Autosomal recessive congenital ichthyosis 6

Summary

Autosomal recessive congenital ichthyosis 6 (MONDO:0012847) is a disease caused by NIPAL4 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: NIPAL4 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 103

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive congenital ichthyosis 6
Mondo ID	MONDO:0012847
OMIM	612281
DOID	DOID:0060715
UMLS	C2677065
MedGen	436851
GARD	0015547
Is cancer (heuristic)	no

Also known as: ARCI6 · autosomal recessive congenital ichthyosis type 6 · ichthyosis, congenital, autosomal recessive 6 · ichthyosis, congenital, autosomal recessive type 6

Data availability: 103 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › lamellar ichthyosis › autosomal recessive congenital ichthyosis 6

Related subtypes (5): ichthyosis, lamellar, autosomal dominant, autosomal recessive congenital ichthyosis 4A, autosomal recessive congenital ichthyosis 5, autosomal recessive congenital ichthyosis 3, autosomal recessive congenital ichthyosis 8

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

103 retrieved; paginated sample, class counts are floors:

41 uncertain significance, 24 pathogenic, 14 benign, 11 conflicting classifications of pathogenicity, 6 likely benign, 3 likely pathogenic, 2 pathogenic/likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
638533	NM_001099287.1(NIPAL4):c.2T>C (p.Met1Thr)	LOC129995124	Pathogenic	no assertion criteria provided
1729	NM_001099287.2(NIPAL4):c.247C>T (p.Arg83Ter)	NIPAL4	Pathogenic	criteria provided, multiple submitters, no conflicts
1730	A114N	NIPAL4	Pathogenic	no assertion criteria provided
1731	NM_001099287.2(NIPAL4):c.341C>A (p.Ala114Asp)	NIPAL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1732	NM_001099287.2(NIPAL4):c.586+1G>A	NIPAL4	Pathogenic	no assertion criteria provided
1994481	NM_001099287.2(NIPAL4):c.421del (p.Leu140_Ile141insTer)	NIPAL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372383	NM_001099287.2(NIPAL4):c.502G>A (p.Gly168Arg)	NIPAL4	Pathogenic	criteria provided, multiple submitters, no conflicts
3775110	NM_001099287.2(NIPAL4):c.586G>A (p.Gly196Arg)	NIPAL4	Pathogenic	criteria provided, single submitter
633804	NM_001099287.2(NIPAL4):c.897C>A (p.Tyr299Ter)	NIPAL4	Pathogenic	criteria provided, single submitter
633805	NM_001099287.2(NIPAL4):c.520_526del (p.Ile174fs)	NIPAL4	Pathogenic	criteria provided, single submitter
638534	NM_001099287.2(NIPAL4):c.37+5G>C	NIPAL4	Pathogenic	no assertion criteria provided
638535	NM_001099287.2(NIPAL4):c.97del (p.Leu33fs)	NIPAL4	Pathogenic	no assertion criteria provided
638537	NM_001099287.2(NIPAL4):c.239G>T (p.Gly80Val)	NIPAL4	Pathogenic	no assertion criteria provided
638539	NM_001099287.2(NIPAL4):c.284G>A (p.Gly95Glu)	NIPAL4	Pathogenic	no assertion criteria provided
638540	NM_001099287.2(NIPAL4):c.348A>C (p.Glu116Asp)	NIPAL4	Pathogenic	no assertion criteria provided
638541	NM_001099287.2(NIPAL4):c.369C>G (p.Tyr123Ter)	NIPAL4	Pathogenic	no assertion criteria provided
638542	NM_001099287.2(NIPAL4):c.425+1G>A	NIPAL4	Pathogenic	no assertion criteria provided
638543	NM_001099287.2(NIPAL4):c.426-3del	NIPAL4	Pathogenic	no assertion criteria provided
638544	NM_001099287.2(NIPAL4):c.437C>T (p.Ser146Phe)	NIPAL4	Pathogenic	no assertion criteria provided
638545	NM_001099287.2(NIPAL4):c.509C>G (p.Thr170Arg)	NIPAL4	Pathogenic	no assertion criteria provided
638547	NM_001099287.2(NIPAL4):c.523del (p.His175fs)	NIPAL4	Pathogenic	no assertion criteria provided
638548	NM_001099287.2(NIPAL4):c.650C>T (p.Pro217Leu)	NIPAL4	Pathogenic	no assertion criteria provided
638550	NM_001099287.2(NIPAL4):c.703G>A (p.Gly235Arg)	NIPAL4	Pathogenic	criteria provided, multiple submitters, no conflicts
638551	NM_001099287.2(NIPAL4):c.753C>G (p.Asn251Lys)	NIPAL4	Pathogenic	no assertion criteria provided
638552	NM_001099287.2(NIPAL4):c.828C>A (p.Ser276Arg)	NIPAL4	Pathogenic	no assertion criteria provided
638553	NM_001099287.2(NIPAL4):c.1082del (p.Asn361fs)	NIPAL4	Pathogenic	no assertion criteria provided
3220883	NM_001099287.2(NIPAL4):c.834G>T (p.Gln278His)	NIPAL4	Likely pathogenic	criteria provided, single submitter
3591902	NM_001099287.2(NIPAL4):c.-17C>A	NIPAL4	Likely pathogenic	criteria provided, single submitter
3591903	NM_001099287.2(NIPAL4):c.1105dup (p.Glu369fs)	NIPAL4	Likely pathogenic	criteria provided, single submitter
352508	NM_001099287.2(NIPAL4):c.193C>T (p.Leu65=)	NIPAL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · 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
NIPAL4	Definitive	Autosomal recessive	autosomal recessive congenital ichthyosis 6	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NIPAL4	Orphanet:313	Lamellar ichthyosis
NIPAL4	Orphanet:79394	Congenital ichthyosiform erythroderma

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NIPAL4	HGNC:28018	ENSG00000172548	Q0D2K0	Magnesium transporter NIPA4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NIPAL4	Magnesium transporter NIPA4	Acts as a Mg(2+) transporter.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NIPAL4	Other/Unknown	no		Mg_trans_NIPA, EmrE-like

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
skin of abdomen	1
skin of leg	1
upper arm skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NIPAL4	165	broad	marker	upper arm skin, skin of abdomen, skin of leg

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NIPAL4	540

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NIPAL4	Q0D2K0	78.91

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Miscellaneous transport and binding events	1	439.2×	0.002	NIPAL4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
magnesium ion transport	1	1203.7×	8e-04	NIPAL4

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NIPAL4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NIPAL4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NIPAL4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.