Autosomal recessive congenital ichthyosis 9

Summary

Autosomal recessive congenital ichthyosis 9 (MONDO:0014010) is a disease caused by CERS3 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: CERS3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 19

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive congenital ichthyosis 9
Mondo ID	MONDO:0014010
OMIM	615023
DOID	DOID:0060718
UMLS	C3554349
MedGen	767263
GARD	0015896
Is cancer (heuristic)	no

Also known as: ARCI9 · autosomal recessive congenital ichthyosis 9 · autosomal recessive congenital ichthyosis type 9 · ichthyosis, congenital, autosomal recessive 9 · ichthyosis, congenital, autosomal recessive type 9

Data availability: 19 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › congenital non-bullous ichthyosiform erythroderma › autosomal recessive congenital ichthyosis 9

Related subtypes (5): autosomal recessive congenital ichthyosis 2, autosomal recessive congenital ichthyosis 3, autosomal recessive congenital ichthyosis 6, autosomal recessive congenital ichthyosis 7, autosomal recessive congenital ichthyosis 10

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

19 retrieved; paginated sample, class counts are floors:

7 likely pathogenic, 5 benign, 4 uncertain significance, 3 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2691721	NM_001378789.1(CERS3):c.540G>A (p.Trp180Ter)	CERS3	Pathogenic	criteria provided, single submitter
633803	NM_001378789.1(CERS3):c.731G>A (p.Trp244Ter)	CERS3	Pathogenic	criteria provided, single submitter
64621	NM_001378789.1(CERS3):c.43T>C (p.Trp15Arg)	CERS3	Pathogenic	no assertion criteria provided
1180727	NM_001378789.1(CERS3):c.223C>T (p.Arg75Ter)	CERS3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3576919	NM_001378789.1(CERS3):c.873del (p.Met292fs)	CERS3	Likely pathogenic	criteria provided, single submitter
3576920	NM_001378789.1(CERS3):c.565del (p.Tyr189fs)	CERS3	Likely pathogenic	criteria provided, single submitter
3576921	NM_001378789.1(CERS3):c.466-1G>T	CERS3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3576922	NM_001378789.1(CERS3):c.303_304dup (p.Leu102fs)	CERS3	Likely pathogenic	criteria provided, single submitter
55838	NM_001378789.1(CERS3):c.609+1G>T	CERS3	Likely pathogenic	criteria provided, single submitter
804475	NM_001378789.1(CERS3):c.46del (p.Leu16fs)	CERS3	Likely pathogenic	criteria provided, single submitter
2585612	NM_001378789.1(CERS3):c.632A>T (p.His211Leu)	CERS3	Uncertain significance	criteria provided, single submitter
3068609	NM_001378789.1(CERS3):c.1000-85C>A	CERS3	Uncertain significance	criteria provided, single submitter
3779053	NM_001378789.1(CERS3):c.631C>G (p.His211Asp)	CERS3	Uncertain significance	criteria provided, single submitter
800985	NM_001378789.1(CERS3):c.530C>T (p.Ser177Phe)	CERS3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1209729	NM_001378789.1(CERS3):c.*75C>A	CERS3	Benign	criteria provided, multiple submitters, no conflicts
1209730	NM_001378789.1(CERS3):c.1108A>G (p.Arg370Gly)	CERS3	Benign	criteria provided, multiple submitters, no conflicts
1209731	NM_001378789.1(CERS3):c.999+60G>A	CERS3	Benign	criteria provided, multiple submitters, no conflicts
1209732	NM_001378789.1(CERS3):c.845+53C>T	CERS3	Benign	criteria provided, multiple submitters, no conflicts
1209733	NM_001378789.1(CERS3):c.159A>G (p.Arg53=)	CERS3	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
CERS3	Strong	Autosomal recessive	autosomal recessive congenital ichthyosis 9	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CERS3	Orphanet:363992	Ichthyosis-short stature-brachydactyly-microspherophakia syndrome
CERS3	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
CERS3	HGNC:23752	ENSG00000154227	Q8IU89	Ceramide synthase 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CERS3	Ceramide synthase 3	Ceramide synthase that catalyzes the transfer of the acyl chain from acyl-CoA to a sphingoid base, with high selectivity toward very- and ultra-long-chain fatty acyl-CoA (chain length greater than C22).

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CERS3	Transcription factor	no	2.3.1.24	HD, TLC-dom, Homeodomain-like_sf

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
esophagus mucosa	1
lower esophagus mucosa	1
skin of abdomen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CERS3	160	tissue_specific	marker	lower esophagus mucosa, skin of abdomen, esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CERS3	837

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CERS3	Q8IU89	87.52

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
Sphingolipid de novo biosynthesis	1	285.5×	0.004	CERS3

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
cornification	1	1053.2×	0.005	CERS3
ceramide biosynthetic process	1	421.3×	0.005	CERS3
sphingolipid biosynthetic process	1	358.6×	0.005	CERS3
keratinocyte differentiation	1	247.8×	0.005	CERS3
epidermis development	1	210.7×	0.005	CERS3

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
CERS3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CERS3	2.3.1.24, 2.3.1.298	sphingosine N-acyltransferase, ultra-long-chain ceramide synthase

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	CERS3

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)
CERS3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.