Autosomal recessive congenital ichthyosis 2

Summary

Autosomal recessive congenital ichthyosis 2 (MONDO:0009439) is a disease caused by ALOX12B (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: ALOX12B (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 230

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive congenital ichthyosis 2
Mondo ID	MONDO:0009439
OMIM	242100
DOID	DOID:0060710
NCIT	C132827
UMLS	C3888093
MedGen	854762
GARD	0015187
Is cancer (heuristic)	no

Also known as: ARCI2 · autosomal recessive congenital ichthyosis type 2 · ichthyosiform erythroderma, Brocq congenital, nonbullous form · ichthyosiform erythroderma, congenital, nonbullous, 1 · ichthyosiform erythroderma, nonbullous congenital, 1 · ichthyosis, congenital, autosomal recessive 2 · ichthyosis, congenital, autosomal recessive type 2 · NBCIE · NCIE

Data availability: 230 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › epidermal disease › ichthyosis › inherited ichthyosis › autosomal recessive congenital ichthyosis › self-healing collodion baby › autosomal recessive congenital ichthyosis 2

Related subtypes (1): autosomal recessive congenital ichthyosis 3

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

230 retrieved; paginated sample, class counts are floors:

94 pathogenic, 64 uncertain significance, 25 conflicting classifications of pathogenicity, 16 likely pathogenic, 16 pathogenic/likely pathogenic, 11 benign, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1380312	NM_001139.3(ALOX12B):c.1926+1G>A	ALOX12B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1398067	NM_001139.3(ALOX12B):c.1158dup (p.Tyr387fs)	ALOX12B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1526047	NM_001139.3(ALOX12B):c.1625_1626del (p.Lys542fs)	ALOX12B	Pathogenic	criteria provided, multiple submitters, no conflicts
212729	NM_001139.3(ALOX12B):c.1579G>A (p.Val527Met)	ALOX12B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265037	NM_001139.3(ALOX12B):c.242del (p.Pro81fs)	ALOX12B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265039	NM_001139.3(ALOX12B):c.1790C>A (p.Ala597Glu)	ALOX12B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3021156	NM_001139.3(ALOX12B):c.799dup (p.Gln267fs)	ALOX12B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382516	NM_001139.3(ALOX12B):c.1693C>T (p.Arg565Ter)	ALOX12B	Pathogenic	criteria provided, single submitter
373376	NM_001139.3(ALOX12B):c.530G>A (p.Trp177Ter)	ALOX12B	Pathogenic	criteria provided, multiple submitters, no conflicts
386689	NM_001139.3(ALOX12B):c.1163C>T (p.Ala388Val)	ALOX12B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39538	NM_001139.3(ALOX12B):c.340C>T (p.Arg114Trp)	ALOX12B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39539	NM_001139.3(ALOX12B):c.1294C>T (p.Arg432Ter)	ALOX12B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39540	NM_001139.3(ALOX12B):c.2036G>T (p.Arg679Leu)	ALOX12B	Pathogenic	no assertion criteria provided
39541	NM_001139.3(ALOX12B):c.1180G>A (p.Glu394Lys)	ALOX12B	Pathogenic	no assertion criteria provided
39544	NM_001139.3(ALOX12B):c.353-1G>A	ALOX12B	Pathogenic	no assertion criteria provided
39545	NM_001139.3(ALOX12B):c.1642C>T (p.Arg548Trp)	ALOX12B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39546	NM_001139.3(ALOX12B):c.1562A>G (p.Tyr521Cys)	ALOX12B	Pathogenic	criteria provided, multiple submitters, no conflicts
39547	NM_001139.3(ALOX12B):c.199A>T (p.Ile67Phe)	ALOX12B	Pathogenic	no assertion criteria provided
437455	NM_001139.3(ALOX12B):c.527+2T>G	ALOX12B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
437467	NM_001139.3(ALOX12B):c.353-2A>G	ALOX12B	Pathogenic	criteria provided, multiple submitters, no conflicts
6082	NM_001139.3(ALOX12B):c.1389del (p.Phe463fs)	ALOX12B	Pathogenic	no assertion criteria provided
6083	NM_001139.3(ALOX12B):c.1277T>C (p.Leu426Pro)	ALOX12B	Pathogenic	no assertion criteria provided
6084	NM_001139.3(ALOX12B):c.1734C>A (p.His578Gln)	ALOX12B	Pathogenic	no assertion criteria provided
633823	NM_001139.3(ALOX12B):c.149_353del (p.Val50fs)	ALOX12B	Pathogenic	criteria provided, single submitter
633825	NM_001139.3(ALOX12B):c.286_287dup (p.Tyr97fs)	ALOX12B	Pathogenic	criteria provided, single submitter
633827	NM_001139.3(ALOX12B):c.1350dup (p.Leu451fs)	ALOX12B	Pathogenic	criteria provided, multiple submitters, no conflicts
803318	NM_001139.3(ALOX12B):c.435-2A>G	ALOX12B	Pathogenic	criteria provided, single submitter
872119	NM_001139.3(ALOX12B):c.1148C>T (p.Thr383Met)	ALOX12B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
982978	NM_001139.3(ALOX12B):c.1272dup (p.Lys425fs)	ALOX12B	Pathogenic	criteria provided, multiple submitters, no conflicts
995475	NM_001139.3(ALOX12B):c.864del (p.Val289fs)	ALOX12B	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 8 · 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
ALOX12B	Definitive	Autosomal recessive	autosomal recessive congenital ichthyosis 2	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALOX12B	Orphanet:281122	Self-improving collodion baby
ALOX12B	Orphanet:313	Lamellar ichthyosis
ALOX12B	Orphanet:79394	Congenital ichthyosiform erythroderma
SULT2B1	Orphanet:313	Lamellar ichthyosis
SULT2B1	Orphanet:79394	Congenital ichthyosiform erythroderma
ALOXE3	Orphanet:281122	Self-improving collodion baby
ALOXE3	Orphanet:313	Lamellar ichthyosis
ALOXE3	Orphanet:79394	Congenital ichthyosiform erythroderma

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ALOX12B	HGNC:430	ENSG00000179477	O75342	Arachidonate 12-lipoxygenase, 12R-type	gencc,clinvar
SULT2B1	HGNC:11459	ENSG00000088002	O00204	Sulfotransferase 2B1	clinvar
ALOXE3	HGNC:13743	ENSG00000179148	Q9BYJ1	Hydroperoxide isomerase ALOXE3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALOX12B	Arachidonate 12-lipoxygenase, 12R-type	Catalyzes the regio and stereo-specific incorporation of a single molecule of dioxygen into free and esterified polyunsaturated fatty acids generating lipid hydroperoxides that can be further reduced to the corresponding hydroxy species.
SULT2B1	Sulfotransferase 2B1	Sulfotransferase that utilizes 3’-phospho-5’-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfate conjugation.
ALOXE3	Hydroperoxide isomerase ALOXE3	Non-heme iron-containing lipoxygenase which is atypical in that it displays a prominent hydroperoxide isomerase activity and a reduced lipoxygenases activity.

Protein-family classification

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

Family distribution

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

Family	Genes	Fold	FDR
Enzyme (other)	2	8.0×	0.039
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALOX12B	Enzyme (other)	yes	1.13.11.31	LipOase, PLAT/LH2_dom, LipOase_mml
SULT2B1	Other/Unknown	no		Sulfotransferase_dom, P-loop_NTPase
ALOXE3	Enzyme (other)	yes	4.2.1.152	LipOase, PLAT/LH2_dom, LipOase_mml

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
skin of abdomen	3
skin of leg	2
zone of skin	2
esophagus mucosa	1
lower esophagus mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALOX12B	168	broad	yes	skin of leg, skin of abdomen, zone of skin
SULT2B1	198	broad	marker	lower esophagus mucosa, esophagus mucosa, skin of abdomen
ALOXE3	141	tissue_specific	yes	skin of leg, skin of abdomen, zone of skin

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALOXE3	1,129
ALOX12B	1,126
SULT2B1	953

Intra-cohort edges

A	B	Sources
ALOX12B	ALOXE3	intact
ALOX12B	SULT2B1	string_interaction
ALOXE3	SULT2B1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SULT2B1	O00204	4
ALOXE3	Q9BYJ1	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ALOX12B	O75342	92.07

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Synthesis of 12-eicosatetraenoic acid derivatives	2	1087.6×	6e-06	ALOX12B, ALOXE3
Arachidonate metabolism	2	380.7×	3e-05	ALOX12B, ALOXE3
Fatty acid metabolism	2	87.5×	3e-04	ALOX12B, ALOXE3
Metabolism of lipids	2	21.0×	0.004	ALOX12B, ALOXE3
Cytosolic sulfonation of small molecules	1	173.0×	0.007	SULT2B1
Metabolism	2	7.7×	0.021	ALOX12B, ALOXE3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
lipid oxidation	2	1404.3×	6e-06	ALOX12B, ALOXE3
hepoxilin biosynthetic process	2	1404.3×	6e-06	ALOX12B, ALOXE3
lipoxygenase pathway	2	1021.3×	8e-06	ALOX12B, ALOXE3
sphingolipid metabolic process	2	660.9×	2e-05	ALOX12B, ALOXE3
linoleic acid metabolic process	2	468.1×	2e-05	ALOX12B, ALOXE3
arachidonate metabolic process	2	321.0×	4e-05	ALOX12B, ALOXE3
establishment of skin barrier	2	303.6×	4e-05	ALOX12B, ALOXE3
ceramide biosynthetic process	2	280.9×	4e-05	ALOX12B, ALOXE3
protein lipidation	1	1123.5×	0.002	ALOX12B
positive regulation of mucus secretion	1	1123.5×	0.002	ALOX12B
positive regulation of epidermal cell differentiation	1	702.2×	0.003	SULT2B1
peroxisome proliferator activated receptor signaling pathway	1	510.7×	0.003	ALOXE3
3’-phosphoadenosine 5’-phosphosulfate metabolic process	1	374.5×	0.004	SULT2B1
sulfation	1	351.1×	0.004	SULT2B1
sensory perception of pain	1	124.8×	0.011	ALOXE3
steroid metabolic process	1	112.3×	0.012	SULT2B1
cholesterol metabolic process	1	65.3×	0.019	SULT2B1
fat cell differentiation	1	60.4×	0.019	ALOXE3
positive regulation of MAPK cascade	1	26.9×	0.041	ALOX12B
negative regulation of cell population proliferation	1	14.0×	0.073	SULT2B1
positive regulation of gene expression	1	12.9×	0.075	ALOX12B

Therapeutics

Drug target analysis

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

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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ALOX12B	0	0
SULT2B1	0	0
ALOXE3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
SULT2B1	2	ADMET:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALOX12B	1.13.11.31	arachidonate 12-lipoxygenase
ALOXE3	4.2.1.152	hydroperoxy icosatetraenoate dehydratase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	1	ALOXE3
D	Druggable family + AlphaFold only, no drug	1	ALOX12B
E	Difficult family or no structure, no drug	1	SULT2B1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ALOX12B	0	—
SULT2B1	2	—
ALOXE3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.