mitochondrial complex V (ATP synthase) deficiency, nuclear type 5

Summary

mitochondrial complex V (ATP synthase) deficiency, nuclear type 5 (MONDO:0020858) is a disease caused by ATP5F1D (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: ATP5F1D (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial complex V (ATP synthase) deficiency, nuclear type 5
Mondo ID	MONDO:0020858
OMIM	618120
DOID	DOID:0070463
UMLS	C4748269
MedGen	1648429
GARD	0018670
Is cancer (heuristic)	no

Also known as: MC5DN5 · Mitochondrial Complex 5 (ATP Synthase) Deficiency, ATP5F1D Type · mitochondrial complex v (atp synthase) deficiency · MITOCHONDRIAL COMPLEX V (ATP SYNTHASE) DEFICIENCY, NUCLEAR TYPE 5

Data availability: 6 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › mitochondrial respiratory chain complex deficiency › mitochondrial complex V (ATP synthase) deficiency, nuclear type 5

Related subtypes (8): mitochondrial complex V (ATP synthase) deficiency, nuclear type 1, mitochondrial complex V (ATP synthase) deficiency, nuclear type 2, mitochondrial complex V (ATP synthase) deficiency, nuclear type 3, mitochondrial complex V (ATP synthase) deficiency, nuclear type 4B, mitochondrial complex III deficiency, mitochondrial complex IV deficiency, nuclear-type, mitochondrial complex I deficiency, SDHC-related Mitochondrial Disease

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

6 retrieved; paginated sample, class counts are floors:

2 pathogenic, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic, 1 uncertain significance, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
453296	NM_001687.5(ATP5F1D):c.245C>T (p.Pro82Leu)	ATP5F1D	Pathogenic	no assertion criteria provided
489386	NM_001687.5(ATP5F1D):c.317T>G (p.Val106Gly)	ATP5F1D	Pathogenic	no assertion criteria provided
2413150	NM_007103.4(NDUFV1):c.475C>T (p.Arg159Ter)	NDUFV1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
693440	NC_012920.1(MT-ND5):m.12425del	MT-ND5	Likely pathogenic	reviewed by expert panel
1682802	NM_001687.5(ATP5F1D):c.25C>T (p.Arg9Cys)	ATP5F1D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2439381	NM_001687.5(ATP5F1D):c.349G>T (p.Glu117Ter)	ATP5F1D	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 6 · 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
ATP5F1D	Strong	Autosomal recessive	mitochondrial complex V (ATP synthase) deficiency, nuclear type 5	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATP5F1D	Orphanet:254913	Isolated ATP synthase deficiency
MT-ND5	Orphanet:104	Leber hereditary optic neuropathy
MT-ND5	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND5	Orphanet:550	MELAS
MT-ND5	Orphanet:551	MERRF
NDUFV1	Orphanet:2609	Isolated complex I deficiency

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
ATP5F1D	HGNC:837	ENSG00000099624	P30049	ATP synthase F(1) complex subunit delta, mitochondrial	gencc,clinvar
MT-ND5	HGNC:7461	ENSG00000198786	P03915	NADH-ubiquinone oxidoreductase chain 5	clinvar
NDUFV1	HGNC:7716	ENSG00000167792	P49821	NADH dehydrogenase [ubiquinone] flavoprotein 1, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATP5F1D	ATP synthase F(1) complex subunit delta, mitochondrial	Subunit delta, of the mitochondrial membrane ATP synthase complex (F(1)F(0) ATP synthase or Complex V) that produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes o…
MT-ND5	NADH-ubiquinone oxidoreductase chain 5	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.
NDUFV1	NADH dehydrogenase [ubiquinone] flavoprotein 1, mitochondrial	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATP5F1D	Other/Unknown	no		ATP_synth_F1_dsu/esu, ATP_synth_F1_dsu/esu_N, ATPsynth_dsu/esu_N
MT-ND5	Other/Unknown	no		Proton_antipo_N, ND/Mrp_TM, NU5C-like
NDUFV1	Other/Unknown	no		NADH-UbQ_OxRdtase_51kDa_CS, NADH-UbQ_OxRdtase_suF, Nuo51_FMN-bd

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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
apex of heart	2
hindlimb stylopod muscle	1
mucosa of transverse colon	1
heart right ventricle	1
lateral nuclear group of thalamus	1
postcentral gyrus	1
metanephros cortex	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP5F1D	292	ubiquitous	marker	apex of heart, hindlimb stylopod muscle, mucosa of transverse colon
MT-ND5	247	ubiquitous	marker	heart right ventricle, postcentral gyrus, lateral nuclear group of thalamus
NDUFV1	292	ubiquitous	marker	apex of heart, right hemisphere of cerebellum, metanephros cortex

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NDUFV1	3,982
ATP5F1D	3,748
MT-ND5	2,825

Intra-cohort edges

A	B	Sources
ATP5F1D	NDUFV1	string_interaction
MT-ND5	NDUFV1	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP5F1D	P30049	10
MT-ND5	P03915	7
NDUFV1	P49821	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Complex I biogenesis	2	110.3×	0.001	MT-ND5, NDUFV1
Mitochondrial protein degradation	2	76.1×	0.001	MT-ND5, NDUFV1
Respiratory electron transport	2	63.4×	0.001	MT-ND5, NDUFV1
Aerobic respiration and respiratory electron transport	2	59.0×	0.001	ATP5F1D, NDUFV1
Formation of ATP by chemiosmotic coupling	1	190.3×	0.012	ATP5F1D
Cristae formation	1	115.3×	0.016	ATP5F1D
Mitochondrial biogenesis	1	56.0×	0.028	ATP5F1D
Metabolism	2	7.7×	0.029	ATP5F1D, NDUFV1
Mitochondrial translation termination	1	36.6×	0.033	MT-ND5
Organelle biogenesis and maintenance	1	22.0×	0.049	ATP5F1D
Metabolism of proteins	1	4.1×	0.223	NDUFV1

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
proton motive force-driven mitochondrial ATP synthesis	3	263.3×	3e-07	ATP5F1D, MT-ND5, NDUFV1
aerobic respiration	3	247.8×	3e-07	ATP5F1D, MT-ND5, NDUFV1
mitochondrial electron transport, NADH to ubiquinone	2	239.0×	8e-05	MT-ND5, NDUFV1
electron transport coupled proton transport	1	1404.3×	0.002	MT-ND5
mitochondrial proton-transporting ATP synthase complex assembly	1	702.2×	0.003	ATP5F1D
mitochondrial ATP synthesis coupled electron transport	1	624.1×	0.003	NDUFV1
response to copper ion	1	510.7×	0.003	ATP5F1D
proton motive force-driven ATP synthesis	1	267.5×	0.005	ATP5F1D
response to hydrogen peroxide	1	156.0×	0.008	MT-ND5
mitochondrial respiratory chain complex I assembly	1	137.0×	0.008	MT-ND5
response to hypoxia	1	31.9×	0.031	MT-ND5

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 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
ATP5F1D	0	0
MT-ND5	0	0
NDUFV1	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
NDUFV1	5	Binding:5
MT-ND5	4	Binding:4
ATP5F1D	1	Binding:1

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	ATP5F1D, MT-ND5, NDUFV1

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)
ATP5F1D	1	—
MT-ND5	4	—
NDUFV1	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.