Pancreatic insufficiency-anemia-hyperostosis syndrome

Summary

Pancreatic insufficiency-anemia-hyperostosis syndrome (MONDO:0012992) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 7

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	pancreatic insufficiency-anemia-hyperostosis syndrome
Mondo ID	MONDO:0012992
MeSH	C567195
OMIM	612714
Orphanet	199337
SNOMED CT	722207000
UMLS	C2675184
MedGen	436369
GARD	0017095
Is cancer (heuristic)	no

Also known as: pancreatic insufficiency, dyserythropoietic anemia, calvarial hyperostosis syndrome

Data availability: 7 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › pancreas disorder › exocrine pancreatic insufficiency › pancreatic insufficiency-anemia-hyperostosis syndrome

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

7 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 2 conflicting classifications of pathogenicity, 1 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1032977	NM_032609.3(COX4I2):c.175G>C (p.Ala59Pro)	COX4I2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2073077	NM_032609.3(COX4I2):c.333C>G (p.Phe111Leu)	COX4I2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2154681	NM_032609.3(COX4I2):c.28G>A (p.Val10Met)	COX4I2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2655	NM_032609.3(COX4I2):c.412G>A (p.Glu138Lys)	COX4I2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3893069	NM_032609.3(COX4I2):c.348dup (p.Ala117fs)	COX4I2	Uncertain significance	criteria provided, single submitter
618043	NM_032609.3(COX4I2):c.88G>C (p.Gly30Arg)	COX4I2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
811601	NM_032609.3(COX4I2):c.408G>A (p.Thr136=)	COX4I2	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · Orphanet: 1 · 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
COX4I2	Supportive	Autosomal recessive	pancreatic insufficiency-anemia-hyperostosis syndrome

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COX4I2	Orphanet:199337	Pancreatic insufficiency-anemia-hyperostosis syndrome

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
COX4I2	HGNC:16232	ENSG00000131055	Q96KJ9	Cytochrome c oxidase subunit 4 isoform 2, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COX4I2	Cytochrome c oxidase subunit 4 isoform 2, mitochondrial	Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation.

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)
COX4I2	Other/Unknown	no		Cyt_c_oxidase_su4_fam, Cyt_c_oxidase_su4, Cyt_c_oxidase_su4_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
apex of heart	1
right lung	1
upper lobe of left lung	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COX4I2	196	tissue_specific	marker	apex of heart, right lung, upper lobe of left lung

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COX4I2	1,775

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
COX4I2	Q96KJ9	80.84

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Complex IV assembly	1	228.4×	0.010	COX4I2
Cytoprotection by HMOX1	1	184.2×	0.010	COX4I2
TP53 Regulates Metabolic Genes	1	129.8×	0.010	COX4I2
Respiratory electron transport	1	95.2×	0.011	COX4I2

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
mitochondrial electron transport, cytochrome c to oxygen	1	766.0×	0.003	COX4I2
cellular respiration	1	432.1×	0.003	COX4I2
generation of precursor metabolites and energy	1	343.9×	0.003	COX4I2

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
COX4I2	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	COX4I2

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)
COX4I2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.