NDUFAF4

Chr 6

NADH:ubiquinone oxidoreductase complex assembly factor 4

Also known as: C6orf66, HRPAP20, HSPC125, MC1DN15, My013, bA22L21.1

NCBI Gene: 29078 ENSG00000123545 UniProt: Q9P032

NDUFAF4 encodes a complex I assembly factor required for proper assembly of NADH:ubiquinone oxidoreductase (complex I), which catalyzes electron transfer from NADH to ubiquinone and proton translocation across the inner mitochondrial membrane. Autosomal recessive mutations cause mitochondrial complex I deficiency (nuclear type 15) through impaired complex I assembly. The pathogenic mechanism involves disrupted mitochondrial respiratory chain function due to defective complex I assembly rather than direct enzymatic dysfunction.

ResearchSummary from RefSeq, OMIM, UniProt

NADH:ubiquinone oxidoreductase (complex I) catalyzes the transfer of electrons from NADH to ubiquinone (coenzyme Q) in the first step of the mitochondrial respiratory chain, resulting in the translocation of protons across the inner mitochondrial membrane. This gene encodes a complex I assembly factor. Mutations in this gene are a cause of mitochondrial complex I deficiency. [provided by RefSeq, Oct 2009]

ResearchGenerating clinical summary…

LOEUF 0.72

Clinical Summary— NDUFAF4

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Gene-Disease Validity (ClinGen)

Leigh syndrome · ARLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.55) — some intolerance to loss-of-function variants.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 78 VUS of 142 total submissions

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.72LOEUF

pLI 0.553

Z-score 2.02

OE 0.15 (0.05–0.72)

Moderately constrained

Typical tolerance to LoF variation

Missense Constraint?

0.06Z-score

OE missense 0.98 (0.83–1.17)

90 obs / 91.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.15 (0.05–0.72)

0≤0.351.4

Missense OE?0.98 (0.83–1.17)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 1 / 6.6Missense obs/exp: 90 / 91.7Syn Z: -0.38

ClinVar Variant Classifications

142 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS78

Likely Benign32

Benign19

Conflicting8

Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	0	0	0	0	0
VUS	1	35	40	2	78
Likely Benign	0	2	18	12	32
Benign	0	1	15	3	19
Conflicting	—				8
Total	1	39	73	17	138

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

View in ClinVar →

15 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap NDUFAF4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →