mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A

Summary

mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A (MONDO:0957254) is a disease caused by ATP5F1A (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: ATP5F1A (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 8

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 4A
Mondo ID	MONDO:0957254
OMIM	620358
DOID	DOID:0070461
UMLS	C5830480
MedGen	1841116
GARD	0026798
Is cancer (heuristic)	no

Data availability: 8 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 › combined oxidative phosphorylation deficiency › mitochondrial proton-transporting ATP synthase complex deficiency › mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A

Related subtypes (7): mitochondrial complex V (ATP synthase) deficiency, nuclear type 1, mitochondrial complex V (ATP synthase) deficiency, nuclear type 3, mitochondrial complex V (ATP synthase) deficiency, nuclear type 4B, combined oxidative phosphorylation deficiency 22, mitochondrial complex 5 (ATP synthase) deficiency, mitochondrial type 1, mitochondrial complex 5 (ATP synthase) deficiency, nuclear type 6, mitochondrial complex V (ATP synthase) deficiency, nuclear type 7

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

8 retrieved; paginated sample, class counts are floors:

3 conflicting classifications of pathogenicity, 3 uncertain significance, 1 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
432972	NM_004046.6(ATP5F1A):c.620G>A (p.Arg207His)	ATP5F1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2572074	NM_004046.6(ATP5F1A):c.1252G>A (p.Gly418Arg)	ATP5F1A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1185778	NM_004046.6(ATP5F1A):c.545G>A (p.Arg182Gln)	ATP5F1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1321065	NM_004046.6(ATP5F1A):c.1037C>T (p.Ser346Phe)	ATP5F1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2177979	NM_004046.6(ATP5F1A):c.504G>A (p.Thr168=)	ATP5F1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2459715	NM_004046.6(ATP5F1A):c.505C>T (p.Arg169Cys)	ATP5F1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
3907676	NM_004046.6(ATP5F1A):c.385G>A (p.Asp129Asn)	ATP5F1A	Uncertain significance	criteria provided, single submitter
50353	NM_004046.6(ATP5F1A):c.985C>T (p.Arg329Cys)	ATP5F1A	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
ATP5F1A	Strong	Autosomal dominant	mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATP5F1A	Orphanet:254913	Isolated ATP synthase 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
ATP5F1A	HGNC:823	ENSG00000152234	P25705	ATP synthase F(1) complex subunit alpha, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATP5F1A	ATP synthase F(1) complex subunit alpha, mitochondrial	Subunit alpha, 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…

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)
ATP5F1A	Other/Unknown	no		ATPase_F1/V1/A1_a/bsu_nucl-bd, ATP_synth_asu_C, ATPase_F1/V1/A1_a/bsu_N

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 squamous epithelium	1
heart right ventricle	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP5F1A	295	ubiquitous	marker	heart right ventricle, esophagus squamous epithelium, renal medulla

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP5F1A	6,160

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP5F1A	P25705	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
Formation of ATP by chemiosmotic coupling	1	571.0×	0.012	ATP5F1A
Cristae formation	1	346.1×	0.012	ATP5F1A
Protein localization	1	190.3×	0.012	ATP5F1A
Mitochondrial protein import	1	167.9×	0.012	ATP5F1A
Mitochondrial biogenesis	1	167.9×	0.012	ATP5F1A
Mitochondrial protein degradation	1	114.2×	0.015	ATP5F1A
Aerobic respiration and respiratory electron transport	1	88.5×	0.016	ATP5F1A
Organelle biogenesis and maintenance	1	66.0×	0.019	ATP5F1A
Metabolism of proteins	1	12.4×	0.086	ATP5F1A
Metabolism	1	11.6×	0.086	ATP5F1A

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
ATP biosynthetic process	1	991.3×	0.003	ATP5F1A
cellular response to nitric oxide	1	936.2×	0.003	ATP5F1A
proton motive force-driven ATP synthesis	1	802.5×	0.003	ATP5F1A
response to muscle activity	1	581.1×	0.003	ATP5F1A
cellular response to dexamethasone stimulus	1	581.1×	0.003	ATP5F1A
negative regulation of endothelial cell proliferation	1	543.6×	0.003	ATP5F1A
positive regulation of blood vessel endothelial cell migration	1	391.9×	0.004	ATP5F1A
proton motive force-driven mitochondrial ATP synthesis	1	263.3×	0.005	ATP5F1A
response to ethanol	1	146.5×	0.008	ATP5F1A
lipid metabolic process	1	91.6×	0.011	ATP5F1A

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
ATP5F1A	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
ATP5F1A	6	Binding:6

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	ATP5F1A

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)
ATP5F1A	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.