002534870 (5:157460310 C>A,T), RS1002546916 (5:157464153 T>C), RS1002918288 (5:157470232 C>T), RS1003021823 (5:157468265 A>C), RS1003241569 (5:157467914 T>A), RS1003386133 (5:157469086 C>T), RS1003490472 (5:157462638 T>C), RS10037184 (5:157471221 G>C,T)

Disease associations

OMIM: gene MIM:609383 | disease phenotypes: MIM:612281, MIM:133200, MIM:242300

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive congenital ichthyosis 6	Definitive	Autosomal recessive
lamellar ichthyosis	Supportive	Autosomal recessive
congenital non-bullous ichthyosiform erythroderma	Supportive	Autosomal recessive

Mondo (5): autosomal recessive congenital ichthyosis 6 (MONDO:0012847), erythrokeratodermia variabilis et progressiva 1 (MONDO:0033010), lamellar ichthyosis (MONDO:0017778), autosomal recessive congenital ichthyosis (MONDO:0017265), congenital non-bullous ichthyosiform erythroderma (MONDO:0019306)

Orphanet (4): Lamellar ichthyosis (Orphanet:313), Congenital ichthyosiform erythroderma (Orphanet:79394), Erythrokeratodermia variabilis (Orphanet:317), Autosomal recessive congenital ichthyosis (Orphanet:281097)

HPO phenotypes

36 total (30 of 36 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:0000365	Hearing impairment
HP:0000389	Chronic otitis media
HP:0000491	Keratitis
HP:0000656	Ectropion
HP:0000958	Dry skin
HP:0000962	Hyperkeratosis
HP:0000966	Hypohidrosis
HP:0000982	Palmoplantar keratoderma
HP:0000989	Pruritus
HP:0001019	Erythroderma
HP:0001036	Parakeratosis
HP:0001508	Failure to thrive
HP:0001596	Alopecia
HP:0001597	Abnormal nail morphology
HP:0001944	Dehydration
HP:0002205	Recurrent respiratory infections
HP:0003577	Congenital onset
HP:0004322	Short stature
HP:0007479	Congenital nonbullous ichthyosiform erythroderma
HP:0007503	Generalized ichthyosis
HP:0008064	Ichthyosis
HP:0008070	Sparse hair
HP:0011039	Abnormal helix morphology
HP:0025092	Epidermal acanthosis
HP:0040162	Orthokeratosis
HP:0040189	Scaling skin

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009798_48	Asthma	2.000000e-10

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: transporter — SLC57 NiPA-like magnesium transporter family

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants, Occupational	increases expression	2
aristolochic acid I	increases expression	1
sotorasib	affects cotreatment, decreases expression	1
propionaldehyde	increases expression	1
butyraldehyde	increases expression	1
tobacco tar	decreases expression	1
potassium chromate(VI)	increases expression	1
1-hydroxypyrene	increases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
nutlin 3	affects cotreatment, increases expression	1
abrine	increases expression	1
trametinib	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	increases expression	1
Temozolomide	decreases expression	1
Aldehydes	increases expression	1
Arsenicals	increases expression	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Folic Acid	increases expression, affects cotreatment	1
Lipopolysaccharides	increases expression, decreases reaction	1
Methotrexate	affects cotreatment, increases expression	1
Nickel	increases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Tobacco Smoke Pollution	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01222000	PHASE3	UNKNOWN	Treatment of the Recessive Nonbullous Congenital Ichthyosis by the Epigallocatechine Cutaneous
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
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