NDUFAF1

Chr 15AR

NADH:ubiquinone oxidoreductase complex assembly factor 1

Also known as: CGI-65, CGI65, CIA30, MC1DN11

NCBI Gene: 51103 ENSG00000137806 UniProt: Q9Y375 OMIM: 606934

The protein is a complex I assembly factor required for proper assembly of mitochondrial complex I (NADH-ubiquinone oxidoreductase), which catalyzes electron transfer from NADH to coenzyme Q in the respiratory chain. Mutations cause mitochondrial complex I deficiency through an autosomal recessive inheritance pattern. The pathogenic mechanism involves disrupted complex I assembly leading to impaired mitochondrial respiratory function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a complex I assembly factor protein. Complex I (NADH-ubiquinone oxidoreductase) 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. The encoded protein is required for assembly of complex I, and mutations in this gene are a cause of mitochondrial complex I deficiency. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 19. [provided by RefSeq, Dec 2011]

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.911 OMIM phenotype

Clinical Summary— NDUFAF1

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ARModerate

Moderate evidence — consider for supplementary testing

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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

4 unique Pathogenic / Likely Pathogenic· 132 VUS of 206 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.91LOEUF

pLI 0.004

Z-score 1.82

OE 0.46 (0.25–0.91)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.44Z-score

OE missense 1.09 (0.97–1.23)

198 obs / 181.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.46 (0.25–0.91)

0≤0.351.4

Missense OE?1.09 (0.97–1.23)

0≤0.61.4

Synonymous OE?0.84

0≤1.21.6

LoF obs/exp: 6 / 13.1Missense obs/exp: 198 / 181.3Syn Z: 1.04

This gene — mechanism propensity

0.6355th %ile

GOF

0.3689th %ile

LOF

0.2582th %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

206 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic1

VUS132

Likely Benign40

Benign18

Conflicting8

Pathogenic

Likely Pathogenic

132

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	2	0	0	3
Likely Pathogenic	0	1	0	0	1
VUS	5	106	19	2	132
Likely Benign	0	5	11	24	40
Benign	0	4	11	3	18
Conflicting	—				8
Total	6	118	41	29	202

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

View in ClinVar →

8 pathogenic / likely-pathogenic (of 11) ClinVar copy-number / structural variants overlap NDUFAF1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →