mitochondrial complex V (ATP synthase) deficiency, nuclear type 1

Summary

mitochondrial complex V (ATP synthase) deficiency, nuclear type 1 (MONDO:0011421) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 47

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 1
Mondo ID	MONDO:0011421
OMIM	604273
DOID	DOID:0050768
UMLS	C3276276
MedGen	477906
GARD	0018660
Is cancer (heuristic)	no

Also known as: ATPAF2 mitochondrial proton-transporting ATP synthase complex deficiency · Complex 5 mitochondrial respiratory chain deficiency · MC5DN1 · mitochondrial complex V (ATP synthase) deficiency, nuclear type 1 · mitochondrial complex V deficiency · mitochondrial proton-transporting ATP synthase complex deficiency caused by mutation in ATPAF2

Data availability: 47 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 1

Related subtypes (8): 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 V (ATP synthase) deficiency, nuclear type 5, 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

47 retrieved; paginated sample, class counts are floors:

27 uncertain significance, 6 conflicting classifications of pathogenicity, 6 benign, 3 benign/likely benign, 3 likely pathogenic, 1 no classifications from unflagged records, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
4845818	NM_145691.4(ATPAF2):c.436G>T (p.Glu146Ter)	ATPAF2	Likely pathogenic	criteria provided, single submitter
4849379	NM_145691.4(ATPAF2):c.179-2A>G	ATPAF2	Likely pathogenic	criteria provided, single submitter
930235	NM_145691.4(ATPAF2):c.98del (p.Ile33fs)	ATPAF2	Likely pathogenic	criteria provided, single submitter
136466	NM_145691.4(ATPAF2):c.346T>C (p.Leu116=)	ATPAF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214137	NM_145691.4(ATPAF2):c.785T>C (p.Leu262Pro)	ATPAF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
322095	NM_145691.4(ATPAF2):c.634G>T (p.Ala212Ser)	ATPAF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
890505	NM_145691.4(ATPAF2):c.565C>G (p.Arg189Gly)	ATPAF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
890506	NM_145691.4(ATPAF2):c.422+11T>C	ATPAF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
422342	NM_145691.4(ATPAF2):c.133+1G>T	LOC130060409	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1027768	NM_145691.4(ATPAF2):c.480A>C (p.Pro160=)	ATPAF2	Uncertain significance	criteria provided, single submitter
1032471	NM_145691.4(ATPAF2):c.713G>A (p.Arg238His)	ATPAF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1995	NM_145691.4(ATPAF2):c.280T>A (p.Trp94Arg)	ATPAF2	no classifications from unflagged records	no classifications from unflagged records
214135	NM_145691.4(ATPAF2):c.40C>G (p.Arg14Gly)	ATPAF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
214138	NM_145691.4(ATPAF2):c.802G>A (p.Ala268Thr)	ATPAF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
214139	NM_145691.4(ATPAF2):c.389C>A (p.Ala130Glu)	ATPAF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2439406	NM_145691.4(ATPAF2):c.511G>T (p.Val171Leu)	ATPAF2	Uncertain significance	criteria provided, single submitter
322089	NM_145691.4(ATPAF2):c.*378A>T	ATPAF2	Uncertain significance	criteria provided, single submitter
322090	NM_145691.4(ATPAF2):c.*337T>C	ATPAF2	Uncertain significance	criteria provided, single submitter
322091	NM_145691.4(ATPAF2):c.*194C>A	ATPAF2	Uncertain significance	criteria provided, single submitter
322093	NM_145691.4(ATPAF2):c.*132C>T	ATPAF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
322096	NM_145691.4(ATPAF2):c.250G>A (p.Glu84Lys)	ATPAF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
322097	NM_145691.4(ATPAF2):c.-1G>T	ATPAF2	Uncertain significance	criteria provided, single submitter
3362749	NM_145691.4(ATPAF2):c.700G>A (p.Val234Met)	ATPAF2	Uncertain significance	criteria provided, single submitter
429844	NM_145691.4(ATPAF2):c.8G>A (p.Arg3Lys)	ATPAF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
635075	NM_145691.4(ATPAF2):c.412G>A (p.Asp138Asn)	ATPAF2	Uncertain significance	criteria provided, single submitter
888801	NM_145691.4(ATPAF2):c.*108C>T	ATPAF2	Uncertain significance	criteria provided, single submitter
888802	NM_145691.4(ATPAF2):c.*54C>T	ATPAF2	Uncertain significance	criteria provided, single submitter
888803	NM_145691.4(ATPAF2):c.*26G>C	ATPAF2	Uncertain significance	criteria provided, single submitter
890507	NM_145691.4(ATPAF2):c.113G>T (p.Arg38Leu)	ATPAF2	Uncertain significance	criteria provided, multiple submitters, no conflicts
891000	NM_145691.4(ATPAF2):c.*526C>T	ATPAF2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
ATPAF2	Supportive	Autosomal recessive	mitochondrial proton-transporting ATP synthase complex deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATPAF2	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
ATPAF2	HGNC:18802	ENSG00000171953	Q8N5M1	ATP synthase mitochondrial F1 complex assembly factor 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATPAF2	ATP synthase mitochondrial F1 complex assembly factor 2	Plays a role in the assembly of the F1 component of the mitochondrial ATP synthase (ATPase).

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)
ATPAF2	Other/Unknown	no		ATP12_ATP_synth-F1-assembly, ATP12_ortho_dom_sf, ATP12_ATP_synth-F1-assembly_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
hindlimb stylopod muscle	1
left testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATPAF2	226	ubiquitous	marker	right testis, left testis, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATPAF2	2,081

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATPAF2	Q8N5M1	86.07

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
proton-transporting ATP synthase complex assembly	1	16852.0×	1e-04	ATPAF2
mitochondrial proton-transporting ATP synthase complex assembly	1	2106.5×	5e-04	ATPAF2

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
ATPAF2	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	ATPAF2

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)
ATPAF2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.