Mitochondrial trifunctional protein deficiency 2

Summary

Mitochondrial trifunctional protein deficiency 2 (MONDO:0958185) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 39

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial trifunctional protein deficiency 2
Mondo ID	MONDO:0958185
OMIM	620300
DOID	DOID:0060999
UMLS	C5830374
MedGen	1841010
GARD	0026962
Is cancer (heuristic)	no

Data availability: 39 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inherited lipid metabolism disorder › mitochondrial trifunctional protein deficiency › mitochondrial trifunctional protein deficiency 2

Related subtypes (1): mitochondrial trifunctional protein deficiency 1

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

39 retrieved; paginated sample, class counts are floors:

9 pathogenic, 7 uncertain significance, 7 conflicting classifications of pathogenicity, 6 pathogenic/likely pathogenic, 4 likely pathogenic, 4 benign, 1 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1075534	NM_000183.3(HADHB):c.97C>T (p.Arg33Ter)	HADHB	Pathogenic	criteria provided, multiple submitters, no conflicts
1217468	NM_000183.3(HADHB):c.1289T>C (p.Phe430Ser)	HADHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14844	NM_000183.3(HADHB):c.788A>G (p.Asp263Gly)	HADHB	Pathogenic	no assertion criteria provided
14845	NM_000183.3(HADHB):c.182G>A (p.Arg61His)	HADHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14846	NM_000183.3(HADHB):c.740G>A (p.Arg247His)	HADHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14847	NM_000183.3(HADHB):c.1331G>A (p.Arg444Lys)	HADHB	Pathogenic	no assertion criteria provided
14848	NM_000183.3(HADHB):c.776_777insT (p.Leu260fs)	HADHB	Pathogenic	no assertion criteria provided
14849	NM_000183.3(HADHB):c.1364T>G (p.Val455Gly)	HADHB	Pathogenic	criteria provided, multiple submitters, no conflicts
1526383	NM_000183.3(HADHB):c.583C>T (p.Arg195Ter)	HADHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
203752	NM_000183.3(HADHB):c.1059del (p.Gly354fs)	HADHB	Pathogenic	criteria provided, multiple submitters, no conflicts
253049	NM_000183.3(HADHB):c.357dup (p.Ala120fs)	HADHB	Pathogenic	no assertion criteria provided
2627356	NC_000002.11:g.(26477343_26486247)_(26486348_26492820)del	HADHB	Pathogenic	criteria provided, single submitter
2675989	NM_000183.3(HADHB):c.631-1G>A	HADHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3359235	NM_000183.3(HADHB):c.1390-515_1390-499del	HADHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
579455	NM_000183.3(HADHB):c.685C>T (p.Arg229Ter)	HADHB	Pathogenic	criteria provided, multiple submitters, no conflicts
1324526	NM_000183.3(HADHB):c.527C>G (p.Ser176Ter)	HADHB	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1722336	NM_000183.3(HADHB):c.811+1G>A	HADHB	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3237180	NM_000183.3(HADHB):c.1174_1176del (p.Ala392del)	HADHB	Likely pathogenic	criteria provided, single submitter
3586251	NM_000183.3(HADHB):c.65-1G>C	HADHB	Likely pathogenic	criteria provided, single submitter
1378781	NM_000183.3(HADHB):c.901G>A (p.Gly301Ser)	HADHB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2084834	NM_000183.3(HADHB):c.341A>G (p.Asn114Ser)	HADHB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
235337	NM_000183.3(HADHB):c.397A>G (p.Thr133Ala)	HADHB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3339681	NM_000183.3(HADHB):c.725A>G (p.Asp242Gly)	HADHB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
335406	NM_000183.3(HADHB):c.712C>T (p.Arg238Trp)	HADHB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
429516	NM_000183.3(HADHB):c.686G>A (p.Arg229Gln)	HADHB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
808706	NM_000183.3(HADHB):c.487G>A (p.Gly163Ser)	HADHB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031453	NM_000183.3(HADHB):c.493G>A (p.Val165Ile)	HADHB	Uncertain significance	criteria provided, single submitter
1305701	NM_000183.3(HADHB):c.1405G>A (p.Val469Met)	HADHB	Uncertain significance	criteria provided, multiple submitters, no conflicts
2432361	NM_000183.3(HADHB):c.1252A>G (p.Asn418Asp)	HADHB	Uncertain significance	criteria provided, single submitter
2432362	NM_000183.3(HADHB):c.1399A>C (p.Met467Leu)	HADHB	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HADHB	Orphanet:746	Mitochondrial trifunctional protein deficiency

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
HADHB	HGNC:4803	ENSG00000138029	P55084	Trifunctional enzyme subunit beta, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HADHB	Trifunctional enzyme subunit beta, mitochondrial	Mitochondrial trifunctional enzyme catalyzes the last three of the four reactions of the mitochondrial beta-oxidation pathway.

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)
HADHB	Other/Unknown	no		Thiolase, Thiolase-like, Thiolase_AS

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
deltoid	1
heart right ventricle	1
left ventricle myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HADHB	295	ubiquitous	marker	heart right ventricle, left ventricle myocardium, deltoid

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HADHB	4,047

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HADHB	P55084	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
Beta oxidation of myristoyl-CoA to lauroyl-CoA	1	3806.7×	5e-04	HADHB
Beta oxidation of palmitoyl-CoA to myristoyl-CoA	1	3806.7×	5e-04	HADHB
Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA	1	2284.0×	5e-04	HADHB
Beta oxidation of octanoyl-CoA to hexanoyl-CoA	1	2284.0×	5e-04	HADHB
Beta oxidation of hexanoyl-CoA to butanoyl-CoA	1	2284.0×	5e-04	HADHB
Acyl chain remodeling of CL	1	1903.3×	5e-04	HADHB
mitochondrial fatty acid beta-oxidation of unsaturated fatty acids	1	1903.3×	5e-04	HADHB
Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA	1	1903.3×	5e-04	HADHB

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
fatty acid beta-oxidation	1	374.5×	0.008	HADHB
cellular response to lipopolysaccharide	1	98.0×	0.013	HADHB
gene expression	1	79.9×	0.013	HADHB

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HADHB	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
HADHB	2	Binding:2

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	HADHB

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)
HADHB	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.