NDUFS5

Chr 1

NADH:ubiquinone oxidoreductase subunit S5

Also known as: CI-15k, CI15K

NCBI Gene: 4725 ENSG00000168653 UniProt: O43920 OMIM: 603847

The encoded protein is an accessory subunit of mitochondrial complex I (NADH dehydrogenase), which transfers electrons from NADH to ubiquinone in the respiratory chain. Mutations cause Leigh syndrome and mitochondrial complex I deficiency, typically presenting in infancy or early childhood with progressive neurodegeneration affecting the brain, brainstem, and spinal cord. These conditions follow autosomal recessive inheritance.

OMIM ResearchSummary from RefSeq, UniProt

This gene is a member of the NADH dehydrogenase (ubiquinone) iron-sulfur protein family. The encoded protein is a subunit of the NADH:ubiquinone oxidoreductase (complex I), the first enzyme complex in the electron transport chain located in the inner mitochondrial membrane. Alternative splicing results in multiple transcript variants and pseudogenes have been identified on chromosomes 1, 4 and 17. [provided by RefSeq, May 2010]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.35

Clinical Summary— NDUFS5

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Population Constraint (gnomAD)

Low constraint (pLI 0.03) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

12 VUS of 21 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?

1.35LOEUF

pLI 0.026

Z-score 1.03

OE 0.53 (0.24–1.35)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.01Z-score

OE missense 1.00 (0.82–1.22)

69 obs / 69.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.53 (0.24–1.35)

0≤0.351.4

Missense OE?1.00 (0.82–1.22)

0≤0.61.4

Synonymous OE?0.73

0≤1.21.6

LoF obs/exp: 3 / 5.6Missense obs/exp: 69 / 69.3Syn Z: 0.95

This gene — mechanism propensity

0.7229th %ile

GOF

0.6346th %ile

LOF

0.1993th %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

21 submitted variants in ClinVar

ClinVar

Classification Summary

VUS12

Likely Benign2

Benign2

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	12	0	0	12
Likely Benign	2	0	0	2
Benign	0	1	1	2
Total	14	1	1	16

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

View in ClinVar →

7 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap NDUFS5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →