NDUFA8

Chr 9AR

NADH:ubiquinone oxidoreductase subunit A8

Also known as: CI-19KD, CI-PGIV, MC1DN37, PGIV

NCBI Gene: 4702 ENSG00000119421 UniProt: P51970 OMIM: 603359

The protein is an accessory subunit of mitochondrial respiratory chain complex I that functions in electron transfer from NADH to ubiquinone. Biallelic mutations cause mitochondrial complex I deficiency, nuclear type 37, inherited in an autosomal recessive pattern. The pathogenic mechanism involves impaired mitochondrial respiratory chain function leading to cellular energy deficiency.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene belongs to the complex I 19 kDa subunit family. Mammalian complex I is composed of 45 different subunits. This protein has NADH dehydrogenase activity and oxidoreductase activity. It plays an important role in transfering electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.721 OMIM phenotype

Clinical Summary— NDUFA8

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ARModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 30 VUS of 42 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.72LOEUF

pLI 0.344

Z-score 2.10

OE 0.23 (0.09–0.72)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.48Z-score

OE missense 0.86 (0.72–1.03)

86 obs / 99.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.23 (0.09–0.72)

0≤0.351.4

Missense OE?0.86 (0.72–1.03)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 2 / 8.7Missense obs/exp: 86 / 99.5Syn Z: 0.63

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongNDUFA8-related developmental disorderLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6259th %ile

GOF

0.5856th %ile

LOF

0.2385th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

42 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic1

VUS30

Likely Benign2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Synonymous	Total
Pathogenic	0	2	0	2
Likely Pathogenic	1	0	0	1
VUS	0	30	0	30
Likely Benign	0	1	1	2
Benign	0	0	0	0
Total	1	33	1	35

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

View in ClinVar →

28 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap NDUFA8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →