NDUFS4

Chr 5AR

NADH:ubiquinone oxidoreductase subunit S4

Also known as: AQDQ, CI-18, CI-18 kDa, CI-AQDQ, MC1DN1

NCBI Gene: 4724 ENSG00000164258 UniProt: O43181 OMIM: 602694

The protein functions as a nuclear-encoded accessory subunit of mitochondrial complex I (NADH dehydrogenase), which removes electrons from NADH and transfers them to ubiquinone in the electron transport chain. Autosomal recessive mutations cause mitochondrial complex I deficiency, which can present as Leigh syndrome and other mitochondrial disorders. The pathogenic mechanism involves dominant-negative effects that disrupt normal complex I assembly and function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes an nuclear-encoded accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I, or NADH:ubiquinone oxidoreductase). Complex I removes electrons from NADH and passes them to the electron acceptor ubiquinone. Mutations in this gene can cause mitochondrial complex I deficiencies such as Leigh syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.161 OMIM phenotype

Clinical Summary— NDUFS4

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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

50 unique Pathogenic / Likely Pathogenic· 64 VUS of 255 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — NDUFS4

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?

1.16LOEUF

pLI 0.000

Z-score 1.20

OE 0.62 (0.35–1.16)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.84Z-score

OE missense 1.25 (1.07–1.46)

114 obs / 91.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.62 (0.35–1.16)

0≤0.351.4

Missense OE?1.25 (1.07–1.46)

0≤0.61.4

Synonymous OE?1.35

0≤1.21.6

LoF obs/exp: 7 / 11.4Missense obs/exp: 114 / 91.3Syn Z: -1.55

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveNDUFS4-related Leigh syndromeLOFAR

This gene — mechanism propensity

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

0.6840th %ile

GOF

0.3590th %ile

LOF

0.3065th %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

255 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20

Likely Pathogenic30

VUS64

Likely Benign94

Benign28

Conflicting9

Pathogenic

Likely 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	17	0	3	0	20
Likely Pathogenic	29	1	0	0	30
VUS	2	55	6	1	64
Likely Benign	0	4	47	43	94
Benign	0	0	25	3	28
Conflicting	—				9
Total	48	60	81	47	245

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap NDUFS4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →