Combined oxidative phosphorylation defect type 14

Summary

Combined oxidative phosphorylation defect type 14 (MONDO:0013986) is a disease caused by FARS2 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FARS2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 510

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	combined oxidative phosphorylation defect type 14
Mondo ID	MONDO:0013986
OMIM	614946
Orphanet	319519
DOID	DOID:0111477
UMLS	C4755312
MedGen	1663069
GARD	0017455
Is cancer (heuristic)	no

Also known as: combined oxidative phosphorylation deficiency 14 · combined oxidative phosphorylation deficiency caused by mutation in FARS2 · combined oxidative phosphorylation deficiency type 14 · COXPD14 · FARS2 combined oxidative phosphorylation deficiency

Data availability: 510 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 defect type 14

Related subtypes (57): severe X-linked mitochondrial encephalomyopathy, hepatoencephalopathy due to combined oxidative phosphorylation defect type 1, combined oxidative phosphorylation defect type 2, fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3, combined oxidative phosphorylation defect type 4, hypotonia with lactic acidemia and hyperammonemia, combined oxidative phosphorylation defect type 7, combined oxidative phosphorylation defect type 8, combined oxidative phosphorylation defect type 9, mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency, combined oxidative phosphorylation defect type 11, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome, combined oxidative phosphorylation defect type 13, combined oxidative phosphorylation defect type 15, infantile hypertrophic cardiomyopathy due to MRPL44 deficiency, combined oxidative phosphorylation defect type 17, growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndrome, combined oxidative phosphorylation deficiency 19, combined oxidative phosphorylation defect type 20, combined oxidative phosphorylation defect type 21, mitochondrial proton-transporting ATP synthase complex deficiency, combined oxidative phosphorylation defect type 23, combined oxidative phosphorylation defect type 24, combined oxidative phosphorylation defect type 25, combined oxidative phosphorylation defect type 26, combined oxidative phosphorylation defect type 27, combined oxidative phosphorylation deficiency 28, combined oxidative phosphorylation deficiency 29, combined oxidative phosphorylation defect type 30, lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome, combined oxidative phosphorylation deficiency 40, combined oxidative phosphorylation deficiency 41, combined oxidative phosphorylation deficiency 42, combined oxidative phosphorylation deficiency 43, combined oxidative phosphorylation deficiency 44, combined oxidative phosphorylation deficiency 52, combined oxidative phosphorylation deficiency 53, combined oxidative phosphorylation deficiency 54, combined oxidative phosphorylation deficiency 37, combined oxidative phosphorylation deficiency 38, combined oxidative phosphorylation deficiency 39, combined oxidative phosphorylation deficiency 45, combined oxidative phosphorylation deficiency 46, combined oxidative phosphorylation deficiency 47, combined oxidative phosphorylation deficiency 48, combined oxidative phosphorylation deficiency 51, combined oxidative phosphorylation deficiency 32, combined oxidative phosphorylation deficiency 33, combined oxidative phosphorylation deficiency 34, combined oxidative phosphorylation deficiency 35, combined oxidative phosphorylation deficiency 36, combined oxidative phosphorylation deficiency 55, combined oxidative phosphorylation deficiency 56, combined oxidative phosphorylation deficiency 57, combined oxidative phosphorylation deficiency 58, combined oxidative phosphorylation deficiency 59, combined oxidative phosphorylation deficiency 60

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

510 retrieved; paginated sample, class counts are floors:

220 uncertain significance, 161 likely benign, 47 pathogenic, 26 likely pathogenic, 23 conflicting classifications of pathogenicity, 12 benign/likely benign, 11 pathogenic/likely pathogenic, 10 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2425612	NC_000006.11:g.(?5109657)(6320826_?)del	F13A1	Pathogenic	criteria provided, single submitter
1069067	NM_006567.5(FARS2):c.298C>T (p.Gln100Ter)	FARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070492	NC_000006.11:g.(?5368804)(5369425_?)del	FARS2	Pathogenic	criteria provided, single submitter
1073793	NM_006567.5(FARS2):c.1156C>T (p.Arg386Ter)	FARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076463	NC_000006.11:g.(?5545403)(5545583_?)del	FARS2	Pathogenic	criteria provided, single submitter
1076465	NC_000006.11:g.(?5368784)(5545593_?)del	FARS2	Pathogenic	criteria provided, single submitter
1351885	NM_006567.5(FARS2):c.999G>A (p.Trp333Ter)	FARS2	Pathogenic	criteria provided, single submitter
1375428	NM_006567.5(FARS2):c.425del (p.Asp142fs)	FARS2	Pathogenic	criteria provided, single submitter
1450668	NC_000006.11:g.(?5260861)(5369435_?)del	FARS2	Pathogenic	criteria provided, single submitter
1450690	NC_000006.11:g.(?5339261)(5404834_?)del	FARS2	Pathogenic	criteria provided, single submitter
1452947	NM_006567.5(FARS2):c.694del (p.Thr232fs)	FARS2	Pathogenic	criteria provided, single submitter
1455928	NM_006567.5(FARS2):c.877del (p.Gly292_Val293insTer)	FARS2	Pathogenic	criteria provided, single submitter
1460186	NC_000006.11:g.(?5431254)(5653711_?)del	FARS2	Pathogenic	criteria provided, single submitter
1946683	NM_006567.5(FARS2):c.929G>A (p.Trp310Ter)	FARS2	Pathogenic	criteria provided, single submitter
2092976	NM_006567.5(FARS2):c.497dup (p.Leu168fs)	FARS2	Pathogenic	criteria provided, single submitter
2134155	NM_006567.5(FARS2):c.1110G>A (p.Trp370Ter)	FARS2	Pathogenic	criteria provided, single submitter
214335	NM_006567.5(FARS2):c.1082C>T (p.Pro361Leu)	FARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
214336	NM_006567.5(FARS2):c.1255C>T (p.Arg419Cys)	FARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2425605	NC_000006.11:g.(?5368804)(5404954_?)del	FARS2	Pathogenic	criteria provided, single submitter
2425606	NC_000006.11:g.(?5404755)(5431425_?)del	FARS2	Pathogenic	criteria provided, single submitter
2425607	NC_000006.11:g.(?5404755)(5545593_?)del	FARS2	Pathogenic	criteria provided, single submitter
2425613	NC_000006.11:g.(?5368804)(5369435_?)del	FARS2	Pathogenic	criteria provided, single submitter
2425614	NC_000006.11:g.(?5216831)(5431425_?)del	FARS2	Pathogenic	criteria provided, single submitter
2500183	NC_000006.11:g.(?5172693)(5459957_?)del	FARS2	Pathogenic	criteria provided, single submitter
2674634	NM_006567.5:c.(?-4)(612+185_613-1)del	FARS2	Pathogenic	no assertion criteria provided
2771426	NM_006567.5(FARS2):c.1218-73_1289delinsC	FARS2	Pathogenic	criteria provided, single submitter
2861363	NM_006567.5(FARS2):c.11C>G (p.Ser4Ter)	FARS2	Pathogenic	criteria provided, single submitter
3246032	NC_000006.11:g.(?5109657)(5771662_?)del	FARS2	Pathogenic	criteria provided, single submitter
3246034	NC_000006.12:g.(?5613149)(5613340_?)del	FARS2	Pathogenic	criteria provided, single submitter
3246035	NC_000006.11:g.(?5545393)(5613573_?)del	FARS2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 3 · 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
FARS2	Strong	Autosomal recessive	combined oxidative phosphorylation defect type 14	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FARS2	Orphanet:319519	Combined oxidative phosphorylation defect type 14
FARS2	Orphanet:466722	Autosomal recessive spastic paraplegia type 77
F13A1	Orphanet:331	Congenital factor XIII deficiency

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
FARS2	HGNC:21062	ENSG00000145982	O95363	Phenylalanine–tRNA ligase, mitochondrial	gencc,clinvar
F13A1	HGNC:3531	ENSG00000124491	P00488	Coagulation factor XIII A chain	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FARS2	Phenylalanine–tRNA ligase, mitochondrial	Is responsible for the charging of tRNA(Phe) with phenylalanine in mitochondrial translation.
F13A1	Coagulation factor XIII A chain	Factor XIII is activated by thrombin and calcium ion to a transglutaminase that catalyzes the formation of gamma-glutamyl-epsilon-lysine cross-links between fibrin chains, thus stabilizing the fibrin clot.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Antibody/Immunoglobulin	1	14.6×	0.135
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FARS2	Enzyme (other)	yes	6.1.1.20	Phenylalanyl-tRNA_Synthase, Phe-tRNA-synth_IIc_mito, Fdx_antiC-bd
F13A1	Antibody/Immunoglobulin	yes	2.3.2.13	Transglutaminase_N, Transglutaminase-like, Transglutaminase_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
endothelial cell	1
gluteal muscle	1
triceps brachii	1
monocyte	1
mononuclear cell	1
pericardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FARS2	260	ubiquitous	marker	triceps brachii, endothelial cell, gluteal muscle
F13A1	261	broad	marker	monocyte, mononuclear cell, pericardium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FARS2	2,506
F13A1	2,346

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
F13A1	P00488	15
FARS2	O95363	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Fibrin formation	1	439.2×	0.013	F13A1
Mitochondrial tRNA aminoacylation	1	259.6×	0.013	FARS2
tRNA Aminoacylation	1	142.8×	0.016	FARS2
Interleukin-4 and Interleukin-13 signaling	1	51.4×	0.032	F13A1
Platelet degranulation	1	43.9×	0.032	F13A1
Translation	1	31.0×	0.037	FARS2
Metabolism of proteins	1	6.2×	0.155	FARS2

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
phenylalanyl-tRNA aminoacylation	1	2106.5×	0.003	FARS2
blood coagulation, fibrin clot formation	1	842.6×	0.003	F13A1
peptide cross-linking	1	702.2×	0.003	F13A1
tRNA aminoacylation for protein translation	1	421.3×	0.003	FARS2
tRNA processing	1	421.3×	0.003	FARS2
blood coagulation	1	86.9×	0.011	F13A1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
F13A1	1	3
FARS2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SPERMIDINE	3	F13A1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
F13A1	42	Binding:42
FARS2	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FARS2	6.1.1.20	phenylalanine-tRNA ligase
F13A1	2.3.2.13	protein-glutamine gamma-glutamyltransferase

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
SPERMIDINE	3	F13A1

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	1	F13A1
C	Druggable family + PDB, no drug	1	FARS2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
FARS2	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.