NDUFAF6

Chr 8AR

NADH:ubiquinone oxidoreductase complex assembly factor 6

Also known as: C8orf38, FRTS5, MC1DN17, lncREST

NCBI Gene: 137682 ENSG00000156170 UniProt: Q330K2 OMIM: 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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a protein that localizes to mitochondria and contains a predicted phytoene synthase domain. The encoded protein plays an important role in the assembly of complex I (NADH-ubiquinone oxidoreductase) of the mitochondrial respiratory chain through regulation of subunit ND1 biogenesis. Mutations in this gene are associated with complex I enzymatic deficiency. [provided by RefSeq, Nov 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

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

36 unique Pathogenic / Likely Pathogenic· 150 VUS of 354 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 OE?0.75 (0.49–1.20)

0≤0.351.4

Missense OE?0.87 (0.76–1.00)

0≤0.61.4

Synonymous OE?0.82

0≤1.21.6

LoF obs/exp: 13 / 17.3Missense obs/exp: 142 / 162.5Syn Z: 1.09

This gene — mechanism propensity

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

354 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic16

Likely Pathogenic20

VUS150

Likely Benign90

Benign41

Conflicting16

Pathogenic

Likely Pathogenic

150

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	8	6	2	0	16
Likely Pathogenic	14	4	2	0	20
VUS	2	144	4	0	150
Likely Benign	0	9	44	37	90
Benign	0	0	37	4	41
Conflicting	—				16
Total	24	163	89	41	333

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

View in ClinVar →

39 pathogenic / likely-pathogenic (of 42) ClinVar copy-number / structural variants overlap NDUFAF6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →