NDUFAF5

Chr 20AR

NADH:ubiquinone oxidoreductase complex assembly factor 5

Also known as: C20orf7, MC1DN16, bA526K24.2, dJ842G6.1

NCBI Gene: 79133ENSG00000101247UniProt: Q5TEU4

The NADH-ubiquinone oxidoreductase complex (complex I) of the mitochondrial respiratory chain catalyzes the transfer of electrons from NADH to ubiquinone, and consists of at least 43 subunits. The complex is located in the inner mitochondrial membrane. This gene encodes a mitochondrial protein that is associated with the matrix face of the mitochondrial inner membrane and is required for complex I assembly. A mutation in this gene results in mitochondrial complex I deficiency. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

Primary Disease Associations & Inheritance

Mitochondrial complex I deficiency, nuclear type 16MIM #618238
AR
494
ClinVar variants
106
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— NDUFAF5
🧬
Gene-Disease Validity (ClinGen)
Leigh syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
106 Pathogenic / Likely Pathogenic· 118 VUS of 494 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.20LOEUF
pLI 0.000
Z-score 0.85
OE 0.80 (0.55–1.20)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.15Z-score
OE missense 0.97 (0.86–1.09)
187 obs / 192.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.80 (0.55–1.20)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.97 (0.86–1.09)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.06
0≤1.21.6
LoF obs/exp: 17 / 21.2Missense obs/exp: 187 / 192.9Syn Z: -0.41

ClinVar Variant Classifications

494 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic44
Likely Pathogenic62
VUS118
Likely Benign229
Benign26
Conflicting15
44
Pathogenic
62
Likely Pathogenic
118
VUS
229
Likely Benign
26
Benign
15
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
15
5
24
0
44
Likely Pathogenic
37
12
13
0
62
VUS
2
95
18
3
118
Likely Benign
1
9
110
109
229
Benign
0
0
26
0
26
Conflicting
—15
Total55121191112494

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

NDUFAF5 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Mitochondrial complex I deficiency, nuclear type 16

MIM #618238

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — NDUFAF5
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Case report of atypical Leigh syndrome in an adolescent male with novel biallelic variants in NDUFAF5 and review of the natural history of NDUFAF5-related disorders.
Legro NR et al.·Am J Med Genet A
2022Review
Phenotypic Heterogeneity in Patients with Mutations in the Mitochondrial Complex I Assembly Gene NDUFAF5.
Chen PS et al.·Mov Disord
2023Cohort
A Leigh syndrome caused by compound heterozygous mutations on NDUFAF5 induce early infant death: A case report.
Wen Y et al.·Mol Genet Genomic Med
2022Case report
Unique prenatal manifestations of biallelic NDUFAF5 variants: expansion of phenotype.
Brabbing-Goldstein D et al.·Ultrasound Obstet Gynecol
2024
Whole-exome sequencing and adrenocorticotropic hormone therapy in individuals with infantile spasms.
Demarest S et al.·Dev Med Child Neurol
2022
Genotypic Spectrum and Natural History of Cavitating Leukoencephalopathies in Childhood.
Zhang J et al.·Pediatr Neurol
2019Natural history
Leigh Syndrome: Spectrum of Molecular Defects and Clinical Features in Russia.
Kistol D et al.·Int J Mol Sci
2023
Novel mutations in the mitochondrial complex I assembly gene NDUFAF5 reveal heterogeneous phenotypes.
Simon MT et al.·Mol Genet Metab
2019Case report
Generation of a human induced pluripotent stem cell line NTUHi004-A from a patient with Leigh syndrome harboring a homozygous missense mutation c.836 T > G (p.Met279Arg) in NDUFAF5 gene.
Ou-Yang CH et al.·Stem Cell Res
2024
Whole-exome Sequencing Helps the Diagnosis and Treatment in Children with Neurodevelopmental Delay Accompanied Unexplained Dyspnea.
Tong W et al.·Sci Rep
2018
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools