NDUFAF8

Chr 17AR

NADH:ubiquinone oxidoreductase complex assembly factor 8

Also known as: C17orf89, MC1DN34

NCBI Gene: 284184 ENSG00000224877 UniProt: A1L188

Involved in mitochondrial respiratory chain complex I assembly. Located in mitochondrial matrix. Implicated in nuclear type mitochondrial complex I deficiency 34. [provided by Alliance of Genome Resources, Jul 2025]

Primary Disease Associations & Inheritance

Mitochondrial complex I deficiency, nuclear type 34MIM #618776

Active trials

Pathogenic / LP

ClinVar variants

Pubs (1 yr)

0.4

Missense Z

1.76

LOEUF

Clinical Summary— NDUFAF8

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Gene-Disease Validity (ClinGen)

Leigh syndrome · ARModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Low constraint (pLI 0.14) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

23 Pathogenic / Likely Pathogenic· 9 VUS of 43 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.

1.76LOEUF

pLI 0.143

Z-score 0.63

OE 0.52 (0.17–1.76)

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.

0.39Z-score

OE missense 0.79 (0.56–1.13)

21 obs / 26.7 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.0.52 (0.17–1.76)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.79 (0.56–1.13)

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.0.91

0≤1.21.6

LoF obs/exp: 1 / 1.9Missense obs/exp: 21 / 26.7Syn Z: 0.24

0.6649th %ile

GOF

0.6247th %ile

LOF

0.2777th %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.