NDUFAF6

Chr 8AR

NADH:ubiquinone oxidoreductase complex assembly factor 6

Also known as: C8orf38, FRTS5, MC1DN17, lncREST

NCBI Gene: 137682ENSG00000156170UniProt: Q330K2OMIM: 612392

The protein localizes to the mitochondrial inner membrane and regulates ND1 subunit biogenesis during complex I assembly of the respiratory chain. Mutations cause autosomal recessive mitochondrial complex I deficiency (nuclear type 17) and Fanconi renotubular syndrome 5. The pathogenic mechanism involves dominant-negative effects disrupting complex I assembly and function.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
DNmechanismARLOEUF 1.202 OMIM phenotypes
Clinical Summary— NDUFAF6
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Gene-Disease Validity (ClinGen)
Leigh syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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ClinVar Variants
75 unique Pathogenic / Likely Pathogenic· 153 VUS of 396 total submissions
Explore recent and relevant literature in Research Assistant →
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GeneReview available — NDUFAF6
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
1.20LOEUF
pLI 0.000
Z-score 0.95
OE 0.75 (0.49–1.20)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
0.57Z-score
OE missense 0.87 (0.76–1.00)
142 obs / 162.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.75 (0.49–1.20)
0≤0.351.4
Missense OE0.87 (0.76–1.00)
0≤0.61.4
Synonymous OE0.82
0≤1.21.6
LoF obs/exp: 13 / 17.3Missense obs/exp: 142 / 162.5Syn Z: 1.09
DN
0.6839th %ile
GOF
0.5660th %ile
LOF
0.3068th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

396 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic53
Likely Pathogenic22
VUS153
Likely Benign90
Benign41
Conflicting16
53
Pathogenic
22
Likely Pathogenic
153
VUS
90
Likely Benign
41
Benign
16
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
8
6
39
0
53
Likely Pathogenic
14
4
4
0
22
VUS
2
144
7
0
153
Likely Benign
0
9
44
37
90
Benign
0
0
37
4
41
Conflicting
—16
Total2416313141375

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

View in ClinVar →

Protein Context — Lollipop Plot

NDUFAF6 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 4 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Clinical and genetic analysis of Chinese patients with Leigh syndrome caused by biallelic loss-of-function variants of the NDUFAF6 gene.
Yang Q et al.·Front Neurol
2026Open AccessCohort
Neurological manifestations and genotype-phenotype correlations in NDUFAF6-associated mitochondrial disease.
Torraco A et al.·Brain Commun
2026Open Access
Functional Screening of NDUFAF6 Variants in Knockout Cells and Complementary Computational Analysis.
Jiang F et al.·J Clin Lab Anal
2026Open AccessFunctional
Knockdown of NDUFAF6 inhibits breast cancer progression via promoting mitophagy and apoptosis.
Wu S et al.·Cancer Biol Ther
2025Open Access
Biallelic variants in the NDUFAF6 cause mitochondrial respiratory complex assembly defects associated with Leigh syndrome in probands.
Zhou Y et al.·Mol Genet Metab Rep
2024Open Access
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients