Combined oxidative phosphorylation deficiency 40

disease

On this page

Also known as COXPD40

Summary

Combined oxidative phosphorylation deficiency 40 (MONDO:0030006) is a disease caused by QRSL1 (GenCC Strong), with 2 cohort genes.

At a glance

Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
Causal gene: QRSL1 (GenCC Strong)
Cohort genes: 2
ClinVar variants: 15

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

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

Identifiers

Disease identifiers

Field	Value
Canonical name	combined oxidative phosphorylation deficiency 40
Mondo ID	MONDO:0030006
OMIM	618835
Orphanet	570491
DOID	DOID:0112117
UMLS	C5394232
MedGen	1714731
GARD	0018006
Is cancer (heuristic)	no

Also known as: COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 40 · combined oxidative phosphorylation deficiency 40 · COXPD40

Data availability: 15 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 › combined oxidative phosphorylation deficiency 40

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

15 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
559413	NM_018292.5(QRSL1):c.555C>A (p.Tyr185Ter)	QRSL1	Pathogenic	criteria provided, single submitter
559414	NM_018292.5(QRSL1):c.398G>T (p.Gly133Val)	QRSL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
834718	NM_018292.5(QRSL1):c.350G>A (p.Gly117Glu)	QRSL1	Pathogenic	no assertion criteria provided
834719	NM_018292.5(QRSL1):c.850-3A>G	QRSL1	Pathogenic	criteria provided, multiple submitters, no conflicts
3780516	NM_018292.5(QRSL1):c.45del (p.Gly16fs)	QRSL1	Likely pathogenic	criteria provided, single submitter
559416	NM_018292.5(QRSL1):c.1279_1280delinsTT (p.Ala427Leu)	QRSL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1460859	NM_018292.5(QRSL1):c.16C>T (p.Leu6Phe)	LOC129996910	Uncertain significance	criteria provided, multiple submitters, no conflicts
2444389	NM_018292.5(QRSL1):c.677C>T (p.Ser226Leu)	QRSL1	Uncertain significance	criteria provided, single submitter
3064863	NM_018292.5(QRSL1):c.173G>T (p.Arg58Ile)	QRSL1	Uncertain significance	criteria provided, single submitter
3242046	NM_018292.5(QRSL1):c.1495C>T (p.Gln499Ter)	QRSL1	Uncertain significance	criteria provided, single submitter
3391693	NM_197968.4(ZMYM2):c.3079C>T (p.Pro1027Ser)	ZMYM2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3474007	NM_197968.4(ZMYM2):c.596A>G (p.Asp199Gly)	ZMYM2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1228689	NM_018292.5(QRSL1):c.381-47A>C	QRSL1	Benign	criteria provided, multiple submitters, no conflicts
1251173	NM_018292.5(QRSL1):c.1425G>A (p.Leu475=)	QRSL1	Benign	criteria provided, multiple submitters, no conflicts
1327928	NM_018292.5(QRSL1):c.557+49_557+50del	QRSL1	Benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 2 · 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
QRSL1	Strong	Autosomal recessive	combined oxidative phosphorylation deficiency 40	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
QRSL1	Orphanet:570491	QRSL1-related combined oxidative phosphorylation defect
ZMYM2	Orphanet:528084	Non-specific syndromic intellectual disability

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
QRSL1	HGNC:21020	ENSG00000130348	Q9H0R6	Glutamyl-tRNA(Gln) amidotransferase subunit A, mitochondrial	gencc,clinvar
ZMYM2	HGNC:12989	ENSG00000121741	Q9UBW7	Zinc finger MYM-type protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
QRSL1	Glutamyl-tRNA(Gln) amidotransferase subunit A, mitochondrial	Allows the formation of correctly charged Gln-tRNA(Gln) through the transamidation of misacylated Glu-tRNA(Gln) in the mitochondria.
ZMYM2	Zinc finger MYM-type protein 2	Involved in the negative regulation of transcription.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.228
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
QRSL1	Enzyme (other)	yes	6.3.5.7	Amidase, GatA, Amidase_dom
ZMYM2	Transcription factor	no		Znf_MYM, TRASH_dom, ZMYM2-like_C

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
biceps brachii	1
skeletal muscle tissue of biceps brachii	1
triceps brachii	1
oocyte	1
secondary oocyte	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
QRSL1	273	ubiquitous	marker	biceps brachii, triceps brachii, skeletal muscle tissue of biceps brachii
ZMYM2	294	ubiquitous	marker	sperm, oocyte, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
QRSL1	3,158
ZMYM2	2,565

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
QRSL1	Q9H0R6	93.40
ZMYM2	Q9UBW7	61.50

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 2 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
Signaling by cytosolic FGFR1 fusion mutants	1	634.4×	0.004	ZMYM2
Signaling by FLT3 fusion proteins	1	571.0×	0.004	ZMYM2
Signaling by FGFR1 in disease	1	292.8×	0.005	ZMYM2
Negative Regulation of CDH1 Gene Transcription	1	120.2×	0.008	ZMYM2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glutaminyl-tRNAGln biosynthesis via transamidation	1	2808.7×	0.001	QRSL1
mitochondrial translation	1	86.9×	0.021	QRSL1
regulation of protein stability	1	62.9×	0.021	QRSL1
negative regulation of DNA-templated transcription	1	15.8×	0.062	ZMYM2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
QRSL1	0	0
ZMYM2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
QRSL1	6.3.5.7	glutaminyl-tRNA synthase (glutamine-hydrolysing)

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	1	QRSL1
E	Difficult family or no structure, no drug	1	ZMYM2

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
QRSL1	0	—
ZMYM2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: QRSL1, ZMYM2